Patent Publication Number: US-2017357750-A1

Title: Method for evaluating drug sensitivity and disease vulnerability by analyzing cyclic amp responsive element binding protein gene

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a Continuation of copending application Ser. No. 14/347,500, filed on Mar. 26, 2014, which is the National Phase under 35 U.S.C. §371 of PCT International Application No. PCT/JP2012/076054, filed on Oct. 1, 2012, which claims priority under 35 U.S.C. §119(a) to Patent Application No. 2011-217104, filed in JAPAN on Sep. 30, 2011, all of which are hereby expressly incorporated by reference into the present application. 
    
    
     TECHNICAL FIELD 
     The present invention relates to a method for evaluating drug sensitivity and disease vulnerability, comprising analyzing a cyclic AMP responsive element binding protein (cAMP responsive element binding protein; CREB) gene. Specifically, the present invention relates to a method for evaluating drug sensitivity and disease vulnerability, comprising associating a gene polymorphism of a CREB gene or a haplotype constituted by the gene polymorphism with the drug sensitivity and disease vulnerability of an individual. More specifically, the present invention relates to a method for evaluating a tendency in the presence or absence of the drug sensitivity and disease vulnerability of an individual, based on the results from the analysis of the above-described gene polymorphism or haplotype. 
     BACKGROUND ART 
     Pain is a pathology which is most frequently observed in the medical field, and it is often the case that the pain accompanying a disease is serious for the patient rather than the disease itself. The pain sensation plays an important role in terms of a biological warning system, however, excessive pain would significantly decrease QOL (quality of life) unless it is properly controlled. Recently, the importance of pain control has been recognized, and palliative care including pain therapy has remarkably progressed, and there is a tendency of increasing the frequency and amount of use of various analgesics. 
     It has been previously known that narcotic analgesics including morphine as a representative example act on a protein known as an “opioid receptor,” so as to cause analgesic action. The opioid receptor includes three types of receptors, a μ-type opioid receptor, a δ-type opioid receptor, and a κ-type opioid receptor, and all of these receptors are related to analgesic action. Since these receptors are Gi/o protein-coupled receptors, they activate a GIRK channel and suppression of a calcium channel through the mediation of a Gi-o protein. In addition, the receptors suppress adenylate cyclase (Non Patent Literature 1: Pierce K. et al., Seven-transmembrane receptors, Nat Rev Mol Cell Biol, (2002) 3: 639-650; Non Patent Literature 2: Bokoch G M. et al., Purification and properties of the inhibitory guanine nucleotide-binding regulatory component of adenylate cyclase, J Biol Chem, (1984) 259: 3560-3567). Activation of adenylate cyclase activates cyclic AMP-dependent protein kinase, and it causes activation of a cyclic AMP responsive element binding protein (CREB) through phosphorylation of the serine residue at position 133 of the protein (Non Patent Literature 3: Gonzalez G A. et al., Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133, Cell, (1989) 59: 675-680). The activated CREB binds to a CREB-binding protein acting as an activation cofactor (Non Patent Literature 4: Chrivia J C, et al., Phosphorylated CREB binds specifically to the nuclear protein CBP., Nature, (1993) 365: 855-859), and it binds to the cyclic AMP responsive element of genomic DNA, thereby promoting gene expression (Non Patent Literature 5: Montminy M R. et al., Identification of a cyclic-AMP-responsive element within the rat somatostatin gene., Proc Natl Acad Sci USA, (1986) 83: 6682-6686). 
     SUMMARY OF INVENTION 
     The objective of the present invention is to provide a method for evaluating (predicting, etc.) an individual difference (the tendency of every individual) in terms of drug sensitivity and disease vulnerability, comprising using a gene polymorphism of a cyclic AMP responsive element binding protein (CREB) gene or the like. 
     The present inventors focused on the cyclic AMP responsive element binding protein (CREB) gene and conducted extensive examinations based on conventional findings and clinical data. As a result, the inventors identified several useful gene polymorphisms by analyzing the association of each CREB gene polymorphism with sensitivity to drugs such as analgesics, and with disease vulnerability including pain sensitivity. Thereafter, the inventors found linkage disequilibrium among the thus identified gene polymorphisms, and we also revealed a significant correlation between drug sensitivity and disease vulnerability (more specifically, a change in the required administration amount of an analgesic and a change in the threshold value of pain sensitivity due to a difference in specific CREB gene polymorphisms), thereby accomplishing the present invention. 
     Thus, the present invention relates to the following: 
     1. A method for evaluating drug sensitivity, comprising associating a gene polymorphism of a cyclic AMP responsive element binding protein gene or a haplotype constituted by the gene polymorphism with an individual drug sensitivity. 
     The above-described evaluation method includes a method for evaluating a tendency in the presence or absence of an individual drug sensitivity based on the results from the analysis of the gene polymorphism or the haplotype. 
     2. The method according to 1 above, comprising the following steps: (1) a step of performing linkage disequilibrium analysis and haplotype analysis on a healthy subject and selecting gene polymorphisms in a linkage disequilibrium block; (2) a step of analyzing the association between the genotypes of the gene polymorphisms and drug sensitivity in a test subject; and (3) a step of using the gene polymorphism that has been significantly associated with drug sensitivity in the test subject for evaluation of the drug sensitivity. 
     3. A method for evaluating disease vulnerability, comprising associating a gene polymorphism of a cyclic AMP responsive element binding protein gene or a haplotype constituted by the gene polymorphism with an individual disease vulnerability. 
     The above-described evaluation method includes a method for evaluating a tendency in the presence or absence of an individual disease vulnerability is evaluated based on the results from the analysis of the gene polymorphism or the haplotype. 
     4. The method according to 3 above, comprising the following steps: (1) a step of performing linkage disequilibrium analysis and haplotype analysis on a healthy subject and selecting gene polymorphisms in a linkage disequilibrium block; (2) a step of analyzing the association between the genotypes of the gene polymorphisms and pain sensitivity; and (3) a step of using the gene polymorphism that has been significantly associated with pain sensitivity in the test subject for evaluation of the disease vulnerability. 
     5. The method according to 3 or 4 above, wherein the disease vulnerability is pain sensitivity or vulnerability to substance dependence (in particular, vulnerability to drug dependence). 
     6. The method according to any one of 1 to 5 above, wherein the gene polymorphism is at least one selected from the group consisting of a single nucleotide polymorphism, an insertion polymorphism, a deletion polymorphism, and a nucleotide repeat polymorphism. 
     7. The method according to any one of 1 to 6 above, wherein the gene polymorphism is at least one selected from among: rs16839837, rs2360969, rs10932200, rs2253206, rs2551640, rs11904814, rs16839883, rs6740584, rs3770704, rs2254137, rs2551645, rs2551946, rs4234080, rs2952768, rs2709386, rs7591784, and rs7594560 of a CREB1 subtype gene (which is a CREB1 gene as a subtype of the CREB gene (the same shall apply hereafter); rs1243872, rs2145925, rs2025126, rs1885373, rs1885374, GA007473, rs2295794, rs4879926, GA007477, rs867194, rs11541908, rs741917, rs7862485, rs2756894, rs2249250, rs2295795, rs877365, rs2737273, rs2295797, rs2295798, rs1534847, rs7873822, rs2737274, rs10972567, rs3763630, rs10814274, rs3750434, rs1570246, GA025684, rs1570248, rs1570249, rs34478611, rs1322045, rs1951432, GA025687, rs10814275, rs10758320, rs4878628, rs10758321, and rs10758322 of a CREB3 subtype gene (which is a CREB3 gene as a subtype of the CREB gene (the same shall apply hereafter); rs4722778, rs177479, rs177480, rs11981754, rs177486, rs177498, rs2175738, rs17156579, rs17156603, rs17642145, rs10229500, rs10243659, rs4722785, rs16874503, rs11772815, rs6958133, rs16874525, rs17715174, rs6953524, rs10239810, rs17156649, rs1811248, rs887623, rs740988, rs7794304, rs6952227, rs42695, rs1029897, rs4722793, rs10233653, rs6955105, rs17156685, rs17156694, rs17156699, rs177572, rs177573, rs177574, rs177576, rs13437706, rs177580, rs177581, rs12666636, rs177584, rs177585, rs216715, rs10951197, rs160335, rs1008262, rs310353, rs310359, rs41273, rs1637457, rs17156919, rs41276, rs160375, rs917275, rs41348, rs886816, rs17157048, rs6462098, rs10951201, rs13311248, rs12540480, rs10265166, rs7798774, rs7799246, rs6972081, rs12533079, rs7806547, rs6462100, rs6979352, rs6950574, rs4722835, rs2066979, rs10486591, rs721993, rs2237351, rs3735566, rs11975539, rs6462107, rs2190306, rs4719955, and rs10228137 of a CREB5 subtype gene (which is a CREB5 gene as a subtype of the CREB gene (the same shall apply hereafter); and rs1153711, rs1153702, rs7583431, rs1153699, rs2302663, rs3845744, rs212349, rs212347, rs12693057, rs1153685, rs212360, rs212361, rs2072538, rs1205399, rs1153676, rs7566401, rs7578569, rs3755490, rs13388308, rs11888507, rs10497434, rs268214, rs166531, rs268228, rs268229, rs268230, rs268231, rs10497435, rs1982235, rs268237, rs13030474, and rs268174 of an ATF2 subtype gene (which is an ATF2 gene as an alias of a CREB2 gene that is a subtype of the CREB gene (the same shall apply hereafter)). 
     8. The method according to any one of 1 to 7 above, wherein the haplotype is at least one selected from the following table. 
     It is to be noted that haplotypes constituted by a combination of any given number and type of various gene polymorphisms according to 7 above can also be selected as haplotypes used in the evaluation method and the like of the present invention. 
     
       
         
           
               
             
               
                 TABLE 1  
               
             
            
               
                   
               
               
                 Gene name CREB1 
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
               
                   
                 1 
               
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 1 
                 2 
                 3 
                   
                   
                   
                   
                   
                   
                   
                   
                 12 
                 13 
                   
                   
                   
                 17 
               
               
                 Haplotype No. 
                 Tag 
                 Tag 
                 Tag 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 Tag 
                 Tag 
                 14 
                 15 
                 16 
                 Tag 
               
               
                   
               
               
                 H1 
                 C 
                 C 
                 C 
                 A 
                 G 
                 G 
                 G 
                 T 
                 C 
                 C 
                 C 
                 C 
                 C 
                 C 
                 A 
                 A 
                 T 
               
               
                 H2 
                 C 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 C 
                 C 
                 T 
                 G 
                 G 
                 T 
               
               
                 H3 
                 C 
                 T 
                 C 
                 A 
                 G 
                 G 
                 A 
                 T 
                 T 
                 C 
                 C 
                 C 
                 C 
                 C 
                 A 
                 A 
                 T 
               
               
                 H4 
                 T 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 C 
                 A 
                 T 
                 G 
                 G 
                 C 
               
               
                 H5 
                 C 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 A 
                 C 
                 C 
                 A 
                 A 
                 T 
               
               
                 H6 
                 T 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 C 
                 C 
                 T 
                 G 
                 G 
                 T 
               
               
                 H7 
                 T 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 C 
                 A 
                 T 
                 G 
                 G 
                 T 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
               
                 () 1~17: (in this order)rs16839837, rs2360969, rs10932200, rs2253206, rs2551640, rs11904814, rs16839883, rs6740584, rs3770704, rs2254137, rs2551645, rs2551946, rs4234080, rs2952768, rs2709386, rs7591784 and rs7594560 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2  
               
               
                   
               
               
                 Gene name CREB3 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
               
                   
                 1 
               
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 1 
                 2 
                 3 
                   
                   
                   
                   
                   
                 9 
                   
                 11 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Haplotype No. 
                 Tag 
                 Tag 
                 Tag 
                 4 
                 5 
                 6 
                 7 
                 8 
                 Tag 
                 10 
                 Tag 
                 12 
                 13 
                 14 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
                 21 
                 22 
                 23 
                 24 
               
               
                   
               
               
                 H1 
                 G 
                 C 
                 G 
                 T 
                 A 
                 T 
                 T 
                 T 
                 C 
                 T 
                 C 
                 C 
                 G 
                 C 
                 T 
                 G 
                 T 
                 G 
                 T 
                 C 
                 A 
                 G 
                 G 
                 A 
               
               
                 H2 
                 G 
                 C 
                 G 
                 T 
                 A 
                 T 
                 T 
                 T 
                 T 
                 T 
                 C 
                 C 
                 G 
                 C 
                 T 
                 G 
                 T 
                 G 
                 T 
                 C 
                 A 
                 G 
                 G 
                 A 
               
               
                 H3 
                 T 
                 T 
                 A 
                 T 
                 A 
                 T 
                 C 
                 T 
                 C 
                 T 
                 T 
                 C 
                 G 
                 A 
                 G 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
                 T 
                 G 
                 C 
               
               
                 H4 
                 T 
                 T 
                 A 
                 T 
                 A 
                 T 
                 C 
                 T 
                 C 
                 T 
                 C 
                 C 
                 G 
                 A 
                 G 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
                 T 
                 G 
                 C 
               
               
                 H5 
                 T 
                 C 
                 G 
                 C 
                 C 
                 C 
                 C 
                 C 
                 C 
                 T 
                 C 
                 C 
                 A 
                 A 
                 G 
                 G 
                 C 
                 A 
                 T 
                 C 
                 A 
                 T 
                 A 
                 C 
               
               
                 H6 
                 T 
                 T 
                 G 
                 T 
                 A 
                 T 
                 C 
                 T 
                 C 
                 C 
                 C 
                 T 
                 G 
                 A 
                 T 
                 G 
                 C 
                 G 
                 T 
                 C 
                 A 
                 G 
                 G 
                 C 
               
               
                 H7 
                 T 
                 C 
                 A 
                 T 
                 A 
                 T 
                 C 
                 T 
                 C 
                 T 
                 T 
                 C 
                 G 
                 A 
                 G 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
                 T 
                 G 
                 C 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
               
                   
                 2 
               
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 25 
                 26 
                   
                   
                 29 
                   
                   
                   
                   
                   
                   
                 36 
                   
                 38 
                 39 
                   
               
               
                 Haplotype No. 
                 Tag 
                 Tag 
                 27 
                 28 
                 Tag 
                 30 
                 31 
                 32 
                 33 
                 34 
                 35 
                 Tag 
                 37 
                 Tag 
                 Tag 
                 40 
               
               
                   
               
               
                 H8 
                 C 
                 C 
                 G 
                 G 
                 G 
                 C 
                 G 
                 G 
                 G 
                 A 
                 T 
                 A 
                 C 
                 C 
                 G 
                 C 
               
               
                 H9 
                 C 
                 T 
                 A 
                 T 
                 G 
                 T 
                 A 
                 G 
                 A 
                 G 
                 A 
                 A 
                 T 
                 C 
                 A 
                 T 
               
               
                 H10 
                 T 
                 C 
                 G 
                 G 
                 C 
                 T 
                 G 
                 A 
                 A 
                 G 
                 A 
                 A 
                 T 
                 C 
                 G 
                 C 
               
               
                 H11 
                 C 
                 T 
                 A 
                 G 
                 G 
                 T 
                 A 
                 G 
                 A 
                 G 
                 A 
                 A 
                 T 
                 C 
                 G 
                 T 
               
               
                 H12 
                 C 
                 C 
                 G 
                 G 
                 C 
                 T 
                 G 
                 A 
                 A 
                 G 
                 A 
                 A 
                 T 
                 C 
                 G 
                 C 
               
               
                 H13 
                 C 
                 T 
                 A 
                 T 
                 G 
                 T 
                 A 
                 G 
                 A 
                 G 
                 A 
                 G 
                 T 
                 C 
                 A 
                 T 
               
               
                 H14 
                 C 
                 C 
                 G 
                 G 
                 G 
                 C 
                 G 
                 G 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 G 
                 C 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
               
                 () 1~40: (in this order)rs1243872, rs2145925, rs2025126, rs1885373, rs1885374, GA007473, rs2295794, rs4879926, GA007477, rs867194, rs11541908, rs741917, rs7862485, rs2756894, rs2249250, rs2295795, rs877365, rs2737273, rs2295797, rs2295798, rs1534847, rs7873822, rs2737274, rs10972567, rs3763630, rs10814274, rs3750434, rs1570246, GA025684, rs1570248, rs1570249, rs34478611, rs1322045, rs1951432, GA025687, rs10814275, rs10758320, rs4878628, rs10758321 and rs10758322 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 Gene name CREB5 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 1 
                   
                 5 
                   
                 6 
                   
                 9 
                   
                 10 
               
            
           
           
               
               
            
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 1 
                 2 
                   
                   
                 5 
                 6 
                   
                 7 
                 8 
                 9 
                   
                 11 
                   
                   
                 13 
                 14 
                   
                 15 
                 16 
                   
                 17 
                 18 
               
               
                 Haplotype (H) No. 
                 Tag 
                 Tag 
                 3 
                 4 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 Tag 
                 10 
                 Tag 
                 12 
                 H No. 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
               
               
                   
               
               
                 H1 
                 C 
                 T 
                 A 
                 A 
                 G 
                 C 
                 H6 
                 C 
                 C 
                 G 
                 C 
                 A 
                 G 
                 H11 
                 T 
                 G 
                 H14 
                 T 
                 A 
                 H17 
                 G 
                 T 
               
               
                 H2 
                 G 
                 C 
                 G 
                 A 
                 G 
                 T 
                 H7 
                 C 
                 A 
                 A 
                 C 
                 G 
                 G 
                 H12 
                 C 
                 C 
                 H15 
                 C 
                 A 
                 H18 
                 G 
                 G 
               
               
                 H3 
                 G 
                 C 
                 G 
                 A 
                 A 
                 T 
                 H8 
                 C 
                 C 
                 G 
                 C 
                 G 
                 G 
                 H13 
                 C 
                 G 
                 H16 
                 C 
                 G 
                 H19 
                 A 
                 G 
               
               
                 H4 
                 C 
                 C 
                 G 
                 A 
                 G 
                 T 
                 H9 
                 T 
                 A 
                 A 
                 C 
                 G 
                 A 
                 . . . 
                   
                   
                 . . . 
                   
                   
                 . . . 
               
               
                 H5 
                 G 
                 C 
                 G 
                 A 
                 G 
                 C 
                 H10 
                 C 
                 C 
                 A 
                 C 
                 G 
                 G 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 11 
                   
                 12 
                   
                 13 
                   
                 15 
                   
                 16 
               
            
           
           
               
               
            
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 19 
                 20 
                   
                 21 
                 22 
                 23 
                   
                 24 
                 25 
                   
                 26 
                 27 
                 28 
                   
                 29 
                 30 
                 31 
                   
                   
               
               
                 Haplotype (H) No. 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 Tag 
                 32 
                 33 
               
               
                   
               
               
                 H20 
                 T 
                 A 
                 H24 
                 G 
                 C 
                 C 
                 H28 
                 A 
                 A 
                 H31 
                 G 
                 T 
                 C 
                 H35 
                 C 
                 C 
                 C 
                 G 
                 C 
               
               
                 H21 
                 T 
                 G 
                 H25 
                 G 
                 C 
                 T 
                 H29 
                 G 
                 A 
                 H32 
                 A 
                 C 
                 T 
                 H36 
                 T 
                 C 
                 A 
                 G 
                 C 
               
               
                 H22 
                 C 
                 G 
                 H26 
                 A 
                 C 
                 T 
                 H30 
                 G 
                 G 
                 H33 
                 A 
                 T 
                 T 
                 H37 
                 C 
                 C 
                 A 
                 G 
                 C 
               
               
                 H23 
                 C 
                 A 
                 H27 
                 G 
                 T 
                 T 
                 . . . 
                   
                   
                 H34 
                 A 
                 T 
                 C 
                 H38 
                 T 
                 T 
                 C 
                 A 
                 T 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 25 
                   
                 26 
                   
                 27 
                   
                 32 
               
            
           
           
               
               
            
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 34 
                 35 
                   
                 36 
                 37 
                 38 
                 39 
                   
                 40 
                   
                   
                 42 
                 43 
                 44 
                 45 
                   
                 47 
                   
                   
                 50 
               
               
                 Haplotype (H) No. 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 41 
                 H No. 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 46 
                 Tag 
                 48 
                 49 
                 Tag 
               
               
                   
               
               
                 H39 
                 T 
                 A 
                 H42 
                 G 
                 A 
                 G 
                 G 
                 H47 
                 A 
                 A 
                 H49 
                 A 
                 T 
                 C 
                 G 
                 T 
                 G 
                 T 
                 T 
                 T 
               
               
                 H40 
                 C 
                 G 
                 H43 
                 G 
                 A 
                 A 
                 A 
                 H48 
                 G 
                 G 
                 H50 
                 A 
                 T 
                 C 
                 G 
                 T 
                 G 
                 T 
                 T 
                 C 
               
               
                 H41 
                 T 
                 G 
                 H44 
                 A 
                 G 
                 G 
                 A 
                 . . . 
                   
                   
                 H51 
                 A 
                 T 
                 A 
                 C 
                 C 
                 G 
                 T 
                 C 
                 C 
               
               
                 . . . 
                   
                   
                 H45 
                 G 
                 A 
                 G 
                 A 
                   
                   
                   
                 H52 
                 C 
                 T 
                 A 
                 C 
                 T 
                 T 
                 C 
                 T 
                 C 
               
               
                   
                   
                   
                 H46 
                 G 
                 G 
                 G 
                 A 
                   
                   
                   
                 H53 
                 C 
                 T 
                 A 
                 C 
                 T 
                 G 
                 C 
                 T 
                 C 
               
               
                   
                   
                   
                 . . . 
                   
                   
                   
                   
                   
                   
                   
                 H54 
                 A 
                 C 
                 C 
                 G 
                 T 
                 G 
                 T 
                 T 
                 T 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 H55 
                 A 
                 T 
                 A 
                 G 
                 T 
                 G 
                 T 
                 T 
                 C 
               
            
           
           
               
               
            
               
                   
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 33 
                   
                 35 
                   
                 40 
               
            
           
           
               
               
            
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 51 
                 52 
                 53 
                 54 
                   
                   
                   
                 57 
                 58 
                   
                 59 
                   
                   
                   
                   
                   
               
               
                 Haplotype (H) No. 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 55 
                 56 
                 H No. 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 60 
                 61 
                 62 
                 63 
                 64 
               
               
                   
               
               
                 H56 
                 T 
                 G 
                 G 
                 C 
                 A 
                 A 
                 H61 
                 C 
                 T 
                 H64 
                 G 
                 G 
                 C 
                 T 
                 T 
                 C 
               
               
                 H57 
                 T 
                 A 
                 A 
                 T 
                 G 
                 C 
                 H62 
                 T 
                 C 
                 H65 
                 A 
                 A 
                 T 
                 C 
                 C 
                 A 
               
               
                 H58 
                 G 
                 A 
                 A 
                 C 
                 G 
                 C 
                 H63 
                 T 
                 T 
                 . . . 
               
               
                 H59 
                 T 
                 A 
                 G 
                 C 
                 A 
                 A 
                 . . . 
               
               
                 H60 
                 T 
                 A 
                 A 
                 C 
                 G 
                 C 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
               
                 () 1~64: (in this order) rs4722778, rs177479, rs177480, rs11981754, rs177486, rs177498, rs10229500, rs10243659, rs4722785, rs16874503, rs11772815, rs6958133, rs16874525, rs17715174, rs6953524, rs10239810, rs17156649, rs1811248, rs887623, rs740988, rs6952227, rs42695, rs1029897, rs10233653, rs6955105, rs17156699, rs177572, rs177573, rs177580, rs177581, rs12666636, rs177584, rs177585, rs1008262, rs310353, rs41273, rs1637457, rs17156919, rs41276, rs160375, rs917275, rs17157048, rs6462098, rs10951201, rs13311248, rs12540480, rs10265166, rs7798774, rs7799246, rs6972081, rs12533079, rs7806547, rs6462100, rs6979352, rs6950574, rs4722835, rs721993, rs2237351, rs3735566, rs11975539, rs6462107, rs2190306, rs4719955 and rs10228137 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
               
                   
               
               
                 Gene name ATF2 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
            
               
                   
                 1 
                 2 
               
            
           
           
               
               
            
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 1 
                 2 
                 3 
                 4 
                 5 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Haplotype No. 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
                 15 
                 16 
               
               
                   
               
               
                 H1 
                 T 
                 C 
                 A 
                 A 
                 G 
                 C 
                 C 
                 A 
                 G 
                 C 
                 G 
                 T 
                 C 
                 A 
                 A 
                 A 
               
               
                 H2 
                 G 
                 C 
                 A 
                 G 
                 G 
                 T 
                 T 
                 G 
                 A 
                 T 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
               
               
                 H3 
                 T 
                 T 
                 C 
                 G 
                 A 
                 T 
                 T 
                 G 
                 A 
                 T 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
               
               
                 H4 
                 T 
                 T 
                 A 
                 G 
                 A 
                 T 
                 T 
                 G 
                 A 
                 T 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
               
               
                   
                   
                   
                   
                 G 
                 G 
                 T 
                 T 
                 G 
                 A 
                 T 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
               
                   
                 Linkage disequilibrium block No. 
               
               
                   
                 2 
               
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 21 
                   
                   
                   
                   
                   
                   
                 28 
                   
                   
                   
               
               
                 Haplotype No. 
                 17 
                 18 
                 19 
                 20 
                 Tag 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 Tag 
                 29 
                 30 
                 31 
               
               
                   
               
               
                 H5 
                 C 
                 T 
                 T 
                 C 
                 C 
                 C 
                 G 
                 A 
                 C 
                 A 
                 C 
                 T 
                 T 
                 G 
                 T 
               
               
                 H6 
                 T 
                 C 
                 C 
                 T 
                 T 
                 T 
                 A 
                 G 
                 A 
                 C 
                 T 
                 G 
                 C 
                 G 
                 C 
               
               
                 H7 
                 T 
                 C 
                 C 
                 T 
                 T 
                 T 
                 A 
                 G 
                 A 
                 C 
                 T 
                 T 
                 C 
                 G 
                 C 
               
               
                 H8 
                 T 
                 C 
                 C 
                 T 
                 T 
                 T 
                 A 
                 G 
                 A 
                 C 
                 T 
                 G 
                 C 
                 G 
                 C 
               
               
                 H9 
                 T 
                 C 
                 C 
                 T 
                 C 
                 C 
                 G 
                 A 
                 C 
                 A 
                 C 
                 T 
                 T 
                 G 
                 T 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
               
                 () 1~31: (in this order)rs1153711, rs1153702, rs7583431, rs2302663, rs3845744, s212349, rs212347, rs12693057, rs1153685, rs212360, rs212361, rs2072538, rs1205399, rs1153676, rs7566401, rs7578569, rs3755490, rs13388308, rs11888507, rs10497434, rs268214, rs166531, rs268228, rs268229, rs268230, rs268231, rs10497435, rs1982235, rs268237, rs13030474 and rs268174 
               
            
           
         
       
     
     9. A method for determining the type, amount, and/or frequency of administration of a drug to be administered to an individual, comprising using the result from the evaluation by the method according to any one of 1 to 8 above as an index. 
     10. A method for predicting a side effect of a drug to be administered to an individual, comprising using the result from the evaluation by the method according to any one of 1 to 8 above as an index. 
     11. The method according to any one of 1, 2, 5, 9, and 10 above, wherein the drug is an opioid receptor function modulator and/or a cyclic AMP responsive element binding protein function modulator. 
     12. The method according to 11 above, wherein the opioid receptor function modulator is at least one selected from the group consisting of methamphetamine, methylenedioxymethamphetamine, amphetamine, dextroamphetamine, dopamine, morphine, DAMGO, codeine, methadone, carfentanil, fentanyl, heroin, cocaine, naloxone, naltrexone, nalorphine, levallorphan, pentazocine, pethidine, buprenorphine, oxycodone, hydrocodone, levorphanol, etorphine, dihydroetorphine, hydromorphone, oxymorphone, tramadol, diclofenac, indomethacin, ethanol, methanol, diethyl ether, propanol, butanol, flupirtine, laughing gas, F3 (1-chloro-1,2,2-trifluorocyclobutane), halothane, estradiol, dithiothreitol, thioridazine, pimozide, fluoxetine, paroxetine, desipramine, imipramine, clomipramine, tetramide, isoflurane, ginsenoside, ifenprodil, bupivacaine, tertiapin, clozapine, haloperidol, SCH23390, and cocaine; and the cyclic AMP responsive element binding protein function modulator is at least one selected from the group consisting of phosphodiesterase 4 (PDE4), calcineurin, protein kinase A, protein kinase C, p90 ribosome S6 kinase 1 (RSK1), calmodulin kinase, glycogen synthase kinase 3β, and CREB-regulated transcription coactivator 1 (CRTC1). 
     13. The method according to any one of 1 to 12 above, comprising using an oligonucleotide consisting of a nucleotide sequence of at least 10 nucleotides comprising the 51 st  nucleotide of the nucleotide sequence represented by any one of SEQ ID NOS: 1 to 172, or a complementary nucleotide sequence thereto, which can specifically hybridize to a DNA fragment comprising a gene polymorphism of a cyclic AMP responsive element binding protein gene. 
     14. The method according to 13 above, wherein the oligonucleotide spans a length of 10 to 150 nucleotides. 
     15. The method according to 13 or 14 above, wherein the oligonucleotide is selected from the group consisting of the nucleotide sequence represented by any one of SEQ ID NOS: 1 to 38 and a complementary nucleotide sequence thereto. 
     16. A gene polymorphism marker for evaluating a tendency in the presence or absence of an individual drug sensitivity, comprising a gene polymorphism of a cyclic AMP responsive element binding protein gene or a haplotype constituted by the gene polymorphism. Examples of the drug applied herein are the same as those described in 11 and 12 above. 
     17. A gene polymorphism marker for evaluating a tendency in the presence or absence of an individual disease vulnerability, comprising a gene polymorphism of a cyclic AMP responsive element binding protein gene or a haplotype constituted by the gene polymorphism. 
     According to the present invention, there can be provided: a gene polymorphism of a cyclic AMP responsive element binding protein gene or a haplotype constituted by the gene polymorphism, which is capable of evaluating an individual difference in terms of drug sensitivity and disease vulnerability; a method for evaluating drug sensitivity and disease vulnerability, comprising using the gene polymorphism or the haplotype; etc. According to this evaluation method, it becomes possible to readily know or predict a proper prescribed amount, a proper prescribed schedule, and the like, associated with a narcotic drug such as morphine, and hence the method is extremely useful for personalized pain therapy, drug dependence therapy and the like. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1  is a schematic view showing gene polymorphisms identified regarding a CREB1 subtype gene and a linkage disequilibrium found among them. In the figure, high-color squares indicate SNPs showing strong linkage with each other. In addition, the square found at the intersection of squares continued from each SNP to the lower left direction or the lower right direction indicates the calculation value (percentage) of D′ that is an index of the linkage disequilibrium of a SNP and another SNP. For example, the calculation value of D′ between rs16839837 and rs2551640 is 0.91. 
         FIG. 2  is a schematic view showing gene polymorphisms identified regarding a CREB1 subtype gene and a linkage disequilibrium found among them. In the figure, high-color squares indicate SNPs showing strong linkage with each other. In addition, the square found at the intersection of squares continued from each SNP to the lower left direction or the lower right direction indicates the calculation value (percentage) of r 2  that is an index of the linkage disequilibrium of a SNP and another SNP. For example, the calculation value of r 2  between rs16839837 and rs2551640 is 0.12. 
         FIG. 3  is a schematic view showing gene polymorphisms identified regarding a CREB3 subtype gene and a linkage disequilibrium found among them. In the figure, high-color squares indicate SNPs showing strong linkage with each other. In addition, the square found at the intersection of squares continued from each SNP to the lower left direction or the lower right direction indicates the calculation value (percentage) of D′ that is an index of the linkage disequilibrium of a SNP and another SNP. For example, the calculation value of D′ between rs1243872 and rs2025126 is 0.97. 
         FIG. 4  is a schematic view showing gene polymorphisms identified regarding a CREB3 subtype gene and a linkage disequilibrium found among them. In the figure, high-color squares indicate SNPs showing strong linkage with each other. In addition, the square found at the intersection of squares continued from each SNP to the lower left direction or the lower right direction indicates the calculation value (percentage) of r 2  that is an index of the linkage disequilibrium of a SNP and another SNP. For example, the calculation value of r 2  between rs1243872 and rs2025126 is 0.67. 
         FIG. 5  is a schematic view showing gene polymorphisms identified regarding a CREB5 subtype gene and a linkage disequilibrium found among them. In the figure, high-color squares indicate SNPs showing strong linkage with each other. In addition, the square found at the intersection of squares continued from each SNP to the lower left direction or the lower right direction indicates the calculation value (percentage) of D′ that is an index of the linkage disequilibrium of a SNP and another SNP. For example, the calculation value of D′ between rs4722778 and rs177479 is 0.93. 
         FIG. 6  is a schematic view showing gene polymorphisms identified regarding a CREB5 subtype gene and a linkage disequilibrium found among them. In the figure, high-color squares indicate SNPs showing strong linkage with each other. In addition, the square found at the intersection of squares continued from each SNP to the lower left direction or the lower right direction indicates the calculation value (percentage) of r 2  that is an index of the linkage disequilibrium of a SNP and another SNP. For example, the calculation value of r 2  between rs4722778 and rs177479 is 0.85. 
         FIG. 7  is a schematic view showing gene polymorphisms identified regarding a ATF2 subtype gene and a linkage disequilibrium found among them. In the figure, high-color squares indicate SNPs showing strong linkage with each other. In addition, the square found at the intersection of squares continued from each SNP to the lower left direction or the lower right direction indicates the calculation value (percentage) of D′ that is an index of the linkage disequilibrium of a SNP and another SNP. For example, the calculation value of D′ between rs1153711 and rs1153700 is 0.86. 
         FIG. 8  is a schematic view showing gene polymorphisms identified regarding a ATF2 subtype gene and a linkage disequilibrium found among them. In the figure, high-color squares indicate SNPs showing strong linkage with each other. In addition, the square found at the intersection of squares continued from each SNP to the lower left direction or the lower right direction indicates the calculation value (percentage) of r 2  that is an index of the linkage disequilibrium of a SNP and another SNP. For example, the calculation value of r 2  between rs1153711 and rs1153700 is 0.14. 
         FIG. 9  is a graph showing the effect (overall average±standard deviation) of a polymorphism (rs10932200) of a CREB1 subtype gene on the required administration amount (μg/kg) of analgesic in 24 hours after surgery, in all patients who were administered with analgesic in the surgery (orthognathic surgery). 
         FIG. 10  is a graph showing the effect (overall average±standard deviation) of a polymorphism (rs10932200) of a CREB1 subtype gene on the measurement results (sec) of pain sensitivity before surgery, in all patients who were administered with analgesic in the surgery (orthognathic surgery). 
         FIG. 11  is a graph showing the effect (overall average±standard deviation) of a polymorphism (rs10932200) of a CREB1 subtype gene on the measurement results (mm) of VAS (the intensity of pain on a visual analogue scale) 24 hours after surgery, in male patients who were administered with analgesic in the surgery (orthognathic surgery). 
         FIG. 12  is a graph showing the effect (overall average±standard deviation) of a polymorphism (rs7583431) of an ATF2 subtype gene on the measurement results (sec) of a difference in threshold of pain perception latency before surgery, in all patients who were administered with analgesic in the surgery (orthognathic surgery). 
         FIG. 13  is a graph showing the effect (overall average±standard deviation) of a polymorphism (rs2952768) of a CREB1 subtype gene on the required administration amount (μg/kg) of analgesic in 24 hours after surgery, in all patients who were administered with analgesic in the surgery (orthognathic surgery). 
         FIG. 14  is a graph showing the effect (overall average±standard deviation) of a polymorphism (rs2952768) of a CREB1 subtype gene on the required administration amount (μg/kg) of analgesic in 24 hours after surgery, in all patients who were administered with analgesic in the surgery (abdominal surgery). 
         FIG. 15  is a graph showing the effect (overall average±standard deviation) of a polymorphism (rs2952768) of a CREB1 subtype gene on the reward dependence (RD) score (average) of Temperament and Character Inventory (TCI) in all healthy subjects. 
         FIG. 16  is a graph showing the effect (overall average±standard deviation) of a polymorphism (rs2952768) of a CREB1 subtype gene on the expression level of a CREB1 subtype gene in postmortem brain tissue donors at the Stanley Foundation Brain Bank. 
     
    
    
     DESCRIPTION OF EMBODIMENT 
     Hereinafter, the present invention will be described in detail. However, the scope of the invention is not limited to the description, and changes and modifications can be made therein without departing from the spirit of the invention other than the following examples. 
     It is to be noted that the present specification includes all of the contents as disclosed in the specification and/or drawings of Japanese Patent Application No. 2011-217104 (filed on Sep. 30, 2011), which is a priority document of the present application. Moreover, all publications cited in the present specification, including prior art documents and patent literatures such as patent laid-open applications or patent publications, are incorporated herein by reference in their entirety. 
     1. Outline of the Present Invention 
     (1) Cyclic AMP Responsive Element Binding Protein 
     Cyclic AMP responsive element binding protein (cAMP responsive element binding protein; CREB) is a protein, which includes a signaling system downstream of G protein-coupled receptor such as a μ-type opioid receptor, is activated depending on an intracellular cyclic AMP concentration, and binds to a cyclic AMP responsive element (cAMP responsive element) of nuclear genomic DNA, so that it is associated with regulation of gene expression. The cyclic AMP responsive element binding protein is present in various tissues and/or organs such as cardiac muscle, various types of smooth muscle, fat cells, skeletal muscle and brain, and it is also associated with neurogenesis, memory, dependence, etc., through the expression of various genes. 
     Narcotic analgesics including morphine as a representative example act on a protein known as an “opioid receptor,” so as to cause analgesic action. The opioid receptor includes three types of receptors, a μ-type opioid receptor, a δ-type opioid receptor, and a κ-type opioid receptor, and all of these receptors are related to analgesic action. Since these receptors are Gi/o protein-coupled receptors, they activate a GIRK channel and suppression of a calcium channel through the mediation of a Gi-o protein. In addition, the receptors suppress adenylate cyclase. Activation of adenylate cyclase activates cyclic AMP-dependent protein kinase, and it causes activation of a cyclic AMP responsive element binding protein (CREB) through phosphorylation of the serine residue at position 133 of the protein. The activated CREB binds to a CREB-binding protein acting as an activation cofactor, and it binds to the cyclic AMP responsive element of genomic DNA, thereby promoting gene expression. 
     Herein, the cyclic AMP responsive element binding protein will be described. The cyclic AMP responsive element binding protein is distributed in various tissues and/or organs including brain and heart, and plays an important role for neurogenesis, memory, the expression of dependence, etc., through the expression of various types of genes. The cyclic AMP responsive element binding protein has a domain structure comprising a Q-rich domain, a kinase-inducible domain (KID), a basic region/leucine zipper (bZIP), etc. The protein binds to genomic DNA. 
     The cyclic AMP responsive element binding protein functions as a dimer formed from two subunits. The type of a receptor subtype is broadly classified into CREB1, CREB3, CREB5, ATF2 and the like, and their homologs have also been known. These subtypes are expressed in various tissues and/or organs including brain and heart. 
     (2) Gene Polymorphism 
     The present inventors identified gene polymorphisms (such as SNP) of the subtypes CREB1, CREB3, CREB5 and ATF2 (CREB2) capable of constituting a cyclic AMP responsive element binding protein in healthy subjects ( FIGS. 1 to 8 ). Further, a linkage disequilibrium analysis was carried out as needed, and a block exhibiting a strong linkage disequilibrium (a haplotype block) was identified. 
     Here, the linkage equilibrium means a case where the relationship between two gene polymorphisms on the chromosome is independent, and the linkage disequilibrium means a case where a gene polymorphism is linked to the other gene polymorphism thereby deviating from the equilibrium situation according to Mendel&#39;s law of independence. Further, the haplotype means a genetic structure of such as genes or gene polymorphisms located in the vicinity of each other in one allele of a set of alleles (a gene derived from one of the parents). 
     Gene polymorphisms or the like located in the vicinity on a genome are inherited in a haplotype block. In other words, a haplotype also refers to a combination of the arrangement of the same gene in this haplotype block. 
     In the case where several gene polymorphisms appear in association with a certain phenotype in the cyclic AMP responsive element binding protein genes, even if not all the respective gene polymorphisms are typed, by analyzing several gene polymorphisms constituting a haplotype, a relationship between the genotype and the phenotype of a patient can be elucidated. 
     The present inventors analyzed the cyclic AMP responsive element binding protein CREB1 subtype gene, and as a result, they found 4 and 6 gene polymorphisms in the 5′ and 3′ flanking regions, respectively, and also found 7 gene polymorphisms in the intron region (see Table 5). 
     In addition, with regard to the CREB3 subtype gene, the inventors found 25 and 14 gene polymorphisms in the 5′ and 3′ flanking regions, respectively, and also found 1 gene polymorphism in the intron region (see Table 5). 
     Moreover, with regard to the CREB5 subtype gene, the inventors found 9 and 5 gene polymorphisms in the 5′ and 3′ flanking regions, respectively, and also found 241 gene polymorphisms in the intron region and 2 gene polymorphisms (rs2190305 and rs3735566) in the noncoding region of exon (see Table 6). 
     Furthermore, with regard to the ATF2 subtype gene, the inventors found 11 and 6 gene polymorphisms in the 5′ and 3′ flanking regions, respectively, and also found 16 gene polymorphisms in the intron region and 1 gene polymorphism (rs10497434) in the noncoding region of exon (see Table 5). 
     According to the present invention, by analyzing gene polymorphisms of the cyclic AMP responsive element binding protein gene or haplotypes constituted by the gene polymorphisms, an individual difference in phenotypes regarding sensitivity to drugs (i.e. drug sensitivity), such as the effectiveness of a drug, the side effects of a drug, and an effective duration of a drug (e.g. the required number of administration of analgesic, the total amount of analgesic, prolongation of stimulant-induced psychosis, etc.), and in phenotypes regarding the development of a disease including pain sensitivity, vulnerability to substance dependence (in particular, vulnerability to drug dependence), etc., can be easily evaluated. The results of evaluating drug sensitivity and disease vulnerability can be important information for determining the administration number, amount, type or the like of drugs to be administered to an individual, and predicting side effects. Therefore, the present invention provides a method for evaluating drug sensitivity and disease vulnerability based on the results obtained by analyzing gene polymorphisms of the cyclic AMP responsive element binding protein or haplotypes constituted by the gene polymorphisms, and specifically, a method for evaluating (specifically, knowing in advance or predicting) a tendency in the presence or absence of drug sensitivity and disease vulnerability (more specifically, the presence or absence of the genetic factor thereof) in an individual (an individual person). In addition, the present invention also provides a gene polymorphism marker used for evaluating (specifically, knowing in advance or predicting) a tendency in the presence or absence of drug sensitivity and disease vulnerability (more specifically, the presence or absence of the genetic factor thereof) in an individual (an individual person), wherein the gene polymorphism marker comprises gene polymorphisms of the cyclic AMP responsive element binding protein or haplotypes constituted by the gene polymorphisms. 
     In particular, because morphine, a stimulant or the like may cause a big social problem depending on the usage, it is important to know in advance an appropriate amount of drugs to be administered to an individual before administering the drugs. Therefore, the present invention is extremely useful for personalized pain therapy or drug dependence therapy. 
     Moreover, according to the present invention, by analyzing gene polymorphisms of the cyclic AMP responsive element binding protein or haplotypes constituted by the gene polymorphisms, an individual difference in terms of dependence-prone personality can be easily evaluated. The results of evaluating dependence-prone personality can be information for determining whether reward dependence is high or low about the personality of an individual. Therefore, the present invention provides a method for evaluating dependence-prone personality based on the results obtained by analyzing gene polymorphisms of the cyclic AMP responsive element binding protein or haplotypes constituted by the gene polymorphisms, and specifically, a method for evaluating (specifically, knowing in advance or predicting) a tendency in the presence or absence of dependence-prone personality (high reward dependence or low reward dependence) (more specifically, the presence or absence of the genetic factor thereof) in an individual (an individual person). In addition, the present invention also provides a gene polymorphism marker used for evaluating (specifically, knowing in advance or predicting) a tendency in the presence or absence of dependence-prone personality (high reward dependence or low reward dependence) (more specifically, the presence or absence of the genetic factor thereof) in an individual (an individual person), wherein the gene polymorphism marker comprises gene polymorphisms of the cyclic AMP responsive element binding protein or haplotypes constituted by the gene polymorphisms. Herein, with regard to the types of a gene polymorphism and a haplotype constituted by the gene polymorphism that can be applied to the above-described evaluation of dependence-prone personality, the same gene polymorphisms and haplotypes as those that can be applied to the above-described method for evaluating drug sensitivity and disease vulnerability can be used. Moreover, with regard to oligonucleotides used for the above described evaluation of dependence-prone personality as well, the same oligonucleotides as those used for the above-described method for evaluating drug sensitivity and disease vulnerability can be used. 
     Furthermore, according to the present invention, by analyzing gene polymorphisms of the cyclic AMP responsive element binding protein or haplotypes constituted by the gene polymorphisms, an individual difference in terms of the expression level of a CREB1 gene can be easily evaluated. The results of evaluating the expression level of a CREB1 gene can be information for predicting whether the expression level of a CREB1 gene in an individual is high or low. Therefore, the present invention provides a method for evaluating the high or low expression level of a CREB1 gene based on the results obtained by analyzing gene polymorphisms of the cyclic AMP responsive element binding protein or haplotypes constituted by the gene polymorphisms, and specifically, a method for evaluating (specifically, knowing in advance or predicting) a tendency in the presence or absence of the high or low expression level of a CREB1 gene (more specifically, the presence or absence of the genetic factor thereof) in an individual (an individual person). In addition, the present invention also provides a gene polymorphism marker used for evaluating (specifically, knowing in advance or predicting) a tendency in the presence or absence of the high or low expression level of a CREB1 gene (more specifically, the presence or absence of the genetic factor thereof) in an individual (an individual person), wherein the gene polymorphism marker comprises gene polymorphisms of the cyclic AMP responsive element binding protein or haplotypes constituted by the gene polymorphisms. Herein, with regard to the types of a gene polymorphism and a haplotype constituted by the gene polymorphism that can be applied to the above-described evaluation of the high or low expression level of a CREB1 gene, the same gene polymorphisms and haplotypes as those that can be applied to the above-described method for evaluating drug sensitivity and disease vulnerability can be used. Moreover, with regard to oligonucleotides used for the above described evaluation of the high or low expression level of a CREB1 gene as well, the same oligonucleotides as those used for the above-described method for evaluating drug sensitivity and disease vulnerability can be used. 
     2. Gene Polymorphism of Cyclic AMP Responsive Element Binding Protein Gene 
     The human cyclic AMP responsive element binding protein gene polymorphisms of the present invention mainly include single nucleotide polymorphisms (hereinafter also referred to as “SNP”), however it is not limited to this, and insertion polymorphisms, deletion polymorphisms, and nucleotide repeat polymorphisms can also be included. 
     The single nucleotide polymorphism [SNP (SNPs)] means a gene polymorphism caused by substitution of a specific one nucleotide of a gene with another nucleotide. The insertion/deletion polymorphism means a gene polymorphism caused by deletion/insertion of one or more nucleotides. 
     Further, the nucleotide repeat polymorphism means a gene polymorphism caused by a difference in the number of repeats of nucleotide sequence. The nucleotide repeat polymorphism is divided into a microsatellite polymorphism (the number of nucleotides: about 2 to 4 nucleotides) and a VNTR (variable number of tandem repeat) polymorphism (repeated nucleotides: several to several tens of nucleotides) according to the difference in the number of repeated nucleotides, and the number of repeats varies depending on individuals. 
     The information of human cyclic AMP responsive element binding protein gene polymorphisms (SNPs in the CREB1 subtype gene, the CREB3 subtype gene, the CREB5 subtype gene and the ATF2 subtype gene observed on the genome of Japanese healthy subjects) elucidated by the present invention is shown in Table 5 and Table 6. The gene polymorphisms shown in Table 5 and Table 6 include the cyclic AMP responsive element binding protein gene polymorphisms of the present invention. 
     
       
         
           
               
               
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 CREB1 gene polymorphism 
                 CREB3 gene polymorphism 
                 ATF2 gene polymorphism 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 Gene 
                 Major 
                   
                 Gene 
                 Major 
                   
                 Gene 
                 Major 
               
               
                   
                 polymorphism 
                 allele:minor 
                   
                 polymorphism 
                 allele:minor 
                   
                 polymorphism 
                 allele:minor 
               
               
                 Position 
                 name 
                 allele 
                 Position 
                 name 
                 allele 
                 Position 
                 name 
                 allele 
               
               
                   
               
               
                 5′ Flanking 
                 rs16839837 
                 C:T 
                 5′ Flanking 
                 rs1243872 
                 G:T 
                 5′ Flanking 
                 rs268174 
                 C:T 
               
               
                 region 
                 rs2360969 
                 C:T 
                 region 
                 rs2145925 
                 C:T 
                 region 
                 rs13030474 
                 G:T 
               
               
                   
                 rs10932200 
                 A:C 
                   
                 rs2025126 
                 G:A 
                   
                 rs268237 
                 C:T 
               
               
                   
                 rs2253206 
                 G:A 
                   
                 rs1885373 
                 T:C 
                   
                 rs1982235 
                 T:G 
               
               
                 Intron 
                 rs2551640 
                 A:G 
                   
                 rs1885374 
                 A:C 
                   
                 rs10497435 
                 T:C 
               
               
                   
                 rs11904814 
                 T:G 
                   
                 GA007473 
                 T:C 
                   
                 rs268231 
                 C:A 
               
               
                   
                 rs16839883 
                 A:G 
                   
                 rs2295794 
                 T:C 
                   
                 rs268230 
                 A:C 
               
               
                   
                 rs6740584 
                 C:T 
                   
                 rs4879926 
                 T:C 
                   
                 rs268229 
                 G:A 
               
               
                   
                 rs3770704 
                 T:C 
                   
                 GA007477 
                 C:T 
                   
                 rs268228 
                 A:G 
               
               
                   
                 rs2254137 
                 A:C 
                   
                 rs867194 
                 T:C 
                   
                 rs166531 
                 T:C 
               
               
                   
                 rs2551645 
                 T:C 
                   
                 rs11541908 
                 C:T 
                   
                 rs268214 
                 T:C 
               
               
                 3′ Flanking 
                 rs2551946 
                 C:A 
                   
                 rs741917 
                 C:T 
                 Exon 
                 rs10497434 
                 T:C 
               
               
                 region 
                 rs4234080 
                 C:A 
                   
                 rs7862485 
                 G:A 
                 Intron 
                 rs11888507 
                 C:T 
               
               
                   
                 rs2952768 
                 T:C 
                   
                 rs2756894 
                 C:A 
                   
                 rs13388308 
                 C:T 
               
               
                   
                 rs2709386 
                 G:A 
                   
                 rs2249250 
                 T:G 
                   
                 rs3755490 
                 T:C 
               
               
                   
                 rs7591784 
                 G:A 
                   
                 rs2295795 
                 G:A 
                   
                 rs7578569 
                 G:A 
               
               
                   
                 rs7594560 
                 T:C 
                   
                 rs877365 
                 T:C 
                   
                 rs7566401 
                 C:A 
               
               
                   
                   
                   
                   
                 rs2737273 
                 G:A 
                   
                 rs1153676 
                 C:A 
               
               
                   
                   
                   
                   
                 rs2295797 
                 T:C 
                   
                 rs1205399 
                 A:C 
               
               
                   
                   
                   
                   
                 rs2295798 
                 C:T 
                   
                 rs2072538 
                 C:T 
               
               
                   
                   
                   
                   
                 rs1534847 
                 A:G 
                   
                 rs212361 
                 A:G 
               
               
                   
                   
                   
                   
                 rs7873822 
                 G:T 
                   
                 rs212360 
                 T:C 
               
               
                   
                   
                   
                   
                 rs2737274 
                 G:A 
                   
                 rs1153685 
                 A:G 
               
               
                   
                   
                   
                   
                 rs10972567 
                 A:C 
                   
                 rs12693057 
                 G:A 
               
               
                   
                   
                   
                   
                 rs3763630 
                 C:T 
                   
                 rs212347 
                 T:C 
               
               
                   
                   
                   
                 Intron 
                 rs10814274 
                 C:T 
                   
                 rs212349 
                 T:C 
               
               
                   
                   
                   
                 3′ Flanking 
                 rs3750434 
                 G:A 
                   
                 rs3845744 
                 A:G 
               
               
                   
                   
                   
                 region 
                 rs1570246 
                 G:T 
                   
                 rs2302663 
                 G:A 
               
               
                   
                   
                   
                   
                 GA025684 
                 G:C 
                 3′ Flanking 
                 rs35507277 
                 T:G 
               
               
                   
                   
                   
                   
                 rs1570248 
                 T:C 
                 region 
                 rs1153699 
                 G:T 
               
               
                   
                   
                   
                   
                 rs1570249 
                 G:A 
                   
                 rs1153700 
                 C:G 
               
               
                   
                   
                   
                   
                 rs34478611 
                 G:A 
                   
                 rs7583431 
                 A:C 
               
               
                   
                   
                   
                   
                 rs1322045 
                 A:G 
                   
                 rs1153702 
                 T:C 
               
               
                   
                   
                   
                   
                 rs1951432 
                 G:A 
                   
                 rs1153711 
                 T:G 
               
               
                   
                   
                   
                   
                 GA025687 
                 A:T 
               
               
                   
                   
                   
                   
                 rs10814275 
                 A:G 
               
               
                   
                   
                   
                   
                 rs10758320 
                 T:C 
               
               
                   
                   
                   
                   
                 rs4878628 
                 C:T 
               
               
                   
                   
                   
                   
                 rs10758321 
                 G:A 
               
               
                   
                   
                   
                   
                 rs10758322 
                 C:T 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6  
               
             
            
               
                   
               
               
                 CREB5 gene polymorphism 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Gene 
                 Major 
               
               
                   
                   
                 polymorphism 
                 allele:minor 
               
               
                   
                 Position 
                 name 
                 allele 
               
               
                   
                   
               
               
                   
                 5′ Flanking 
                 rs4722778 
                 C:G 
               
               
                   
                 region 
                 rs177479 
                 T:C 
               
               
                   
                   
                 rs177480 
                 A:G 
               
               
                   
                   
                 rs11981754 
                 A:G 
               
               
                   
                   
                 rs177486 
                 G:A 
               
               
                   
                   
                 rs177498 
                 C:T 
               
               
                   
                   
                 rs849322 
                 A:G 
               
               
                   
                   
                 rs177505 
                 T:G 
               
               
                   
                   
                 rs2175738 
                 G:A 
               
               
                   
                 Intron 
                 rs4719932 
                 A:C 
               
               
                   
                   
                 rs10258745 
                 C:T 
               
               
                   
                   
                 rs1013900 
                 G:T 
               
               
                   
                   
                 rs6955393 
                 G:A 
               
               
                   
                   
                 rs6953880 
                 A:G 
               
               
                   
                   
                 rs17156573 
                 T:C 
               
               
                   
                   
                 rs6960209 
                 C:T 
               
               
                   
                   
                 rs17156577 
                 T:C 
               
               
                   
                   
                 rs7811922 
                 A:C 
               
               
                   
                   
                 rs6973453 
                 T:C 
               
               
                   
                   
                 rs17156579 
                 C:T 
               
               
                   
                   
                 rs1073298 
                 T:C 
               
               
                   
                   
                 rs6961801 
                 C:T 
               
               
                   
                   
                 rs6977728 
                 C:A 
               
               
                   
                   
                 rs6978238 
                 C:T 
               
               
                   
                   
                 rs13230543 
                 C:A 
               
               
                   
                   
                 rs12673465 
                 A:G 
               
               
                   
                   
                 rs10251129 
                 T:C 
               
               
                   
                   
                 rs2391656 
                 T:C 
               
               
                   
                   
                 rs6971345 
                 A:G 
               
               
                   
                   
                 rs17156603 
                 A:G 
               
               
                   
                   
                 rs7806362 
                 C:A 
               
               
                   
                   
                 rs17642145 
                 T:C 
               
               
                   
                   
                 rs10229500 
                 C:T 
               
               
                   
                   
                 rs10243659 
                 C:A 
               
               
                   
                   
                 rs4722785 
                 G:A 
               
               
                   
                   
                 rs16874503 
                 C:T 
               
               
                   
                   
                 rs11772815 
                 G:A 
               
               
                   
                   
                 rs6958133 
                 G:A 
               
               
                   
                   
                 rs16874525 
                 C:T 
               
               
                   
                   
                 rs17715174 
                 G:C 
               
               
                   
                   
                 rs10242868 
                 T:G 
               
               
                   
                   
                 rs12700884 
                 G:A 
               
               
                   
                   
                 rs17156635 
                 G:A 
               
               
                   
                   
                 rs10239606 
                 C:T 
               
               
                   
                   
                 rs16874528 
                 G:A 
               
               
                   
                   
                 rs7799687 
                 C:A 
               
               
                   
                   
                 rs714218 
                 G:A 
               
               
                   
                   
                 rs1860759 
                 A:G 
               
               
                   
                   
                 rs997908 
                 G:A 
               
               
                   
                   
                 rs12112050 
                 C:T 
               
               
                   
                   
                 rs2191827 
                 A:G 
               
               
                   
                   
                 rs4498447 
                 T:C 
               
               
                   
                   
                 rs10254657 
                 G:A 
               
               
                   
                   
                 rs6953524 
                 C:T 
               
               
                   
                   
                 rs10239810 
                 A:G 
               
               
                   
                   
                 rs17156649 
                 G:A 
               
               
                   
                   
                 rs1811248 
                 T:G 
               
               
                   
                   
                 rs887623 
                 T:C 
               
               
                   
                   
                 rs740988 
                 A:G 
               
               
                   
                   
                 rs7794304 
                 T:C 
               
               
                   
                   
                 rs42694 
                 A:G 
               
               
                   
                   
                 rs6952227 
                 G:A 
               
               
                   
                   
                 rs42695 
                 C:T 
               
               
                   
                   
                 rs1029897 
                 T:C 
               
               
                   
                   
                 rs42699 
                 A:C 
               
               
                   
                   
                 rs4722793 
                 C:A 
               
               
                   
                   
                 rs735101 
                 T:C 
               
               
                   
                   
                 rs10233653 
                 G:A 
               
               
                   
                   
                 rs6955105 
                 G:A 
               
               
                   
                   
                 rs2286841 
                 C:A 
               
               
                   
                   
                 rs979915 
                 C:T 
               
               
                   
                   
                 rs7794347 
                 C:T 
               
               
                   
                   
                 rs16874562 
                 G:T 
               
               
                   
                   
                 rs17156685 
                 A:G 
               
               
                   
                   
                 rs174024 
                 C:T 
               
               
                   
                   
                 rs6949786 
                 G:A 
               
               
                   
                   
                 rs7793437 
                 A:G 
               
               
                   
                   
                 rs3757677 
                 T:C 
               
               
                   
                   
                 rs6462085 
                 T:G 
               
               
                   
                   
                 rs17717216 
                 T:C 
               
               
                   
                   
                 rs17156694 
                 G:A 
               
               
                   
                   
                 rs17156699 
                 A:G 
               
               
                   
                   
                 rs177572 
                 T:C 
               
               
                   
                   
                 rs177573 
                 T:C 
               
               
                   
                   
                 rs6977204 
                 A:G 
               
               
                   
                   
                 rs177574 
                 A:G 
               
               
                   
                   
                 rs177576 
                 T:C 
               
               
                   
                   
                 rs177578 
                 G:A 
               
               
                   
                   
                 rs13437706 
                 C:T 
               
               
                   
                   
                 rs177580 
                 C:T 
               
               
                   
                   
                 rs177581 
                 C:T 
               
               
                   
                   
                 rs12666636 
                 C:A 
               
               
                   
                   
                 rs177584 
                 G:A 
               
               
                   
                   
                 rs177585 
                 C:T 
               
               
                   
                   
                 rs177588 
                 G:A 
               
               
                   
                   
                 rs6462088 
                 G:A 
               
               
                   
                   
                 rs7796539 
                 C:T 
               
               
                   
                   
                 rs1859020 
                 A:G 
               
               
                   
                   
                 rs1011384 
                 A:G 
               
               
                   
                   
                 rs6462090 
                 G:T 
               
               
                   
                   
                 rs12671247 
                 T:C 
               
               
                   
                   
                 rs217508 
                 T:C 
               
               
                   
                   
                 rs4719936 
                 G:T 
               
               
                   
                   
                 rs217509 
                 G:T 
               
               
                   
                   
                 rs217510 
                 T:C 
               
               
                   
                   
                 rs17718257 
                 G:A 
               
               
                   
                   
                 rs149591 
                 C:A 
               
               
                   
                   
                 rs1910553 
                 C:A 
               
               
                   
                   
                 rs217517 
                 G:A 
               
               
                   
                   
                 rs217519 
                 G:A 
               
               
                   
                   
                 rs2391668 
                 T:G 
               
               
                   
                   
                 rs4722804 
                 G:T 
               
               
                   
                   
                 rs618776 
                 A:G 
               
               
                   
                   
                 rs217503 
                 C:T 
               
               
                   
                   
                 rs217513 
                 C:T 
               
               
                   
                   
                 rs65264 
                 C:T 
               
               
                   
                   
                 rs441355 
                 G:T 
               
               
                   
                   
                 rs2391670 
                 C:T 
               
               
                   
                   
                 rs2391671 
                 A:G 
               
               
                   
                   
                 rs216708 
                 A:G 
               
               
                   
                   
                 rs11980665 
                 C:T 
               
               
                   
                   
                 rs11980669 
                 C:T 
               
               
                   
                   
                 rs11984308 
                 T:C 
               
               
                   
                   
                 rs160346 
                 G:A 
               
               
                   
                   
                 rs150607 
                 A:G 
               
               
                   
                   
                 rs177594 
                 G:A 
               
               
                   
                   
                 rs6969064 
                 A:G 
               
               
                   
                   
                 rs150610 
                 A:G 
               
               
                   
                   
                 rs216715 
                 T:C 
               
               
                   
                   
                 rs10951197 
                 T:C 
               
               
                   
                   
                 rs12539927 
                 A:G 
               
               
                   
                   
                 rs216720 
                 A:G 
               
               
                   
                   
                 rs17156823 
                 G:A 
               
               
                   
                   
                 rs2078980 
                 G:A 
               
               
                   
                   
                 rs216730 
                 T:G 
               
               
                   
                   
                 rs13228899 
                 G:T 
               
               
                   
                   
                 rs160335 
                 G:A 
               
               
                   
                   
                 rs10951200 
                 G:A 
               
               
                   
                   
                 rs10486588 
                 G:A 
               
               
                   
                   
                 rs216735 
                 G:A 
               
               
                   
                   
                 rs216737 
                 C:T 
               
               
                   
                   
                 rs216743 
                 G:A 
               
               
                   
                   
                 rs216744 
                 A:G 
               
               
                   
                   
                 rs216747 
                 C:T 
               
               
                   
                   
                 rs1976489 
                 A:G 
               
               
                   
                   
                 rs150613 
                 C:T 
               
               
                   
                   
                 rs17156878 
                 G:A 
               
               
                   
                   
                 rs767834 
                 C:G 
               
               
                   
                   
                 rs4722820 
                 G:A 
               
               
                   
                   
                 rs160337 
                 C:A 
               
               
                   
                   
                 rs160338 
                 G:A 
               
               
                   
                   
                 rs1008262 
                 T:C 
               
               
                   
                   
                 rs310353 
                 G:A 
               
               
                   
                   
                 rs310359 
                 T:C 
               
               
                   
                   
                 rs310361 
                 C:T 
               
               
                   
                   
                 rs13233942 
                 A:G 
               
               
                   
                   
                 rs310338 
                 T:C 
               
               
                   
                   
                 rs41273 
                 G:A 
               
               
                   
                   
                 rs1637457 
                 A:G 
               
               
                   
                   
                 rs17156919 
                 G:A 
               
               
                   
                   
                 rs41276 
                 A:G 
               
               
                   
                   
                 rs160375 
                 A:G 
               
               
                   
                   
                 rs917275 
                 A:G 
               
               
                   
                   
                 rs160342 
                 A:G 
               
               
                   
                   
                 rs160343 
                 T:C 
               
               
                   
                   
                 rs41295 
                 C:T 
               
               
                   
                   
                 rs160357 
                 A:G 
               
               
                   
                   
                 rs41298 
                 G:A 
               
               
                   
                   
                 rs41305 
                 G:A 
               
               
                   
                   
                 rs41307 
                 C:T 
               
               
                   
                   
                 rs10228740 
                 A:G 
               
               
                   
                   
                 rs3888613 
                 G:A 
               
               
                   
                   
                 rs41320 
                 C:T 
               
               
                   
                   
                 rs41321 
                 A:G 
               
               
                   
                   
                 rs41322 
                 A:G 
               
               
                   
                   
                 rs7780656 
                 G:T 
               
               
                   
                   
                 rs41327 
                 A:G 
               
               
                   
                   
                 rs42322 
                 T:C 
               
               
                   
                   
                 rs41333 
                 A:G 
               
               
                   
                   
                 rs9655280 
                 A:G 
               
               
                   
                   
                 rs9655281 
                 G:A 
               
               
                   
                   
                 rs4719945 
                 A:G 
               
               
                   
                   
                 rs6945988 
                 A:G 
               
               
                   
                   
                 rs10258405 
                 T:G 
               
               
                   
                   
                 rs10243376 
                 G:A 
               
               
                   
                   
                 rs41334 
                 T:C 
               
               
                   
                   
                 rs10245004 
                 C:T 
               
               
                   
                   
                 rs41339 
                 G:T 
               
               
                   
                   
                 rs982947 
                 C:T 
               
               
                   
                   
                 rs982950 
                 A:G 
               
               
                   
                   
                 rs16874653 
                 A:G 
               
               
                   
                   
                 rs41346 
                 G:T 
               
               
                   
                   
                 rs41348 
                 A:G 
               
               
                   
                   
                 rs9969149 
                 C:T 
               
               
                   
                   
                 rs6968464 
                 G:A 
               
               
                   
                   
                 rs886816 
                 G:A 
               
               
                   
                   
                 rs757980 
                 A:G 
               
               
                   
                   
                 rs41351 
                 G:A 
               
               
                   
                   
                 rs9691873 
                 A:C 
               
               
                   
                   
                 rs17157048 
                 A:C 
               
               
                   
                   
                 rs6462098 
                 T:C 
               
               
                   
                   
                 rs10951201 
                 C:A 
               
               
                   
                   
                 rs13311248 
                 G:C 
               
               
                   
                   
                 rs12540480 
                 T:C 
               
               
                   
                   
                 rs10265166 
                 G:T 
               
               
                   
                   
                 rs7798774 
                 T:C 
               
               
                   
                   
                 rs7799246 
                 T:C 
               
               
                   
                   
                 rs6972081 
                 T:C 
               
               
                   
                   
                 rs7777929 
                 T:C 
               
               
                   
                   
                 rs12533079 
                 T:G 
               
               
                   
                   
                 rs7806547 
                 G:A 
               
               
                   
                   
                 rs6462100 
                 G:A 
               
               
                   
                   
                 rs6979352 
                 C:T 
               
               
                   
                   
                 rs6950574 
                 A:G 
               
               
                   
                   
                 rs4722835 
                 A:C 
               
               
                   
                   
                 rs9648352 
                 A:G 
               
               
                   
                   
                 rs879593 
                 A:C 
               
               
                   
                   
                 rs879591 
                 G:T 
               
               
                   
                   
                 rs2299110 
                 C:T 
               
               
                   
                   
                 rs2237349 
                 C:T 
               
               
                   
                   
                 rs2066979 
                 T:C 
               
               
                   
                   
                 rs10486589 
                 A:G 
               
               
                   
                   
                 rs10486591 
                 G:A 
               
               
                   
                   
                 rs6462103 
                 C:T 
               
               
                   
                   
                 rs721993 
                 C:T 
               
               
                   
                   
                 rs2237351 
                 T:C 
               
               
                   
                   
                 rs740315 
                 G:A 
               
               
                   
                   
                 rs2237353 
                 A:C 
               
               
                   
                   
                 rs2073537 
                 T:C 
               
               
                   
                   
                 rs4722844 
                 G:T 
               
               
                   
                   
                 rs17730621 
                 C:T 
               
               
                   
                   
                 rs2282907 
                 G:A 
               
               
                   
                   
                 rs10238623 
                 G:A 
               
               
                   
                   
                 rs2299116 
                 C:A 
               
               
                   
                   
                 rs2299117 
                 T:C 
               
               
                   
                   
                 rs2237355 
                 A:G 
               
               
                   
                   
                 rs2237360 
                 T:G 
               
               
                   
                   
                 rs2237361 
                 T:C 
               
               
                   
                   
                 rs2237362 
                 T:C 
               
               
                   
                   
                 rs7791555 
                 G:T 
               
               
                   
                   
                 rs2237364 
                 A:G 
               
               
                   
                   
                 rs2282909 
                 T:G 
               
               
                   
                   
                 rs2282910 
                 C:T 
               
               
                   
                   
                 rs2282911 
                 T:C 
               
               
                   
                   
                 rs1544470 
                 A:G 
               
               
                   
                   
                 rs1964240 
                 A:C 
               
               
                   
                   
                 rs17669844 
                 T:C 
               
               
                   
                   
                 rs886750 
                 A:G 
               
               
                   
                   
                 rs12531253 
                 G:A 
               
               
                   
                   
                 rs10951205 
                 A:G 
               
               
                   
                 Exon 
                 rs2190305 
                 A:G 
               
               
                   
                   
                 rs3735566 
                 G:A 
               
               
                   
                 3′ Flanking 
                 rs11975539 
                 G:A 
               
               
                   
                 region 
                 rs6462107 
                 C:T 
               
               
                   
                   
                 rs2190306 
                 T:C 
               
               
                   
                   
                 rs4719955 
                 T:C 
               
               
                   
                   
                 rs10228137 
                 C:A 
               
               
                   
                   
               
            
           
         
       
     
     In Table 5 and Table 6, “CREB1” (italic form) indicates a CREB1 subtype gene (a CREB1 gene as a subtype of the cyclic AMP responsive element binding protein (CREB) gene), “CREB3” (italic form) indicates a CREB3 subtype gene (a CREB3 gene as a subtype of the CREB gene), “CREB5” (italic form) indicates a CREB5 subtype gene (a CREB5 gene as a subtype of the CREB gene), and “ATF2” (italic form) indicates an ATF2 subtype gene (an ATF2 gene that is an alias of a CREB2 gene as a subtype of the CREB gene). 
     “Position” means a position on the genome of a cyclic AMP responsive element binding protein gene, and indicates a 5′ flanking region, a 3′ flanking region, intron, and exon. 
     “Gene polymorphism name” is the name of SNP at a position on the genome, and it has been registered in the dbSNP database (which is accessible from the NCBI website dbSNP Short Genetic Variations) (the same shall apply in the present specification). Basically, the ID “rs” is given before four or more digit numbers, so that the type of SNP can be identified. 
     “Major allele” indicates an allele occurring in the majority of the genomes of Japanese healthy subjects, and “minor allele” indicates an allele occurring in the minority of the genomes of Japanese healthy subjects. 
     In the present invention, a method of obtaining gene polymorphism information is as follows, for example. 
     (1) Genomic DNA is purified from a blood specimen collected from a human using the phenol method and the like. At this time, a commercially available genomic DNA extraction kit such as GFX Genomic Blood DNA Purification Kit (manufactured by GE Healthcare Bio-Sciences KK) or a device may be used.
 
(2) Then, the obtained genomic DNA is dissolved in TF buffer (10 mM Tris-HCl, 1 mM EDTA, pH 8.0) and the concentration of the obtained solution is adjusted to 100 ng/μl.
 
(3) Total genome genotyping is carried out by an infinium assay II method or the like, using iScan system (manufactured by Illumina, San Diego, Calif.), in accordance with the protocols provided by the manufacturer.
 
(4) Total genome genotyping data are analyzed using BeadStudio Genotyping module v3.3.7 (Illumina) or the like, and the quality of gene polymorphism data of each sample is evaluated (quality control).
 
(5) Based on these total genome genotyping data, gene polymorphism included in the gene regions and flanking regions of a gene of interest are selected, using the annotation information of the name of the gene of interest as a key, and all information regarding such gene polymorphisms is extracted using an output function of BeadStudio Genotyping module v3.3.7 (Illumina) or the like.
 
     The present invention provides an oligonucleotide, which contains any one of CREB1 subtype gene polymorphisms (rs16839837, rs2360969, rs10932200, rs2253206, rs2551640, rs11904814, rs16839883, rs6740584, rs3770704, rs2254137, rs2551645, rs2551946, rs4234080, rs2952768, rs2709386, rs7591784 and rs7594560), CREB3 subtype gene polymorphisms (rs1243872, rs2145925, rs2025126, rs1885373, rs1885374, GA007473, rs2295794, rs4879926, GA007477, rs867194, rs11541908, rs741917, rs7862485, rs2756894, rs2249250, rs2295795, rs877365, rs2737273, rs2295797, rs2295798, rs1534847, rs7873822, rs2737274, rs10972567, rs3763630, rs10814274, rs3750434, rs1570246, GA025684, rs1570248, rs1570249, rs34478611, rs1322045, rs1951432, GA025687, rs10814275, rs10758320, rs4878628, rs10758321 and rs10758322), CREB5 subtype gene polymorphisms (rs4722778, rs177479, rs177480, rs11981754, rs177486, rs177498, rs2175738, rs17156579, rs17156603, rs17642145, rs10229500, rs10243659, rs4722785, rs16874503, rs11772815, rs6958133, rs16874525, rs17715174, rs6953524, rs10239810, rs17156649, rs1811248, rs887623, rs740988, rs7794304, rs6952227, rs42695, rs1029897, rs4722793, rs10233653, rs6955105, rs17156685, rs17156694, rs17156699, rs177572, rs177573, rs177574, rs177576, rs13437706, rs177580, rs177581, rs12666636, rs177584, rs177585, rs216715, rs10951197, rs160335, rs1008262, rs310353, rs310359, rs41273, rs1637457, rs17156919, rs41276, rs160375, rs917275, rs41348, rs886816, rs17157048, rs6462098, rs10951201, rs13311248, rs12540480, rs10265166, rs7798774, rs7799246, rs6972081, rs12533079, rs7806547, rs6462100, rs6979352, rs6950574, rs4722835, rs2066979, rs10486591, rs721993, rs2237351, rs3735566, rs11975539, rs6462107, rs2190306, rs4719955 and rs10228137), and ATF2 subtype gene polymorphisms (rs1153711, rs1153702, rs7583431, rs1153699, rs2302663, rs3845744, rs212349, rs212347, rs12693057, rs1153685, rs212360, rs212361, rs2072538, rs1205399, rs1153676, rs7566401, rs7578569, rs3755490, rs13388308, rs11888507, rs10497434, rs268214, rs166531, rs268228, rs268229, rs268230, rs268231, rs10497435, rs1982235, rs268237, rs13030474 and rs268174), and which is capable of being specifically hybridized to a DNA fragment containing a gene polymorphism of the cyclic AMP responsive element binding protein gene. The gene polymorphic site is the 51 st  nucleotide in the nucleotide sequence represented by any one of SEQ ID NOS: 1 to 172. 
     It is preferred that the oligonucleotide of the present invention has at least 10 nucleotides, preferably 10 to 150 nucleotides, more preferably 10 to 45 nucleotides, further more preferably 14 to 25 nucleotides. 
     Examples of the oligonucleotide of the present invention include oligonucleotides having a nucleotide sequence represented by any one of SEQ ID NOS: 1 to 172 containing the above-mentioned gene polymorphism of the cyclic AMP responsive element binding protein gene or a nucleotide sequence complementary to the nucleotide sequence (Tables 7 to 10). 
     The oligonucleotides of the present invention can be used as a probe or a primer specific to a cyclic AMP responsive element binding protein gene in the detection of cyclic AMP responsive element binding protein gene polymorphism described in the below-mentioned 6. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 7 
               
               
                   
               
               
                   
                   
                 Gene 
                   
                   
               
               
                 Gene 
                   
                 polymorphism 
                   
                 SEQ 
               
               
                 name 
                 Position 
                 name 
                 Sequence 
                 ID NO: 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 CREB1 
                 5′ Flanking region 
                 rs16839837 
                 ATTTAAAGAAGACCAGCAGAAAAATATTTATGAACTTATTTTCAACTTGT 
                  1 
               
               
                   
                   
                   
                 [T/C]CCCATTTTTGAACTTTTTTATCAGTGAAGAAATGGAAACATTTTT 
                   
               
               
                   
                   
                   
                 TCAAT 
                   
               
               
                   
                   
                 rs2360969 
                 ATGAAAAACTGGGGATGAGGGCCAGTCATCTGTATTTCAACAAGTCTTGC 
                  2 
               
               
                   
                   
                   
                 [T/C]GGTGATTCCGATGCACGCCATAGCGTGAGAACCAGTATAGCAATA 
                   
               
               
                   
                   
                   
                 AAACC 
                   
               
               
                   
                   
                 rs10932200 
                 AATAGGGAGAGCAAAAGAGCAAAGAGGTGGTTGTTCGGTGATCAATTTCC 
                  3 
               
               
                   
                   
                   
                 [A/C]CCAGAGTAGTAAGGAAAGGCCTCACAGAAACAGGAGCATTTGAGC 
                   
               
               
                   
                   
                   
                 AAAGA 
                   
               
               
                   
                   
                 rs2253206 
                 ACAAATAATGAGAAGTAGGAATTGGAAAAGAAAGTGATAAGTTACAGTTA 
                  4 
               
               
                   
                   
                   
                 [A/G]GTAGGAGGAATGGGTGACAGAAAAAAATTCCAGGGGAAGGGAAGG 
                   
               
               
                   
                   
                   
                 GCATG 
                   
               
               
                   
                 Intron 
                 rs2551640 
                 TTATAATACCTTATACAGTGCCTGCCCATCACTTGACTCTTATGGGTTCA 
                  5 
               
               
                   
                   
                   
                 [A/G]CATAGGAGTCAGCATGCAGCAAATTCAAGCTTTACTTCTGGGACT 
                   
               
               
                   
                   
                   
                 TGGGG 
                   
               
               
                   
                   
                 rs11904814 
                 AAGATAGTGTTGTGCATGTAAAGATCTAAGAACTTGATATTTCTATGAAA 
                  6 
               
               
                   
                   
                   
                 [T/G]CACAATGACTGAGCAATAGTCCTTTGCCTTAGTTTTTATTCCATT 
                   
               
               
                   
                   
                   
                 GAGTG 
                   
               
               
                   
                   
                 rs16839883 
                 CGAGGGATAGTACTTAAGTTTCCAAAGGACCATATATAGGTTTAGGAAAC 
                  7 
               
               
                   
                   
                   
                 [A/G]TCGAATATTACCATTGTTTTGATTGGTTCTAGTTACTTTATAGTT 
                   
               
               
                   
                   
                   
                 TATTT 
                   
               
               
                   
                   
                 rs6740584 
                 GTACTTAAGTTTCCAAAGGACCATATATAGGTTTAGGAAACATCGAATAT 
                  8 
               
               
                   
                   
                   
                 [T/C]ACCATTGTTTTGATTGGTTCTAGTTACTTTATAGTTTATTTTAAA 
                   
               
               
                   
                   
                   
                 ATTTC 
                   
               
               
                   
                   
                 rs3770704 
                 AAAATTTAATTTAAAAATTAGATGATTTATTTGGAAGAAGCATTTTTAGA 
                  9 
               
               
                   
                   
                   
                 [T/C]AGGTGGCAATATCCTCTCTAGACAATTCTCCCTGTAGGGGTCAAG 
                   
               
               
                   
                   
                   
                 CTTTT 
                   
               
               
                   
                   
                 rs2254137 
                 AAACCTTTAACTTAAAATTAGAAGCAAGTCTGATCAAGAAGTCTCAAGCA 
                 10 
               
               
                   
                   
                   
                 [A/C]AGGCTGAGTAGTAATATTTAAGACAACACTGCTTACTAAAGAAAA 
                   
               
               
                   
                   
                   
                 GAGTT 
                   
               
               
                   
                   
                 rs2551645 
                 AGGTCATATGTACTAAAACAGTTTATCCAAAAAGGCCTTTCTAAGACACA 
                 11 
               
               
                   
                   
                   
                 [T/C]TATTTTCAAACTCAAAAGTCAAAAACAAAGAAAAAATTCTTATGG 
                   
               
               
                   
                   
                   
                 AACCA 
                   
               
               
                   
                 3′ Flanking region 
                 rs2551946 
                 GTGTTTATGTAATACATATATAATCACTGAAAAATTACTGAATTGTATGA 
                 12 
               
               
                   
                   
                   
                 [A/C]AGTAATGTAAGTGAAAATACTTGTTCTTTAAGTGGTAAGTTAAAG 
                   
               
               
                   
                   
                   
                 TTGTT 
                   
               
               
                   
                   
                 rs4234080 
                 ATTTCTGCAACCCAAATTCCGTGGTCTCCTCATAGGGCACGAGGGCCATT 
                 13 
               
               
                   
                   
                   
                 [A/C]CGCCTGCACCCCGCCCTCTGCTCAGACCTGCCGTGCAAAAGAATC 
                   
               
               
                   
                   
                   
                 CTGGG 
                   
               
               
                   
                   
                 rs2952768 
                 CTCTGTCTCAAAAAAAAAAAAAATAGTGCTTTTTACTTTTATCTGAATGA 
                 14 
               
               
                   
                   
                   
                 [T/C]TGAAATGTCCTTTTCCCAATCCTATGATGCCTGACTGCAAAATAA 
                   
               
               
                   
                   
                   
                 TGGTA 
                   
               
               
                   
                   
                 rs2709386 
                 AACACTGACTTCCTATCACTGACTGTAAATATACAACTGATACATTATCA 
                 15 
               
               
                   
                   
                   
                 [A/G]TTTTCTTGTTATCTTTAACGTGAAAGCAGTATAGAGAGAGTGTGT 
                   
               
               
                   
                   
                   
                 TCAAA 
                   
               
               
                   
                   
                 rs7591784 
                 CTGGCTGTCCAGTCCCCACTCCACACCACAGAGCAACACCTAGCCAAAGA 
                 16 
               
               
                   
                   
                   
                 [A/G]GGTAGGTAAGAAAAGCTAAACACCCAGGGATATGAAACCAGCCTT 
                   
               
               
                   
                   
                   
                 CACAG 
                   
               
               
                   
                   
                 rs7594560 
                 TGGCAATTTTTGAATAAAAAGATTAACTACTAATTCTGAGGCAGTGGAGA 
                 17 
               
               
                   
                   
                   
                 [T/C]TGAGGAGAATAAGAAAGATGGCCAGCACTGCTTGCTTCTCTGGCT 
                   
               
               
                   
                   
                   
                 GTCCA 
                   
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 8 
               
               
                   
               
               
                   
                   
                 Gene 
                   
                   
               
               
                   
                   
                 polymorphism 
                   
                 SEQ 
               
               
                 Gene name 
                 Position 
                 name 
                 Sequence 
                 ID NO: 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Gene name 
                 5′ 
                 rs1243872 
                 AGTCCTCCTGTTCCCTGTGAGAGCACTTCAAGTGCTGGGGCCAG 
                 18 
               
               
                   
                 Flanking 
                   
                 GTCTGA[ T / G ]GCAGCTCTGATTCCTACACAGCAAAGCCTGGCC 
                   
               
               
                   
                 region 
                   
                 CAGGTAAGGGGATGGGA 
                   
               
               
                 Gene name 
                   
                 rs2145925 
                 GGAGACGCGGTGTGTGTAGGGGCGCTACTAAGATTTGGAGGCTA 
                 19 
               
               
                   
                   
                   
                 CTGGGA[ T / C ]GGAAGCGGAATAACATAAAAGGGACAGTACAGT 
                   
               
               
                   
                   
                   
                 CAAGGGTACTGGTGGGA 
                   
               
               
                 Gene name 
                   
                 rs2025126 
                 GTTGCCAACCTAAGACGACTGTCAGAGAGTCCATGCATTATGGA 
                 20 
               
               
                   
                   
                   
                 CAGAGT[ A / G ]GCTGGATGGGGACGTGGAAGCACACAGCATCCA 
                   
               
               
                   
                   
                   
                 CCTCTCTGACTGCCTCT 
                   
               
               
                 Gene name 
                   
                 rs1885373 
                 CCCCCTCTAACAATAAATTCTCACACCTGGGTCAAGCTCTTCAC 
                 21 
               
               
                   
                   
                   
                 TTTTAG[ T / C ]GCTACCCTAGGCAGGAGTGTCCCAACCCAATCA 
                   
               
               
                   
                   
                   
                 AGAGCGGTGCCTACCCG 
                   
               
               
                 Gene name 
                   
                 rs1885374 
                 AATGTCCTGGTAGCCACAAGGAACTGTGGTAGCTGCTGTCCCAG 
                 22 
               
               
                   
                   
                   
                 CAGCAG[ A / C ]AGAACGACACTTTGTGAGGCTTAGGTGCTGGCC 
                   
               
               
                   
                   
                   
                 AGGGAGGTGAGGATAAC 
                   
               
               
                 Gene name 
                   
                 GA007473 
                 GATAGTATCAAAAAACGGTGAAGAGAGCTGATGAGGCTGTGGGG 
                 23 
               
               
                   
                   
                   
                 ACTGGC[ T / C ]GGAAGCTGCTGGCAGGGTGGAGTGGGCTGGGGC 
                   
               
               
                   
                   
                   
                 CCCGGCAGATTCAGATC 
                   
               
               
                 Gene name 
                   
                 rs2295794 
                 AGCTTTAGGCCCCGCAGATCCCTACAGTTTCTCTCCCACTATGT 
                 24 
               
               
                   
                   
                   
                 TCTGGC[ T / C ]CAAAGCTGCCTCACGGAAATGCCTCAAGGATTT 
                   
               
               
                   
                   
                   
                 CTACCTTGCAAGCCCGA 
                   
               
               
                 Gene name 
                   
                 rs4879926 
                 GAACTTGGACTTTTACATAATATGTGAAAGTCATAAAATATTTT 
                 25 
               
               
                   
                   
                   
                 GATGTA[ T / C ]GGGTTCAATCTGCAAACATTTATTAAAGATCAG 
                   
               
               
                   
                   
                   
                 CTAGGTGGCAGATTCTA 
                   
               
               
                 Gene name 
                   
                 GA007477 
                 CTCCCAGCTGCGTTTTGCACCAGGACCTTGGTGTCCTCCACCAG 
                 26 
               
               
                   
                   
                   
                 CACCTT[ T / C ]GCAGTCTTCAGGATGCCCTCCCTGAGGGAGGGC 
                   
               
               
                   
                   
                   
                 CCAGCTTAGTCAGATCT 
                   
               
               
                 Gene name 
                   
                 rs867194 
                 CATAACCCCATACAGGCCACATGGTAATCCACGGCCCTCTGATT 
                 27 
               
               
                   
                   
                   
                 CCCACA[ T / C ]TCAAGCATAAAGTGCTCCTCCCCTTCTCCCCAC 
                   
               
               
                   
                   
                   
                 TGTGCTTAACACAATCC 
                   
               
               
                 Gene name 
                   
                 rs11541908 
                 GTGGATTACCAAACAACTATGGTGCGGACAGCCAAGGCCATTGC 
                 28 
               
               
                   
                   
                   
                 AGTGAC[ T / C ]GTTCAGGAGATGGTGAGTTTGGGCGAGTCCCAG 
                   
               
               
                   
                   
                   
                 AGGACTGCCCTCGGAGA 
                   
               
               
                 Gene name 
                   
                 rs741917 
                 TGCCCATCCTCCATTCTGCCACAATGTATGCCCCCCAGCCACAC 
                 29 
               
               
                   
                   
                   
                 TGGTTC[ T / C ]CCATCCCTCAATACCTCATGCTTGTAATTAGCT 
                   
               
               
                   
                   
                   
                 TCTTGATGGAGTCTGAG 
                   
               
               
                 Gene name 
                   
                 rs7862485 
                 CAGAGATACCCAAAGATGAACTGGGCATGGGAGAGGAAAGACAT 
                 30 
               
               
                   
                   
                   
                 ACTAAT[ A / G ]GAGAAACCATAAGAGGGCATGTGGGAGAGTAAG 
                   
               
               
                   
                   
                   
                 CTCGAACATCTACAGAG 
                   
               
               
                 Gene name 
                   
                 rs2756894 
                 ATGTTGGGTCTTAGAGTGAAAAGTATGGCTTACTGTAAGTAGCA 
                 31 
               
               
                   
                   
                   
                 GTAAAA[ A / C ]GTTTGAGAGCCATATATAAATACACACCTTTGT 
                   
               
               
                   
                   
                   
                 GCACACAAGCAAAGCCT 
                   
               
               
                 Gene name 
                   
                 rs2249250 
                 GAGCTTCTTGAAATGTCCCAGTGCTAGGAGGAAGCTGCAAGGTG 
                 32 
               
               
                   
                   
                   
                 AGAGGG[ T / G ]AAGTCAGACAGAAGAGTGGGGAATGATGCAGGG 
                   
               
               
                   
                   
                   
                 AGAAGTCTGGTAAAGGA 
                   
               
               
                 Gene name 
                   
                 rs2295795 
                 CTGGCATTCTTTGACTCCTACGTTCCCCCACCCCCTACCGTCCT 
                 33 
               
               
                   
                   
                   
                 CCTACC[ A / G ]AGTCACTCAGGAGTCGCTTGCTGGCATCTCCAA 
                   
               
               
                   
                   
                   
                 CTGCCCTCAGGGCATTA 
                   
               
               
                 Gene name 
                   
                 rs877365 
                 CCAGCTCCCATTTTCCTACCTCCCTCACAATATGCCCCATGCCT 
                 34 
               
               
                   
                   
                   
                 GGCTCT[ T / C ]TGCCCACATACCTGCATAATTCTCATTGCCCTG 
                   
               
               
                   
                   
                   
                 GGCAACCTCTCCCAGTA 
                   
               
               
                 Gene name 
                   
                 rs2737273 
                 CCTCCCGAAGTGTTAGGATTGCAGGCATGAGCCACCACACCTGG 
                 35 
               
               
                   
                   
                   
                 CCTAAA[ A / G ]TTATTTTTTAATTGACATAATTTTACATATTCA 
                   
               
               
                   
                   
                   
                 TGAGGTACATAGTGACA 
                   
               
               
                 Gene name 
                   
                 rs2295797 
                 ATGGGGAAGAATTTAGCAAAGAGTTTCATATCACAGCTAAGGAA 
                 36 
               
               
                   
                   
                   
                 TTAAGG[ T / C ]TGGATGCTAACTCTAACGAGAGAGAATTATGGG 
                   
               
               
                   
                   
                   
                 GACACTGGAAAGGTTGA 
                   
               
               
                 Gene name 
                   
                 rs2295798 
                 TCAGATTATGCTACCTCATTTGATCCTATCAGTCCTACACGGGG 
                 37 
               
               
                   
                   
                   
                 CAAGTA[ T / C ]TGTTATCCCAAATCAGAGGTAAATAAAAGATTA 
                   
               
               
                   
                   
                   
                 CAAGAATATTGAACTGA 
                   
               
               
                 Gene name 
                   
                 rs1534847 
                 ATGTAGTTCAGTATCTCTGCCCCTACCCCCATCTCTGAAGCAAG 
                 38 
               
               
                   
                   
                   
                 CATGTC[ A / G ]CTCTTTTTTGAGATTATCTGAAGAATTTTGCTG 
                   
               
               
                   
                   
                   
                 CAGTAGCCAGAGGGAAA 
                   
               
               
                 Gene name 
                   
                 rs7873822 
                 TTATCTGGTCAACTCTTGTGTTTTGGAGAAGGGGAAATAGACTC 
                 39 
               
               
                   
                   
                   
                 TGGGAG[ T / G ]CCAGGAAACATTTTCAAGACAGGCCAGAGAAAG 
                   
               
               
                   
                   
                   
                 GACCCAGTCCCTGTAAC 
                   
               
               
                 Gene name 
                   
                 rs2737274 
                 TCTCACCAGAGGCTTCCGTGCTTGAGGAGGAAGGGGGTGTCTAA 
                 40 
               
               
                   
                   
                   
                 GTGTCC[ A / G ]GAGGAAATGGGGGGAGACATGCAGTTTCAGCTT 
                   
               
               
                   
                   
                   
                 AGTGTGAAGGGTCCTTT 
                   
               
               
                 Gene name 
                   
                 rs10972567 
                 ACAAGTATGAGTAGAAGCTAGCTCATTCCTCCTTTGGCCTGAGA 
                 41 
               
               
                   
                   
                   
                 ACTTTG[ A / C ]TCCCTTTTCCATTGTGTTTGATGGAACAGCAAC 
                   
               
               
                   
                   
                   
                 TCCCCACTGCCGTGTCC 
                   
               
               
                 Gene name 
                   
                 rs3763630 
                 GGTCCCTATTTCCCACCTATGTTGTCTGTAAACAACACAGTCCA 
                 42 
               
               
                   
                   
                   
                 GAATCT[ T / C ]TGTCCCCTAACTGTGGTGGCCACAGCAAGGGCC 
                   
               
               
                   
                   
                   
                 TTGGGCTTAGAGAATGG 
                   
               
               
                   
               
               
                 Gene name 
                 Intron 
                 rs10814274 
                 TTTTTTTAATAGTTTAAAATGGTCTGGCTTGTTAGGGTTAACAC 
                 43 
               
               
                   
                   
                   
                 CTGGTC[ T / C ]GTGGAGGCATTCAGAAAGAATCTGAATGCCTGT 
                   
               
               
                   
                   
                   
                 TGGTCAGGGAAGCTGTA 
                   
               
               
                   
               
               
                 Gene name 
                 3′ 
                 rs3750434 
                 AAGGAACATGTACCTCCCAAGATGGAAAGGATTTGGGGGTTCAG 
                 44 
               
               
                   
                 Flanking 
                   
                 CAGAGT[ A / G ]GGATCATCAAATGAATCCCAGTGCAAGTCTACT 
                   
               
               
                   
                 region 
                   
                 GACTTTGGTGGGTGGAG 
                   
               
               
                 Gene name 
                   
                 rs1570246 
                 ATTCCAGATGCGGGCGCCGGTCGTTGTTAGGTATCGTCCCGGAG 
                 45 
               
               
                   
                   
                   
                 GGCCGG[ T / G ]CGTTGGGGAAAGCTTAAATGAGCTGGTGTTTCA 
                   
               
               
                   
                   
                   
                 GTGGAGCCGGGGAGCTC 
                   
               
               
                 Gene name 
                   
                 GA025684 
                 TTGGCTGGGGAGGCGCTGGAGTGTGTAGTGACCGTCACCAACCC 
                 46 
               
               
                   
                   
                   
                 CCTTCC[ C / G ]CCCACGGCCACTTCTGCATCCAGGTGGGGATGC 
                   
               
               
                   
                   
                   
                 TGGCACTGAAGGTGGTG 
                   
               
               
                 Gene name 
                   
                 rs1570248 
                 TTTAGCCATCTCATGTTAGAATCTAAAACCCTAACCTCTACTCT 
                 47 
               
               
                   
                   
                   
                 CATCTC[ T / C ]GTTCCCTCTCAGCATTACCTCTCCACTCATTCT 
                   
               
               
                   
                   
                   
                 TTCTCTAGGCCTTCAGG 
                   
               
               
                 Gene name 
                   
                 rs1570249 
                 GAGGGTGTAATGGATCCTGATTCCTTATACACACTCCCAGACAT 
                 48 
               
               
                   
                   
                   
                 ACCCAC[ A / G ]TCTAGCCTCTGACCCGGAACAGTTTCTCAGACC 
                   
               
               
                   
                   
                   
                 TTCAACCTCTTCCTGTT 
                   
               
               
                 Gene name 
                   
                 rs34478611 
                 AGTACGCACTATCCCCGTATTTAGTTTGTCTTTCCTGTTTCACA 
                 49 
               
               
                   
                   
                   
                 GCTGGA[ A / G ]GAAGCCTGGGTATTTTGACACGGGATCATCTGT 
                   
               
               
                   
                   
                   
                 AAGGCCCCATCCTCCCT 
                   
               
               
                 Gene name 
                   
                 rs1322045 
                 TGGAGGGGGCACTGGACTGGGCACTTCCCCAGCAAGGAGGCAGG 
                 50 
               
               
                   
                   
                   
                 AGGGGC[ A / G ]AGGGCCCCCAGGTGGTCCCCAGATCTCTTCCCT 
                   
               
               
                   
                   
                   
                 GACCTGGAGAGAAGGAA 
                   
               
               
                 Gene name 
                   
                 rs1951432 
                 CTGGCGCGCAGGTCCCGGAGGGGGCGGCTGGCGCGCACTACACG 
                 51 
               
               
                   
                   
                   
                 CTTGGG[ A / G ]ACAAGGAAAACATCCGCCGGAGGCCCGGCCGGG 
                   
               
               
                   
                   
                   
                 CGGCGCTCCAGCCTCGG 
                   
               
               
                 Gene name 
                   
                 GA025687 
                 GTCGTGGTGTCGCTACGGGCGCGAAACGGACACTGAACACAGTC 
                 52 
               
               
                   
                   
                   
                 TGACTG[ A / T ]ATGGAGGCAGGTGGGGAGGGATCCCCTGGGAGA 
                   
               
               
                   
                   
                   
                 ACTTGGCGGGCCGAGAG 
                   
               
               
                 Gene name 
                   
                 rs10814275 
                 TGCATTGCCTTTGGTCCCAAACAAGCAAATCTGGGTCAATTAAT 
                 53 
               
               
                   
                   
                   
                 GAAAAA[ A / G ]AAAAGAAAAGAAAAGAAAATGTCTTACTTTGGG 
                   
               
               
                   
                   
                   
                 CCCTGTTGCACTCTCCC 
                   
               
               
                 Gene name 
                   
                 rs10758320 
                 TTGGATAACAAATTAACCTCCATTTCCACTGGACAGAGAACTCA 
                 54 
               
               
                   
                   
                   
                 TTCTTC[ T / C ]GGTATGTTTCAGAAGGCTAATGGAGCAAGGATA 
                   
               
               
                   
                   
                   
                 ACCTTATATTACTAATG 
                   
               
               
                 Gene name 
                   
                 rs4878628 
                 TGGCTAGTGTTTTTTGTATCCTGCATAAGAAATCTTCCCTTACA 
                 55 
               
               
                   
                   
                   
                 CCAGGT[ T / C ]ACAAAGATTTTTTTCCTACATTTTCTCCTATAT 
                   
               
               
                   
                   
                   
                 CTAAAAGTTTTATGATT 
                   
               
               
                 Gene name 
                   
                 rs10758321 
                 AGACATCATTAAATTCATCATGGCATTCTTTCTTGCTGAGCCTG 
                 56 
               
               
                   
                   
                   
                 GACATA[ A / G ]CCTGGTAAGACTAGAACTAGATAATAGGAAAAG 
                   
               
               
                   
                   
                   
                 AAATGTAGACATTAAGT 
                   
               
               
                 Gene name 
                   
                 rs10758322 
                 TGGGAGAGGCTGGCATCAAATTACTCCTCTGTTTTTCTCTCTTG 
                 57 
               
               
                   
                   
                   
                 GTGACC[ T / C ]AGCAGGTGTTTAGGACAATGACGACTACTCATG 
                   
               
               
                   
                   
                   
                 TGGAACCTTTGCAGTCA 
                   
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
               
               
               
               
             
               
                 TABLE 9 
               
               
                   
               
               
                   
                   
                 Gene 
                   
                 SEQ 
                   
                 Gene 
                   
                 SEQ 
               
               
                 Gene 
                   
                 polymorphism 
                   
                 ID 
                   
                 polymorphism 
                   
                 ID 
               
               
                 name 
                 Position 
                 name 
                 Sequence 
                 NO: 
                 Position 
                 name 
                 Sequence 
                 NO: 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 CRE 
                 5′ 
                 rs4722778 
                 AATCACCATTTTATGTGAAC 
                 58 
                 Intron 
                 rs177584 
                 GGGTGACGTAAGGGGGTGCA 
                 100 
               
               
                 B5 
                 Flanking 
                   
                 AAATTGAAGTCTTTATAGCA 
                   
                   
                   
                 GAGATTCCCACTTGGGTTTA 
                   
               
               
                   
                 region 
                   
                 TTCTTAATTT[ C / G ]GTTTC 
                   
                   
                   
                 TGCTGGCCTC[ A / G ]TCTTT 
                   
               
               
                   
                   
                   
                 TGAAAGACATTTAGATAATT 
                   
                   
                   
                 GACTGGCTCTGTCATGTTGC 
                   
               
               
                   
                   
                   
                 GGGCAATTTAACAAAAGAGT 
                   
                   
                   
                 CCTTGTGGGGTCCTGTTTTC 
                   
               
               
                   
                   
                   
                 ATGTTC 
                   
                   
                   
                 ATTAA 
                   
               
               
                   
                   
                 rs177479 
                 CAAGTTTCATCCACGTTGTA 
                 59 
                   
                 rs177585 
                 TTTTGCACGGTAAATGCTTC 
                 101 
               
               
                   
                   
                   
                 GCGTGTATCAAAACTTCAAT 
                   
                   
                   
                 GTAAACGTCAGCTATTCATT 
                   
               
               
                   
                   
                   
                 TAATATTCTT[ T / C ]TATAT 
                   
                   
                   
                 AGTGAGGTGT[ T / C ]GGGGA 
                   
               
               
                   
                   
                   
                 GGGTATGTTACATTTTGTTT 
                   
                   
                   
                 GTTGTCGGGGGAAGAGAGAG 
                   
               
               
                   
                   
                   
                 ATCCATTCATCAGTTGGTAG 
                   
                   
                   
                 GAGAAAGAAGGAAGTGAGAG 
                   
               
               
                   
                   
                   
                 ACATG 
                   
                   
                   
                 GGGAG 
                   
               
               
                   
                   
                 rs177480 
                 GCTGCTGTGGACATTTGCAT 
                 60 
                   
                 rs216715 
                 AAAAAGAAAGAGCCAGCCTT 
                 102 
               
               
                   
                   
                   
                 ACAAGTTTTTTTGTGTGGAA 
                   
                   
                   
                 TAAGGAAACGGGAAGTCAAA 
                   
               
               
                   
                   
                   
                 ATATGTTTTC[ A / G ]ATTCT 
                   
                   
                   
                 GCTTGTGTAA[ T / C ]GAAGC 
                   
               
               
                   
                   
                   
                 CTTGGGAATATACCTAGGAC 
                   
                   
                   
                 AAGACCAGACTTTTTAAATC 
                   
               
               
                   
                   
                   
                 TGGAATGGGTCATTTGGAAA 
                   
                   
                   
                 TACCTCCCTTAACCTTTATA 
                   
               
               
                   
                   
                   
                 CTACG 
                   
                   
                   
                 AACAT 
                   
               
               
                   
                   
                 rs11981754 
                 ATTCAAAAATAACAGGATTG 
                 61 
                   
                 rs10951197 
                 ATGGTGCTACATAGGCTGGC 
                 103 
               
               
                   
                   
                   
                 TGAAATATCCAACTAAAATC 
                   
                   
                   
                 TTAACATCTTTTTTTGAAAT 
                   
               
               
                   
                   
                   
                 ATATTTGAAA[ A / G ]TGGTC 
                   
                   
                   
                 AAAAACCAAG[ T / C ]GTAAA 
                   
               
               
                   
                   
                   
                 CAGGAATCCCCAAATAACTT 
                   
                   
                   
                 CATGAGTCAGAATGACAGGG 
                   
               
               
                   
                   
                   
                 TTATGCATGTTATATGAAGA 
                   
                   
                   
                 CATATGCAGGACTCCAACAT 
                   
               
               
                   
                   
                   
                 TAAAT 
                   
                   
                   
                 TTACT 
                   
               
               
                   
                   
                 rs177486 
                 CCTTCCTTTCAGCATGCAGA 
                 62 
                   
                 rs160335 
                 TGAATTTGATGCTGTTCTCT 
                 104 
               
               
                   
                   
                   
                 ATTGAACTTGGCTCTGAAGT 
                   
                   
                   
                 TGGTCTTTTTCACAACTGAA 
                   
               
               
                   
                   
                   
                 AAAACAATAC[ A / G ]GGTTT 
                   
                   
                   
                 ACATTGGGCC[ A / G ]TTGGT 
                   
               
               
                   
                   
                   
                 TTGAGTGATCCAGCAGCTGT 
                   
                   
                   
                 GGGACGTTCTGTGCCTTGAA 
                   
               
               
                   
                   
                   
                 TCTACTTTGGTGAGAGTTTT 
                   
                   
                   
                 ACTTTTAATACGTGCAGCTC 
                   
               
               
                   
                   
                   
                 CTTCT 
                   
                   
                   
                 CATCT 
                   
               
               
                   
                   
                 rs177498 
                 GTCCTCAATTACATCTTTGT 
                 63 
                   
                 rs1008262 
                 GTCTTCTCCCCAAGAGGCCA 
                 105 
               
               
                   
                   
                   
                 GAGAATCAAATGTGATAAGG 
                   
                   
                   
                 CCTTTTTGACCAGGTGACTC 
                   
               
               
                   
                   
                   
                 CATAACACTC[ T / C ]TGGCA 
                   
                   
                   
                 TCCTCAGTGA[ T / C ]GATAT 
                   
               
               
                   
                   
                   
                 TGGTGGCTTTAGATATTAAC 
                   
                   
                   
                 GGTGCAATTTTTATGAGATT 
                   
               
               
                   
                   
                   
                 AACTCTTGCTATGTTGGTTG 
                   
                   
                   
                 TTGGGATGTGAAGCAGCTCT 
                   
               
               
                   
                   
                   
                 TGCTT 
                   
                   
                   
                 GTAGA 
                   
               
               
                   
                   
                 rs2175738 
                 ATTAGTTTCTGGCTATTGCA 
                 64 
                   
                 rs310353 
                 TGCTAACAGTGCCCTTGGGG 
                 106 
               
               
                   
                   
                   
                 GCTAATTCTCGGGTAAAGAA 
                   
                   
                   
                 AATGTTTGGAGGGACTTGAT 
                   
               
               
                   
                   
                   
                 TTTGAATGGC[ A / G ]TTCTA 
                   
                   
                   
                 TCCAGATCAG[ A / G ]AAAGA 
                   
               
               
                   
                   
                   
                 GTATTGCATTTTACCTAGAC 
                   
                   
                   
                 TAAACAGTGATCTGGAGGGT 
                   
               
               
                   
                   
                   
                 TACACTGTTACAGAATTGTG 
                   
                   
                   
                 CTGGTTTAGATGCAAGTCAT 
                   
               
               
                   
                   
                   
                 TGTAG 
                   
                   
                   
                 ATTTC 
                   
               
               
                   
                 Intron 
                 rs17156579 
                 TATCACAGGGTTCTTTGTTG 
                 65 
                   
                 rs310359 
                 CACCCTTTACATACCTGTGT 
                 107 
               
               
                   
                   
                   
                 GCTATTTATTGACCCATCTT 
                   
                   
                   
                 CCCTGGATCTTCCTTTCTCC 
                   
               
               
                   
                   
                   
                 CTCTCAGGCA[ T / C ]GTATA 
                   
                   
                   
                 ATGGTCCTCA[ T / C ]AGCCT 
                   
               
               
                   
                   
                   
                 TTCTCTGGGCAAGTATAGAC 
                   
                   
                   
                 CTCTTCTTTTACACTTACCT 
                   
               
               
                   
                   
                   
                 TCACAAGTGCCTGGAGTCCC 
                   
                   
                   
                 CTCCTTGAGCTCCCTGATGT 
                   
               
               
                   
                   
                   
                 TCCTC 
                   
                   
                   
                 GCCTT 
                   
               
               
                   
                   
                 rs17156603 
                 ATCAGTACATCAAACAACTC 
                 66 
                   
                 rs41273 
                 TGGTTCTGACAAGAAAAAGA 
                 108 
               
               
                   
                   
                   
                 AATTAACAAATGCTTGCATC 
                   
                   
                   
                 AAGTATTCATATTTGGTGGA 
                   
               
               
                   
                   
                   
                 TGCAATGTTC[ A / G ]TTATA 
                   
                   
                   
                 CGTGGTGGTA[ A / G ]GTAAA 
                   
               
               
                   
                   
                   
                 ATACAGCATCATAGTTGCAG 
                   
                   
                   
                 CTACTAATTTGTAAACATTG 
                   
               
               
                   
                   
                   
                 AATTAAAATGGCAAGATTAT 
                   
                   
                   
                 GAAATTTTTACTTTAAGTGA 
                   
               
               
                   
                   
                   
                 AAAAC 
                   
                   
                   
                 GAGCA 
                   
               
               
                   
                   
                 rs17642145 
                 GGAAGTAGGACCACCATCGG 
                 67 
                   
                 rs1637457 
                 AGCTGTTGAGCACACTCGCC 
                 109 
               
               
                   
                   
                   
                 CCCATACAACTTAAGTCCAA 
                   
                   
                   
                 TGTGGTTGACAGGACTCTGG 
                   
               
               
                   
                   
                   
                 TATATAGACT[ T / C ]TTAAC 
                   
                   
                   
                 CACAAGTGCC[ A / G ]TGGAG 
                   
               
               
                   
                   
                   
                 CTATGTCAGTGTGAATAGTT 
                   
                   
                   
                 GATGATGTTAGAGAGGTGGA 
                   
               
               
                   
                   
                   
                 GCCTGCTTGACCAGGGACTT 
                   
                   
                   
                 CACATGGGGTCAGAAGAGGA 
                   
               
               
                   
                   
                   
                 TAATT 
                   
                   
                   
                 AGGAG 
                   
               
               
                   
                   
                 rs10029500 
                 TCCAGTCAGATGACTATTTG 
                 68 
                   
                 rs17156919 
                 ATTCACCGCATACATTCACG 
                 110 
               
               
                   
                   
                   
                 TTCAAATATTTATTCTACTA 
                   
                   
                   
                 CAAAGGGGAAAATTTACTGC 
                   
               
               
                   
                   
                   
                 CATGACACAC[ T / C ]GTGCT 
                   
                   
                   
                 CTAAACAGAG[ A / G ]GACCT 
                   
               
               
                   
                   
                   
                 GGACACTTCAGAGATAGCTG 
                   
                   
                   
                 AAATCCCCCAGGCTAAATAA 
                   
               
               
                   
                   
                   
                 TGAGTTTTGCTTCCTGTGTG 
                   
                   
                   
                 ACCCAATGGAAACACAAGAA 
                   
               
               
                   
                   
                   
                 GTAGC 
                   
                   
                   
                 CTGCA 
                   
               
               
                   
                   
                 rs10243659 
                 GTGGGATGCAGGACAAAGTG 
                 69 
                   
                 rs41276 
                 TAAAAAGGTTTCTTCAAATG 
                 111 
               
               
                   
                   
                   
                 TTTACTTTTGTCTTTCAGAG 
                   
                   
                   
                 AAAAATGGATGGCTGAGCTG 
                   
               
               
                   
                   
                   
                 TCAAAATGGG[ A / C ]AAGGT 
                   
                   
                   
                 CTAATGGCCC[ A / G ]GTAAC 
                   
               
               
                   
                   
                   
                 TAACACAAGGAGTAAACTAA 
                   
                   
                   
                 CTAAAAATTTAACTCTTCCC 
                   
               
               
                   
                   
                   
                 GAAAATATATCCATATCCAT 
                   
                   
                   
                 TAATGCTCAGGGACCTCAGG 
                   
               
               
                   
                   
                   
                 ATTCA 
                   
                   
                   
                 TAAGG 
                   
               
               
                   
                   
                 rs4722785 
                 AACTGGCTTCAGCCAATTAC 
                 70 
                   
                 rs160375 
                 TTTTTGTCCTTTATTATTTT 
                 112 
               
               
                   
                   
                   
                 TATACCTGTTTCCTCTGGCT 
                   
                   
                   
                 TTGAATTACTTTGCTTTATT 
                   
               
               
                   
                   
                   
                 ATAGTGATTG[ A / G ]TTCAG 
                   
                   
                   
                 TTTCATGTGT[ A / G ]AAAAC 
                   
               
               
                   
                   
                   
                 GGAGAGGCCCTTAATCTAGT 
                   
                   
                   
                 ACCATATGGTGGCCACAGTG 
                   
               
               
                   
                   
                   
                 AGCTGTTGAGATGGAAAAAA 
                   
                   
                   
                 GGAAGCCAGGTCCTCTGCAC 
                   
               
               
                   
                   
                   
                 AAACA 
                   
                   
                   
                 TAAGA 
                   
               
               
                   
                   
                 rs16874503 
                 GAGATAGTTCCTATTCAGGA 
                 71 
                   
                 rs917275 
                 ATAGGAGGTTAGGTATGGTT 
                 113 
               
               
                   
                   
                   
                 CACACACCCAGTGCTTGCAG 
                   
                   
                   
                 CTGACATTGCAATATTCTCT 
                   
               
               
                   
                   
                   
                 ATCCATACTG[ T / C ]TAGAC 
                   
                   
                   
                 TCAAGTTAAC[ A / G ]GCAGG 
                   
               
               
                   
                   
                   
                 TACGTGAAGGAGGAAGAAAG 
                   
                   
                   
                 CATTTGTTACATGCTCAGAG 
                   
               
               
                   
                   
                   
                 ATGTTTGCAAAGGAGCCAAG 
                   
                   
                   
                 AATTTTATGATTTATAAAGA 
                   
               
               
                   
                   
                   
                 GGGGA 
                   
                   
                   
                 ACTTT 
                   
               
               
                   
                   
                 rs11772815 
                 ATCCATACTGCTAGACTACG 
                 72 
                   
                 rs41348 
                 TTCATTTACGTTATCAACTT 
                 114 
               
               
                   
                   
                   
                 TGAAGGAGGAAGAAAGATGT 
                   
                   
                   
                 AATTAATTTATTTATAAAAT 
                   
               
               
                   
                   
                   
                 TTGCAAAGGA[ A / G ]CCAAG 
                   
                   
                   
                 TTCCATGACC[ A / G ]TAGGA 
                   
               
               
                   
                   
                   
                 GGGGAAAGCAGGTTGCCTGC 
                   
                   
                   
                 TGACCACGTAGAAGTGTGGA 
                   
               
               
                   
                   
                   
                 ACCAAGATCAGACTGTCTCT 
                   
                   
                   
                 CTATGGATCACTAGCATCAA 
                   
               
               
                   
                   
                   
                 TGTGT 
                   
                   
                   
                 AATCT 
                   
               
               
                   
                   
                 rs6958133 
                 GATGTTTGCAAAGGAGCCAA 
                 73 
                   
                 rs886816 
                 CAGGAAAGCCATCTTTACAT 
                 115 
               
               
                   
                   
                   
                 GGGGGAAAGCAGGTTGCCTG 
                   
                   
                   
                 CACCTCTATTTAAAGCACAG 
                   
               
               
                   
                   
                   
                 CACCAAGATC[ A / G ]GACTG 
                   
                   
                   
                 GGTCCCTTTT[ A / G ]CCTAT 
                   
               
               
                   
                   
                   
                 TCTCTTGTGTTCTTTGATAA 
                   
                   
                   
                 GTCACTGAAAAACAGCAGAA 
                   
               
               
                   
                   
                   
                 CTCTGAGATTTTCCTTTCCT 
                   
                   
                   
                 GCCTGGTATCTAGTGGATTC 
                   
               
               
                   
                   
                   
                 ATTCC 
                   
                   
                   
                 ACCCC 
                   
               
               
                   
                   
                 rs16874525 
                 CTTTCTTCCCATCTATTAAT 
                 74 
                   
                 rs17157048 
                 ATGCAATCTGATTTATTTCC 
                 116 
               
               
                   
                   
                   
                 GAGCATGAACTACATCCTGG 
                   
                   
                   
                 ATGGATTCTGAGCTAGGAAT 
                   
               
               
                   
                   
                   
                 CCTTTAATCA[ T / C ]TGATA 
                   
                   
                   
                 CGCAATTGGG[ A / C ]ATCTC 
                   
               
               
                   
                   
                   
                 TCATTTCATATATACTTTTT 
                   
                   
                   
                 CAGAACCAATGGGGATTTTT 
                   
               
               
                   
                   
                   
                 CATTATCCTCATCTCTCCTT 
                   
                   
                   
                 GCTGTAGGACCATCGTTCTT 
                   
               
               
                   
                   
                   
                 TGCTT 
                   
                   
                   
                 TTCTG 
                   
               
               
                   
                   
                 rs17715174 
                 CATTTTTCATAGAGTCTTTG 
                 75 
                   
                 rs6462098 
                 TTTTCCAAAGCAGCTTAATG 
                 117 
               
               
                   
                   
                   
                 GCATTGGGTTGGACAATGAT 
                   
                   
                   
                 TAGAACAATAGGGCCAAGAA 
                   
               
               
                   
                   
                   
                 GGAAATTAGT[ C / G ]AGTTT 
                   
                   
                   
                 GGGGTTTTTT[ T / C ]GCTCT 
                   
               
               
                   
                   
                   
                 TACTCAGACAAGGTCCCTTC 
                   
                   
                   
                 GAAAAATACCGAGTCCCCTG 
                   
               
               
                   
                   
                   
                 CTTTGAGGAATTTATCCTCC 
                   
                   
                   
                 CCCAAGAGCTCCAGTGCCTC 
                   
               
               
                   
                   
                   
                 ATAAT 
                   
                   
                   
                 CCTCC 
                   
               
               
                   
                   
                 rs6953524 
                 TGGTATTTCCAGGGAAGAAT 
                 76 
                   
                 rs10951201 
                 CCCCAAATACCACATTTGTT 
                 118 
               
               
                   
                   
                   
                 ACATTAGTAATGCAGGCTTG 
                   
                   
                   
                 TGCAAGTAGGAATAGGACTG 
                   
               
               
                   
                   
                   
                 GGTAACCACT[ T / C ]GCAGC 
                   
                   
                   
                 TCTGAGGAAT[ A / C ]ATTTG 
                   
               
               
                   
                   
                   
                 TCACCTCACTACTGAGCAAT 
                   
                   
                   
                 AGAAACTGAGCCAGTCACTC 
                   
               
               
                   
                   
                   
                 GACGTGGAATTGGAGCTGGT 
                   
                   
                   
                 TCTTTGGCAACATGCAGGGC 
                   
               
               
                   
                   
                   
                 ATCAC 
                   
                   
                   
                 CACCA 
                   
               
               
                   
                   
                 rs10239810 
                 ATCAGAGCCTGAGCCAATAA 
                 77 
                   
                 rs13311248 
                 TTGTGTGCCAAGCTCAGTGC 
                 119 
               
               
                   
                   
                   
                 TATGAGCTGTCTTCTTGGAT 
                   
                   
                   
                 TCTCAAATATTCTCCCTTCA 
                   
               
               
                   
                   
                   
                 AGCTTGGGCT[ A / G ]GGCTC 
                   
                   
                   
                 GCCTAGAAGA[ C / G ]AGACT 
                   
               
               
                   
                   
                   
                 CACAACAGAAGAAGCTGGGG 
                   
                   
                   
                 GGTACCTGCTGTAAGGGGTC 
                   
               
               
                   
                   
                   
                 CAAATTGGCTCTGTTGCTGA 
                   
                   
                   
                 TGGCATGGAGAGAAAGCCGG 
                   
               
               
                   
                   
                   
                 GACCT 
                   
                   
                   
                 CTTCC 
                   
               
               
                   
                   
                 rs17156649 
                 TTCTGGCAGTGTGAACTTCA 
                 78 
                   
                 rs12540480 
                 TATTTTCTACAGCAGATCAC 
                 120 
               
               
                   
                   
                   
                 ATGGCCCACATAATTTTTTT 
                   
                   
                   
                 TCATCTCTTAAATAGATTAT 
                   
               
               
                   
                   
                   
                 GACCTAATGT[ A / G ]TAAAC 
                   
                   
                   
                 GCATTGATCG[ T / C ]CTTCA 
                   
               
               
                   
                   
                   
                 ATTTTACCTCATGTGTAGAA 
                   
                   
                   
                 AAGGGCTAAGCACACTCAAA 
                   
               
               
                   
                   
                   
                 ATAGGGACAATGGTACTACC 
                   
                   
                   
                 ATATTCTCTAAAGTCATTCT 
                   
               
               
                   
                   
                   
                 TCGTG 
                   
                   
                   
                 CATGC 
                   
               
               
                   
                   
                 rs1811248 
                 ATCCTCATTTTAAAGGGAAG 
                 79 
                   
                 rs10265166 
                 TCCCTAGAAAGCAAGTCAGA 
                 121 
               
               
                   
                   
                   
                 GAAACCAATGAGAGTGAAAT 
                   
                   
                   
                 CAGGGACAAGTCTATTTTTT 
                   
               
               
                   
                   
                   
                 TTAAGAAACA[ T / G ]ATCAG 
                   
                   
                   
                 AAGAGCCCAA[ T / G ]AAGAG 
                   
               
               
                   
                   
                   
                 ATTATTGGGAAATGGAGTAT 
                   
                   
                   
                 GAAATTTCAAAATCTCTATT 
                   
               
               
                   
                   
                   
                 TCTTCCCAGAGCTCCTCAAA 
                   
                   
                   
                 AGCCATTTAATTGTTTTACA 
                   
               
               
                   
                   
                   
                 ATATC 
                   
                   
                   
                 CTATT 
                   
               
               
                   
                   
                 rs887623 
                 GAGTACCCCTTAACTCAGTG 
                 80 
                   
                 rs7798774 
                 CATCATTATCTGCCAGCCTT 
                 122 
               
               
                   
                   
                   
                 AGGTAGACACCCAAAAGCAA 
                   
                   
                   
                 CTCTAATGTCTCCCCCATGG 
                   
               
               
                   
                   
                   
                 CCATCCTGCA[ T / C ]TTTTT 
                   
                   
                   
                 GCTAAAGAAG[ T / C ]CTTAT 
                   
               
               
                   
                   
                   
                 TCCGTGAGCATTAATAAAGT 
                   
                   
                   
                 TTCCTTTACTTTTCCCATTA 
                   
               
               
                   
                   
                   
                 CTATTGTTCATTGTAGAATG 
                   
                   
                   
                 AGTCTTCCCTTCCGGCTTTT 
                   
               
               
                   
                   
                   
                 TTCTG 
                   
                   
                   
                 TAGTA 
                   
               
               
                   
                   
                 rs740988 
                 TCCCATCTTTCTCACCATTA 
                 81 
                   
                 rs7799246 
                 TCAGCCTTGTTAGGCAATGC 
                 123 
               
               
                   
                   
                   
                 ACATGTACACATTATGCCTA 
                   
                   
                   
                 CCCTTTCCTTGTTCATGTTT 
                   
               
               
                   
                   
                   
                 ACACGAATCC[ A / G ]CCAAT 
                   
                   
                   
                 CCTTGGAGAA[ T / C ]AAGTG 
                   
               
               
                   
                   
                   
                 CCCTTGCAGCCACTGGCATG 
                   
                   
                   
                 ATCCTCTCAGCACGCTATCA 
                   
               
               
                   
                   
                   
                 CTCATTGGTCTCTGCCTCCA 
                   
                   
                   
                 CTTTATCATTAAGAATAGAA 
                   
               
               
                   
                   
                   
                 GACCC 
                   
                   
                   
                 CTTGA 
                   
               
               
                   
                   
                 rs7794304 
                 TCCTTGCTTACTTCTTTCTC 
                 82 
                   
                 rs6972081 
                 TTGGTTAATAAATGAATCAA 
                 124 
               
               
                   
                   
                   
                 AATCACGCATAATGCCTCAA 
                   
                   
                   
                 GCTGACTGCATGACTAATTC 
                   
               
               
                   
                   
                   
                 CTCTTAGAGC[ T / C ]GGCAT 
                   
                   
                   
                 AGATTAATGG[ T / C ]GCAGA 
                   
               
               
                   
                   
                   
                 TTGTTGTATCAGTCCTAATA 
                   
                   
                   
                 AATCAGTCACTAAAGAAGCC 
                   
               
               
                   
                   
                   
                 ACTCTTGAGGTATCTCTGAA 
                   
                   
                   
                 AAAAAAAGTTTGCTTTAATA 
                   
               
               
                   
                   
                   
                 ATCAG 
                   
                   
                   
                 GTCTT 
                   
               
               
                   
                   
                 rs6952227 
                 TAAAGACTTGGAAAGTGTCA 
                 83 
                   
                 rs12533079 
                 GCTTGACAGTAAGATTTGGT 
                 125 
               
               
                   
                   
                   
                 CATTGTAGTACAGTGGGGTT 
                   
                   
                   
                 TCGGAACATGAGCTCATTCA 
                   
               
               
                   
                   
                   
                 TTCTCCTGAT[ A / G ]GCTAC 
                   
                   
                   
                 CAAAAAGATA[ T / G ]GGGTA 
                   
               
               
                   
                   
                   
                 AATTTACATGCCAGGAGCCC 
                   
                   
                   
                 ATAAGACGTCTTTTAAAAAT 
                   
               
               
                   
                   
                   
                 TGTAAGCCCTCTAGCATTTT 
                   
                   
                   
                 ATGGGTCAGGCAGCTTTCTC 
                   
               
               
                   
                   
                   
                 CTTGA 
                   
                   
                   
                 GTGTT 
                   
               
               
                   
                   
                 rs42695 
                 CATAATTTTATCAAAATTTT 
                 84 
                   
                 rs7806547 
                 CTTCAAGAGTCTTTGAGATG 
                 126 
               
               
                   
                   
                   
                 TTTCACATACGTTGGCATGG 
                   
                   
                   
                 CCTATAGGCTCATCTGTTCA 
                   
               
               
                   
                   
                   
                 TCTTCAGACC[ T / C ]GTGGT 
                   
                   
                   
                 TTACAAGATG[ A / G ]TGAAA 
                   
               
               
                   
                   
                   
                 AATAATCACACCTCTCTTAA 
                   
                   
                   
                 TGGAGAGCCTGAAAGTTAAG 
                   
               
               
                   
                   
                   
                 CGGGTGGCGTGCTGATCAAA 
                   
                   
                   
                 AGTCTTTTCCCCCAGTCAAT 
                   
               
               
                   
                   
                   
                 TAAGT 
                   
                   
                   
                 AACTT 
                   
               
               
                   
                   
                 rs1029897 
                 CTGTTGAGTGTTCAAGTCTG 
                 85 
                   
                 rs6462100 
                 CAGATCTTCTGAAGACCTGA 
                 127 
               
               
                   
                   
                   
                 ATTTGGCTTCACCAAGAATA 
                   
                   
                   
                 GAAAGGACAGCAGGGTGGAG 
                   
               
               
                   
                   
                   
                 GAACAATGTT[ T / C ]CTAAA 
                   
                   
                   
                 AGACCCCTTC[ A / G ]CACCT 
                   
               
               
                   
                   
                   
                 AAGTTTGTCATGAAGAGAAG 
                   
                   
                   
                 TCCAGACGAAAGCACTGGCC 
                   
               
               
                   
                   
                   
                 CCCATTTAGAAATTCATCCT 
                   
                   
                   
                 TGAGGATAGGCTTGCCCAAG 
                   
               
               
                   
                   
                   
                 CTAAC 
                   
                   
                   
                 GGCAA 
                   
               
               
                   
                   
                 rs4722793 
                 GGGAGGTGTATTAACTTTTG 
                 86 
                   
                 rs6979352 
                 ACCCCTAGACAGGAAAACAT 
                 128 
               
               
                   
                   
                   
                 CCTATGGAGCTAGTAACAGG 
                   
                   
                   
                 CCTTCGGGGGGAAAAATGAG 
                   
               
               
                   
                   
                   
                 TAGAACCGGG[ A / C ]TTCTT 
                   
                   
                   
                 GACATGAAAT[ T / C ]GCTTG 
                   
               
               
                   
                   
                   
                 TTTTTTCATCATTTTTTATT 
                   
                   
                   
                 CTGCGGTGCCTATCATTCTG 
                   
               
               
                   
                   
                   
                 ATGTAAAATATATATAACAA 
                   
                   
                   
                 TTAAGGACAGTGAAAACACA 
                   
               
               
                   
                   
                   
                 AATTT 
                   
                   
                   
                 GTCTG 
                   
               
               
                   
                   
                 rs10233653 
                 AAGTTCAGAGTAACTTCCCA 
                 87 
                   
                 rs6950574 
                 TATTCAGAATCCAAACATAT 
                 129 
               
               
                   
                   
                   
                 GATTTTAAATATTCTGTGTC 
                   
                   
                   
                 AGGGATCTCAAATAATCCTT 
                   
               
               
                   
                   
                   
                 ATGTAAGAAC[ A / G ]AGGAG 
                   
                   
                   
                 TCCCTTCTAT[ A / G ]CACTA 
                   
               
               
                   
                   
                   
                 GAATCGCTGATCAATTAGGT 
                   
                   
                   
                 CTAATTAGCTTGATCGATAT 
                   
               
               
                   
                   
                   
                 TTAAAAGCTACTGAAATTCT 
                   
                   
                   
                 CATTAGGAAATTATTATTAT 
                   
               
               
                   
                   
                   
                 CAAGA 
                   
                   
                   
                 AATCC 
                   
               
               
                   
                   
                 rs6955105 
                 CGGCTGTCAAATCTCTTGCT 
                 88 
                   
                 rs4722835 
                 ACATTAAGACCGGAGGATAT 
                 130 
               
               
                   
                   
                   
                 GTCTGCTGCCTTTCCTCTCA 
                   
                   
                   
                 CAACAAATTTGGTTGACTGA 
                   
               
               
                   
                   
                   
                 GCATGTGAGC[ A / G ]TGGAG 
                   
                   
                   
                 GCCACATCCT[ A / C ]TACCT 
                   
               
               
                   
                   
                   
                 CTGGGGGTCTGGTGGATCCT 
                   
                   
                   
                 ATCTGACTCAGTCTATCCAC 
                   
               
               
                   
                   
                   
                 GTCAATCATATGTCTGTGGG 
                   
                   
                   
                 CTGTGAAGGAGACTTTAAGA 
                   
               
               
                   
                   
                   
                 CAGCA 
                   
                   
                   
                 CCTAG 
                   
               
               
                   
                   
                 rs17156685 
                 TTTATCATATGTATCTCCAG 
                 89 
                   
                 rs2066979 
                 TGGTGAATGAAAGGCAGTGC 
                 131 
               
               
                   
                   
                   
                 CTTGCACCTCTCTCCTTGGC 
                   
                   
                   
                 AGAGACTGCCTCTCTTTTTG 
                   
               
               
                   
                   
                   
                 AATGGCCTTC[ A / G ]CTGCA 
                   
                   
                   
                 AGGATGTTTG[ T / C ]TACAG 
                   
               
               
                   
                   
                   
                 CCTTTGACATTTTCCAACTG 
                   
                   
                   
                 AGCCTTGGTGTCAGATAATC 
                   
               
               
                   
                   
                   
                 CGCCTTTGACATTTTCCTCT 
                   
                   
                   
                 ATGTAACAAGCACTGGATTG 
                   
               
               
                   
                   
                   
                 AGATG 
                   
                   
                   
                 GCAAG 
                   
               
               
                   
                   
                 rs17156694 
                 CTCAGACTTTCTTTGATGGA 
                 90 
                   
                 rs10486591 
                 GGATTCATTTTCTGAAGAAT 
                 132 
               
               
                   
                   
                   
                 GCCAGCCTCCTTGAAAGCAG 
                   
                   
                   
                 TAAGTCAACAGACATGGCTT 
                   
               
               
                   
                   
                   
                 TTATTTTTAG[ A / G ]TGTTC 
                   
                   
                   
                 CACAATGCAC[ A / G ]TATTG 
                   
               
               
                   
                   
                   
                 CAACAGCCATCTATCTTACA 
                   
                   
                   
                 GATTCCTTTTGGGGGTCAGA 
                   
               
               
                   
                   
                   
                 AAAGGATTTTCTCTTCAGAT 
                   
                   
                   
                 GCAGACTCAGAGCTCTGAGA 
                   
               
               
                   
                   
                   
                 AGGCT 
                   
                   
                   
                 GGCTT 
                   
               
               
                   
                   
                 rs17156699 
                 AGAGGAGCTCAGTCAATGGT 
                 91 
                   
                 rs721993 
                 GAGAGCCTCAGCTTCCCAGT 
                 133 
               
               
                   
                   
                   
                 GAGATCGAATCTTTGGACCT 
                   
                   
                   
                 TGCTTGCTGGACCCTAAAGC 
                   
               
               
                   
                   
                   
                 CCTTTGGACC[ A / G ]CCGGA 
                   
                   
                   
                 TGTAAGAACT[ T / C ]TGTGA 
                   
               
               
                   
                   
                   
                 ATGAAATCACACGTTCCCTA 
                   
                   
                   
                 AACTTGAATGTTTCTTTTTT 
                   
               
               
                   
                   
                   
                 CAATAACAAGAGAAGCTGTT 
                   
                   
                   
                 TAACCAAGGTAAGGAATTTA 
                   
               
               
                   
                   
                   
                 ATTTT 
                   
                   
                   
                 ATGCC 
                   
               
               
                   
                   
                 rs177572 
                 CTCACCTTATTTCCATGATG 
                 92 
                   
                 rs2237351 
                 GGAGGTACCTTCATCCTTGA 
                 134 
               
               
                   
                   
                   
                 CTTGGTTGTCAGTGAACGCA 
                   
                   
                   
                 GAAGAGAGACTTCAGTATCT 
                   
               
               
                   
                   
                   
                 GATATTGGAG[ T / C ]TAAGG 
                   
                   
                   
                 GTGGAACAAG[ T / C ]GAAGC 
                   
               
               
                   
                   
                   
                 CCAGTGTTTGTCCCAGGGCC 
                   
                   
                   
                 TAGAACTTGGCATCGGAGCA 
                   
               
               
                   
                   
                   
                 CCAGATCCAACTGGAGTGAA 
                   
                   
                   
                 TAGTGCTGAGCAAAGAAGCC 
                   
               
               
                   
                   
                   
                 TATTA 
                   
                   
                   
                 TCTAC 
                   
               
               
                   
                   
                 rs177573 
                 TTTCTATGGGTGCTATTAAG 
                 93 
                   
                 rs3735566 
                 TCTCTTAAACTCCCTCCACT 
                 135 
               
               
                   
                   
                   
                 CATATAAAATTTTTTTTCAA 
                   
                   
                   
                 CAACACAACTGATACCTTTC 
                   
               
               
                   
                   
                   
                 AAGGACTGAG[ T / C ]TGAGT 
                   
                   
                   
                 ATTATCTCCT[ A / G ]TAGTG 
                   
               
               
                   
                   
                   
                 TGGTATGCCACTGTGAACAG 
                   
                   
                   
                 TCTGTGGCATTGGTATTCTA 
                   
               
               
                   
                   
                   
                 TAACTTCATCACTTGGAAGA 
                   
                   
                   
                 AAGGAGAAAACTAGAATCTA 
                   
               
               
                   
                   
                   
                 TCCGA 
                   
                   
                   
                 ATGAG 
                   
               
               
                   
                   
                 rs177574 
                 ATTTCCTCATGGTAGCATTT 
                 94 
                   
                 rs11975539 
                 TTGTTGTTTTTGTTGCCACC 
                 136 
               
               
                   
                   
                   
                 GAACCAAGCCTTTAAGTAGA 
                   
                   
                   
                 ACAAGAGCAAAGGTATTTCC 
                   
               
               
                   
                   
                   
                 ACAAGATTTT[ A / G ]CTAAA 
                   
                   
                   
                 TATTTTGTTT[ A / G ]AATTT 
                   
               
               
                   
                   
                   
                 CATAGAAGGCAGAAAGGGCA 
                   
                   
                   
                 GTCACTAAGATCTAAAACAG 
                   
               
               
                   
                   
                   
                 CTGCTGACTAGCTATTTGAA 
                   
                   
                   
                 TGGACACACAATGGGCACAC 
                   
               
               
                   
                   
                   
                 GAAAA 
                   
                   
                   
                 AACAA 
                   
               
               
                   
                   
                 rs177576 
                 TCATTGGTGGATCTGGAGAG 
                 95 
                   
                 rs6462107 
                 ATGCCTCCAGGCTTATGTTC 
                 137 
               
               
                   
                   
                   
                 TAGCTGACCTGAAAACAGTC 
                   
                   
                   
                 TTAGTCTAATACTCAGCCCT 
                   
               
               
                   
                   
                   
                 TTCATCTTTC[ T / C ]GCCAA 
                   
                   
                   
                 TAGCTCACAA[ T / C ]GGAAT 
                   
               
               
                   
                   
                   
                 AATAATTTTAACACTTAAAA 
                   
                   
                   
                 CATCAATCCCAGCAACTAGA 
                   
               
               
                   
                   
                   
                 AAAATTTTTTTGAGAAGGTA 
                   
                   
                   
                 TATTGGGACAGGGAACCTAG 
                   
               
               
                   
                   
                   
                 CTAGA 
                   
                   
                   
                 AGAGT 
                   
               
               
                   
                   
                 rs13437706 
                 CTGAGACACAGTGGGCCTTG 
                 96 
                   
                 rs2190306 
                 TTGATAACCTAGTTTAGTAT 
                 138 
               
               
                   
                   
                   
                 GAAATGGCAGTTCCCATAGG 
                   
                   
                   
                 CCTATGAGTGCCTTAAATAC 
                   
               
               
                   
                   
                   
                 GAGTCCTGCA[ T / C ]GAGCC 
                   
                   
                   
                 AGAGGATGCT[ T / C ]AATGA 
                   
               
               
                   
                   
                   
                 ATGAAGGCGAGAAGCCAAGG 
                   
                   
                   
                 AAATTTATAGACTGCCCGCT 
                   
               
               
                   
                   
                   
                 CTTTGCATGCTATGCTTTGG 
                   
                   
                   
                 CAGCAGCTCACTGGGATTG 
                   
               
               
                   
                   
                   
                 GTGTG 
                   
                   
                   
                 AATAT 
                   
               
               
                   
                   
                 rs177580 
                 TGCAGATCTGATGACAGTAC 
                 97 
                   
                 rs4719955 
                 ATCTGCACATGCCAGTGGTC 
                 139 
               
               
                   
                   
                   
                 ATCCACACCCTGTCGCTTTC 
                   
                   
                   
                 TGAATAACAGAAGGAGTCCT 
                   
               
               
                   
                   
                   
                 CCTGCCAAGA[ T / C ]GAACT 
                   
                   
                   
                 TCCAAGGCCA[ T / C ]CCTGA 
                   
               
               
                   
                   
                   
                 GTAGCCGTCAGAGCCTCCAT 
                   
                   
                   
                 CCTGCAGCCATGTTGGTGTA 
                   
               
               
                   
                   
                   
                 TCTGCTCCCCACACCCATCC 
                   
                   
                   
                 GGAACTGTCTCCAGGGAGCC 
                   
               
               
                   
                   
                   
                 AGTGA 
                   
                   
                   
                 AAAGT 
                   
               
               
                   
                   
                 rs177581 
                 TGACAGTACATCCACACCCT 
                 98 
                   
                 rs10228137 
                 CTAGAAAATATCCGTCTCTT 
                 140 
               
               
                   
                   
                   
                 GTCGCTTTCCCTGCCAAGAC 
                   
                   
                   
                 GTTCTAGCAGCCATAGGTAA 
                   
               
               
                   
                   
                   
                 GAACTGTAGC[ T / C ]GTCAG 
                   
                   
                   
                 ATGACAATGG[ A / C ]GACGC 
                   
               
               
                   
                   
                   
                 AGCCTCCATTCTGCTCCCCA 
                   
                   
                   
                 TACTGAAAAATCACAACTCG 
                   
               
               
                   
                   
                   
                 CACCCATCCAGTGACCATCC 
                   
                   
                   
                 TGTGTTCTAAAATGACCACA 
                   
               
               
                   
                   
                   
                 ACTAA 
                   
                   
                   
                 AAGGG 
                   
               
               
                   
                   
                 rs1266 
                 TCTTCTGCACTCCAGCCTCT 
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 CCCTCTACTTCCCTCCTTTT 
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 TGCTTCAGCC[ A / C ]GAGGC 
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 AGATGGCAGACATGGATACA 
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 CATTTATGGATTGGCTGATG 
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 TGTCT 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 10 
               
               
                   
               
               
                   
                   
                 Gene 
                   
                   
               
               
                   
                   
                 polymorphism 
                   
                 SEQ 
               
               
                 Gene name 
                 Position 
                 name 
                 Sequence 
                 ID NO: 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 ATF2 
                 5′ 
                 rs268174 
                 ACGCGTGTATGTTTTACAATATACATCTCTCATAATATCAACTGAAGCAA[ T / C ] 
                 141 
               
               
                   
                 Flanking 
                   
                 ATTTAATGTTTCAGTCTACCACAGATCATTTATTTTCTAGCAAATGTCTT 
                   
               
               
                   
                 region 
                 rs13030474 
                 ACATGTGAGTTGAAGTTACTCCATGAAGCCCCTAAGAATGTGCAGAAAAG[ T / G ] 
                 142 
               
               
                   
                   
                   
                 GATTGATTCAAATGGATCATTCTTTCTTTTCCATTACCTTTTTTTTTTCC 
                   
               
               
                   
                   
                 rs268237 
                 TGGACTGACTTATATAAAAAATTAGAGAAAAATACAAATTAGTACACATT[ T / C ] 
                 143 
               
               
                   
                   
                   
                 CAGGACAAAGTTGTGTGATGCACTAAGGGAAATCGCATTAGAAAAGAGAT 
                   
               
               
                   
                   
                 rs1982235 
                 TGAGGAGGAAGCAAGAAAGAAGCCAAGATCCACAGTGGCTGCTTCCAAGT[ T / G ] 
                 144 
               
               
                   
                   
                   
                 GCATATGGACTAGTTGCTTGTGGCAGGGAGAGACATGGGTTCCGAATCCC 
                   
               
               
                   
                   
                 rs10497435 
                 AAATAGAGATAATTCACGTGTACTGTTCAACAAGCAATTATTCATATAGT[ T / C ] 
                 145 
               
               
                   
                   
                   
                 TCTCAAGTACTCAATTCTAACCAAGAACATGGTGTCCTGTGGTGTCTACA 
                   
               
               
                   
                   
                 rs268231 
                 GTAATTCTAACAAATGGCTAATGGAAGTGATATCAACACGTCAACATAAA[ A / C ] 
                 146 
               
               
                   
                   
                   
                 GATTAAACATCTAGAATGCCCTGCTAAGAAGATGGCTGGGGACTGAACTC 
                   
               
               
                   
                   
                 rs268230 
                 GAAAGAAGGGTCATTCACTACTTAACAGGAAACTAGGGTCCCCAGCAAAG[ A / C ] 
                 147 
               
               
                   
                   
                   
                 GAAGATATTTATTTCAAGGAACCTGGAAAATGGTTCCAGAAGTATGGCTA 
                   
               
               
                   
                   
                 rs268229 
                 ACAAAAAGAAAAACTGTAGATTCACCCCGGCAGAGAGGACTAAACAGATT[ A / G ] 
                 148 
               
               
                   
                   
                   
                 ACTTTTGATATGAGTTGGCTGCAGGATAGTGGGCCTTTTTCTTCACGTTG 
                   
               
               
                   
                   
                 rs268228 
                 CCCTGTGCCCTCCACTTACCTTCCCAGGAGGCGGCGGCGGCACGGGCTGC[ A / G ] 
                 149 
               
               
                   
                   
                   
                 GCAGAGGTCGAAGGAGTGGGACTCAATGCGCAAGCGCGGTCCGGCTCTTA 
                   
               
               
                   
                   
                 rs166531 
                 GGTGAGCTCCGGAAAGGCTGCTAGAGGGAAAGCAGGATGGGTCCTCCGAG[ T / C ] 
                 150 
               
               
                   
                   
                   
                 CCAGCCCCAGGAGCCGGGTGTCTCCGTTTCCGTCACTTCCCAGCACTAGG 
                   
               
               
                   
                   
                 rs268214 
                 TTCTGGAGGGGGCGGGACCAGAGGGCCCAAGGAGCGTTACTTCTGTAAAC[ T / C ] 
                 151 
               
               
                   
                   
                   
                 CGGAGCTGTGGAAGACTGTGATTGGCTGTCGGCTGGAGGAGGGCGCGGGT 
                   
               
               
                   
                 Exon 
                 rs10497434 
                 TTCTAGCTGGTGGGCCATGAGCTTTATTTACTCTGCTTCCAGGAATACCT[ T / C ] 
                 152 
               
               
                   
                   
                   
                 AGCTGTTATCAATAAGCAGTCCTTTCTCAAGTTTCCATCTAGTACCCTTA 
                   
               
               
                   
                 Intron 
                 rs11888507 
                 CCCCTCTTAAAGAGCTTGATCTGCCAACATTGGAGAAAAGGGCAATCCTA[ T / C ] 
                 153 
               
               
                   
                   
                   
                 ATATCCATGATCCTGACATACCTGCCTCAGGTAAACTAGGGGAGATACTG 
                   
               
               
                   
                   
                 rs13388308 
                 TTTCCCTCCTCCTATCCCACCATGGGCTGGATTCTTCATTTCACATCCTA[ T / C ] 
                 154 
               
               
                   
                   
                   
                 AAAAACTCAGCATAATTTCCAGGTTTGAAATGGCAACTTTCTCTCTGTCT 
                   
               
               
                   
                   
                 rs3755490 
                 AAATTGCATTTTTCATAATTTTGTTCATAAATGAAGTTTCAAGAATGTCA[ T / C ] 
                 155 
               
               
                   
                   
                   
                 GCTCAGAAAAATTTGGTAATTCTTGTGGGGAAATGTGTAACTAGCCAAAG 
                   
               
               
                   
                   
                 rs7578569 
                 ATAAATTTGGGAAATGTTGAATGTGTAGGCTTCATTTCACAGGACTTTTC[ A / G ] 
                 156 
               
               
                   
                   
                   
                 TGACCTTAATGTTATGTCAATTAAGGATTCATAACTTTAAAAAATGCCCC 
                   
               
               
                   
                   
                 rs7566401 
                 ATACTTTCTAAAGCTCAGTTGCACTATTGAAGAAAAAGCAGAATTTCTTG[ A / C ] 
                 157 
               
               
                   
                   
                   
                 CAAAAGTTTCCTGGGTTTTTTTTCATCCTAACTCTAAAATTTTACAGAAT 
                   
               
               
                   
                   
                 rs1153676 
                 GAAGGTAACTGTTAATAATCCAAACAAAAGATGATGATGGTTTGGGCTTA[ A / C ] 
                 158 
               
               
                   
                   
                   
                 GTGGTGTCACTGAACACAGACATAGAGGATGAGATTCAGGTCTGATAAAA 
                   
               
               
                   
                   
                 rs1205399 
                 GCACTCCAGCCTGAGTGACAAAGAGAAAGACTGTCCAAAAACAACAACAA[ A / C ] 
                 159 
               
               
                   
                   
                   
                 AAAAAAAGAATTACAGTCAGGTGCAGTGACTCACGCCTGTAATCCCAACA 
                   
               
               
                   
                   
                 rs2072538 
                 TTAGGTTTTCCCTGTCCCCAGTAAGCAGATCTAGTTCTCTTTTGCTGTTG[ T / C ] 
                 160 
               
               
                   
                   
                   
                 AGGTTTGCCAGTTAATTATTGGATTGTACTGGACTCACATTCAGAGCATG 
                   
               
               
                   
                   
                 rs212361 
                 ACAAGATACAGTTATGTAAATACCTATGCTTAGGTGGCAATCTAAAACTT[ A / G ] 
                 161 
               
               
                   
                   
                   
                 TTTATATGTGTTTCTTTGATTGAAAACTTTTGCTTTTTAATGCCAATGCT 
                   
               
               
                   
                   
                 rs212360 
                 GAAGCTTAATTTCTGCTACTCAGAGTTACATTTGTATATTTTTATGCCTA[ T / C ] 
                 162 
               
               
                   
                   
                   
                 CAAGGATTGGAGGCTTCTTAGAAGTGTATACTGCTCCTTCTCTCCCCATG 
                   
               
               
                   
                   
                 rs1153685 
                 CTTATTTCAGTTGCTTTTCATAATAGTACTTATTCTATCAGTTTGACGGA[ A / G ] 
                 163 
               
               
                   
                   
                   
                 AAACAAAGGCTTAGGAAGATTCTTAGTAAAAGCTTCAAATGTAAGTATTA 
                   
               
               
                   
                   
                 rs12693057 
                 ATTAGAAGCACAGTCTCCATTTTTAAAGTAGCAGCTCAGTTCACTCTGAC[ A / G ] 
                 164 
               
               
                   
                   
                   
                 GTATTTCACTGACGTAGCCTAAGGCTATAGGTAATGGAACATTACTCACT 
                   
               
               
                   
                   
                 rs212347 
                 TCTTATCAAAAAAGAAGGACATTACAAAAAGGAAAAGGCACAATTAACCT[ T / C ] 
                 165 
               
               
                   
                   
                   
                 TAAAATGCTGAAAACAAAAGAATCTCATTCTTTGGGAAAACATTTAGCAG 
                   
               
               
                   
                   
                 rs212349 
                 ACGGAATCTTTTAAATTAAAAAATATTGCCCATTCTGATGAAACTGCTTA[ T / C ] 
                 166 
               
               
                   
                   
                   
                 AATGACTACAAGTAAAGATGGTGGCCATTAAGTTTTATCGTGAGCACCTG 
                   
               
               
                   
                   
                 rs3845744 
                 CCAGTTTTAGCACTGAAAGTCCTGCTTCCTAAGAAGACCCCTCAGTCGTG[ A / G ] 
                 167 
               
               
                   
                   
                   
                 GAAAACCATGACAGTTAGTCACCCCAACAGTTAAGTAATATAAAACCTGA 
                   
               
               
                   
                   
                 rs2302663 
                 TTATCAGCAGCTGGGTGGAAAAAAGAAAAATTATTCATTTTCCTAAAATC[ A / G ] 
                 168 
               
               
                   
                   
                   
                 GTAAGAATGCACCAGTATGCTGAGGCAATACACAGAGTAAAAAGTTAGAA 
                   
               
               
                   
                 3′ 
                 rs1153699 
                 GTGGGTTTGATTCTTGTCCTAGTCTAGCCTCAGTTTTGGGCAGGCACTGC[ T / G ] 
                 169 
               
               
                   
                 Flanking 
                   
                 TTGGGGTGGGGCTTTCTCAAATATCCTGCCCCTTTTCCAGTAGCAGGAAA 
                   
               
               
                   
                 region 
                 rs7583431 
                 ATCCTTTCTGTGTGTCTCCTCTTGTGGCTACACTTGACGGGCCATATTAT[ A / C ] 
                 170 
               
               
                   
                   
                   
                 AAAGAATACAAAACAATAGTACAGACAGGTAAATGTTTATGCCTAGAAAT 
                   
               
               
                   
                   
                 rs1153702 
                 TGTTGTTCATATTTTAAAAAAATTCTTAGCCATTATCTCTTCAAATAACA[ T / C ] 
                 171 
               
               
                   
                   
                   
                 GTTTGCCAAGTTCTCAATATGATATTGTTCCATAGATCTTGGATGCTGTG 
                   
               
               
                   
                   
                 rs1153711 
                 TGTGTGTCTTGCAGCAGCTGGATGAAGGTTCTGTAAATGTATGCTACGTC[ T / G ] 
                 172 
               
               
                   
                   
                   
                 GTTGAGTCCATGGTGTAGTTTAAGTCTGATAATTTTTGTTGATTTTTTTT 
               
               
                   
               
            
           
         
       
     
     In Table 7 to Table 10 (SEQ ID NOS: 1 to 172), 101 nucleotides are shown, and a gene polymorphic site is shown at the 51st nucleotide. For example, one represented by “A/G” means a gene polymorphism associated with transitions between “A” and “G”, and “C/T” means a gene polymorphism associated with transitions between “C” and “T”. 
     3. Haplotype Analysis 
     In the present invention, by using SNP among the above-mentioned gene polymorphisms, a haplotype can be constructed. The SNP to become a target of a haplotype analysis may be any as long as its gene polymorphism frequency is 0.5% or higher, preferably, those with a gene polymorphism frequency of 1%, more preferably those with a gene polymorphism frequency of 5% or higher can be selected. Further, SNP to become a target of a haplotype analysis may be a full or partial sequence thereof. 
     The haplotype analysis can be carried out using various computer programs, and for example, Haploview (available from the following website: Broad Institute) (the same shall apply hereafter); Barrett J C, Fry B, Mailer J, Daly M J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005 Jan. 15 [PubMed ID: 15297300] Whitehead Institute for Biomedical Research Cambridge, Mass. 02142, USA.) can be used. 
     As an example of the haplotype analysis, among cyclic AMP responsive element binding protein gene polymorphisms in Japanese healthy subjects found as in the above-mentioned 2, with regard to the 17 sites of SNPs which are CREB1 subtype gene polymorphisms, the 40 sites of SNPs which are CREB3 subtype gene polymorphisms, the 64 sites of SNPs which are CREB5 subtype gene polymorphisms, and the 31 sites of SNPs which are ATF2 subtype gene polymorphisms, a haplotype was estimated for each linkage disequilibrium block (haplotype block), using Haploview. The estimated haplotypes are shown in Tables 11 to 14. It is to be noted that the “Tag” shown in the tables indicates a Tag SNP that is a typical gene polymorphism in the linkage disequilibrium block. 
     
       
         
           
               
             
               
                 TABLE 11  
               
             
            
               
                   
               
               
                 Gene name CREB1 
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
               
                   
                 1 
               
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 1 
                 2 
                 3 
                   
                   
                   
                   
                   
                   
                   
                   
                 12 
                 13 
                   
                   
                   
                 17 
               
               
                 Haplotype No. 
                 Tag 
                 Tag 
                 Tag 
                 4 
                 5 
                 6 
                   
                 8 
                 9 
                 10 
                 11 
                 Tag 
                 Tag 
                 14 
                 15 
                 16 
                 Tag 
               
               
                   
               
               
                 H1 
                 C 
                 C 
                 C 
                 A 
                 G 
                 G 
                 G 
                 T 
                 C 
                 C 
                 C 
                 C 
                 C 
                 C 
                 A 
                 A 
                 T 
               
               
                 H2 
                 C 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 C 
                 C 
                 T 
                 G 
                 G 
                 T 
               
               
                 H3 
                 C 
                 T 
                 C 
                 A 
                 G 
                 G 
                 A 
                 T 
                 T 
                 C 
                 C 
                 C 
                 C 
                 C 
                 A 
                 A 
                 T 
               
               
                 H4 
                 T 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 C 
                 A 
                 T 
                 G 
                 G 
                 C 
               
               
                 H5 
                 C 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 A 
                 C 
                 C 
                 A 
                 A 
                 T 
               
               
                 H6 
                 T 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 C 
                 C 
                 T 
                 G 
                 G 
                 T 
               
               
                 H7 
                 T 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 C 
                 A 
                 T 
                 G 
                 G 
                 T 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
               
                 () 1~17: (in this order)rs16839837, rs2360969, rs10932200, rs2253206, rs2551640, rs11904814, rs16839883, rs6740584, rs3770704, rs2254137, rs2551645, rs2551946, rs4234080, rs2952768, rs2709386, rs7591784 and rs7594560 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12  
               
               
                   
               
               
                 Gene name CREB3 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
               
                   
                 1 
               
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 1 
                 2 
                 3 
                   
                   
                   
                   
                   
                 9 
                   
                 11 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Haplotype No. 
                 Tag 
                 Tag 
                 Tag 
                 4 
                 5 
                 6 
                 7 
                 8 
                 Tag 
                 10 
                 Tag 
                 12 
                 13 
                 14 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
                 21 
                 22 
                 23 
                 24 
               
               
                   
               
               
                 H1 
                 G 
                 C 
                 G 
                 T 
                 A 
                 T 
                 T 
                 T 
                 C 
                 T 
                 C 
                 C 
                 G 
                 C 
                 T 
                 G 
                 T 
                 G 
                 T 
                 C 
                 A 
                 G 
                 G 
                 A 
               
               
                 H2 
                 G 
                 C 
                 G 
                 T 
                 A 
                 T 
                 T 
                 T 
                 T 
                 T 
                 C 
                 C 
                 G 
                 C 
                 T 
                 G 
                 T 
                 G 
                 T 
                 C 
                 A 
                 G 
                 G 
                 A 
               
               
                 H3 
                 T 
                 T 
                 A 
                 T 
                 A 
                 T 
                 C 
                 T 
                 C 
                 T 
                 T 
                 C 
                 G 
                 A 
                 G 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
                 T 
                 G 
                 C 
               
               
                 H4 
                 T 
                 T 
                 A 
                 T 
                 A 
                 T 
                 C 
                 T 
                 C 
                 T 
                 C 
                 C 
                 G 
                 A 
                 G 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
                 T 
                 G 
                 C 
               
               
                 H5 
                 T 
                 C 
                 G 
                 C 
                 C 
                 C 
                 C 
                 C 
                 C 
                 T 
                 C 
                 C 
                 A 
                 A 
                 G 
                 G 
                 C 
                 A 
                 T 
                 C 
                 A 
                 T 
                 A 
                 C 
               
               
                 H6 
                 T 
                 T 
                 G 
                 T 
                 A 
                 T 
                 C 
                 T 
                 C 
                 C 
                 C 
                 T 
                 G 
                 A 
                 T 
                 G 
                 C 
                 G 
                 T 
                 C 
                 A 
                 G 
                 G 
                 C 
               
               
                 H7 
                 T 
                 C 
                 A 
                 T 
                 A 
                 T 
                 C 
                 T 
                 C 
                 T 
                 T 
                 C 
                 G 
                 A 
                 G 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
                 T 
                 G 
                 C 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
               
                   
                 2 
               
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 25 
                 26 
                   
                   
                 29 
                   
                   
                   
                   
                   
                   
                 36 
                   
                 38 
                 39 
                   
               
               
                 Haplotype No. 
                 Tag 
                 Tag 
                 27 
                 28 
                 Tag 
                 30 
                 31 
                 32 
                 33 
                 34 
                 35 
                 Tag 
                 37 
                 Tag 
                 Tag 
                 40 
               
               
                   
               
               
                 H8 
                 C 
                 C 
                 G 
                 G 
                 G 
                 C 
                 G 
                 G 
                 G 
                 A 
                 T 
                 A 
                 C 
                 C 
                 G 
                 C 
               
               
                 H9 
                 C 
                 T 
                 A 
                 T 
                 G 
                 T 
                 A 
                 G 
                 A 
                 G 
                 A 
                 A 
                 T 
                 C 
                 A 
                 T 
               
               
                 H10 
                 T 
                 C 
                 G 
                 G 
                 C 
                 T 
                 G 
                 A 
                 A 
                 G 
                 A 
                 A 
                 T 
                 C 
                 G 
                 C 
               
               
                 H11 
                 C 
                 T 
                 A 
                 G 
                 G 
                 T 
                 A 
                 G 
                 A 
                 G 
                 A 
                 A 
                 T 
                 C 
                 G 
                 T 
               
               
                 H12 
                 C 
                 C 
                 G 
                 G 
                 C 
                 T 
                 G 
                 A 
                 A 
                 G 
                 A 
                 A 
                 T 
                 C 
                 G 
                 C 
               
               
                 H13 
                 C 
                 T 
                 A 
                 T 
                 G 
                 T 
                 A 
                 G 
                 A 
                 G 
                 A 
                 G 
                 T 
                 C 
                 A 
                 T 
               
               
                 H14 
                 C 
                 C 
                 G 
                 G 
                 G 
                 C 
                 G 
                 G 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 G 
                 C 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
               
                 () 1~40: (in this order)rs1243872, rs2145925, rs2025126, rs1885373, rs1885374, GA007473, rs2295794, rs4879926, GA007477, rs867194, rs11541908, rs741917, rs7862485, rs2756894, rs2249250, rs2295795, rs877365, rs2737273, rs2295797, rs2295798, rs1534847, rs7873822, rs2737274, rs10972567, rs3763630, rs10814274, rs3750434, rs1570246, GA025684, rs1570248, rs1570249, rs34478611, rs1322045, rs1951432, GA025687, rs10814275, rs10758320, rs4878628, rs10758321 and rs10758322 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13  
               
               
                   
               
               
                 Gene name CREB5 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 1 
                   
                 5 
                   
                 6 
                   
                 9 
                   
                 10 
               
            
           
           
               
               
            
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 1 
                 2 
                   
                   
                 5 
                 6 
                   
                 7 
                 8 
                 9 
                   
                 11 
                   
                   
                 13 
                 14 
                   
                 15 
                 16 
                   
                 17 
                 18 
               
               
                 Haplotype (H) No. 
                 Tag 
                 Tag 
                 3 
                 4 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 Tag 
                 10 
                 Tag 
                 12 
                 H No. 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
               
               
                   
               
               
                 H1 
                 C 
                 T 
                 A 
                 A 
                 G 
                 C 
                 H6 
                 C 
                 C 
                 G 
                 C 
                 A 
                 G 
                 H11 
                 T 
                 G 
                 H14 
                 T 
                 A 
                 H17 
                 G 
                 T 
               
               
                 H2 
                 G 
                 C 
                 G 
                 A 
                 G 
                 T 
                 H7 
                 C 
                 A 
                 A 
                 C 
                 G 
                 G 
                 H12 
                 C 
                 C 
                 H15 
                 C 
                 A 
                 H18 
                 G 
                 G 
               
               
                 H3 
                 G 
                 C 
                 G 
                 A 
                 A 
                 T 
                 H8 
                 C 
                 C 
                 G 
                 C 
                 G 
                 G 
                 H13 
                 C 
                 G 
                 H16 
                 C 
                 G 
                 H19 
                 A 
                 G 
               
               
                 H4 
                 C 
                 C 
                 G 
                 A 
                 G 
                 T 
                 H9 
                 T 
                 A 
                 A 
                 C 
                 G 
                 A 
                 . . . 
                   
                   
                 . . . 
                   
                   
                 . . . 
               
               
                 H5 
                 G 
                 C 
                 G 
                 A 
                 G 
                 C 
                 H10 
                 C 
                 C 
                 A 
                 C 
                 G 
                 G 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 11 
                   
                 12 
                   
                 13 
                   
                 15 
                   
                 16 
               
            
           
           
               
               
            
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 19 
                 20 
                   
                 21 
                 22 
                 23 
                   
                 24 
                 25 
                   
                 26 
                 27 
                 28 
                   
                 29 
                 30 
                 31 
                   
                   
               
               
                 Haplotype (H) No. 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 Tag 
                 32 
                 33 
               
               
                   
               
               
                 H20 
                 T 
                 A 
                 H24 
                 G 
                 C 
                 C 
                 H28 
                 A 
                 A 
                 H31 
                 G 
                 T 
                 C 
                 H35 
                 C 
                 C 
                 C 
                 G 
                 C 
               
               
                 H21 
                 T 
                 G 
                 H25 
                 G 
                 C 
                 T 
                 H29 
                 G 
                 A 
                 H32 
                 A 
                 C 
                 T 
                 H36 
                 T 
                 C 
                 A 
                 G 
                 C 
               
               
                 H22 
                 C 
                 G 
                 H26 
                 A 
                 C 
                 T 
                 H30 
                 G 
                 G 
                 H33 
                 A 
                 T 
                 T 
                 H37 
                 C 
                 C 
                 A 
                 G 
                 C 
               
               
                 H23 
                 C 
                 A 
                 H27 
                 G 
                 T 
                 T 
                 . . . 
                   
                   
                 H34 
                 A 
                 T 
                 C 
                 H38 
                 T 
                 T 
                 C 
                 A 
                 T 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 25 
                   
                 26 
                   
                 27 
                   
                 32 
               
            
           
           
               
               
            
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 34 
                 35 
                   
                 36 
                 37 
                 38 
                 39 
                   
                 40 
                   
                   
                 42 
                 43 
                 44 
                 45 
                   
                 47 
                   
                   
                 50 
               
               
                 Haplotype (H) No. 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 41 
                 H No. 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 46 
                 Tag 
                 48 
                 49 
                 Tag 
               
               
                   
               
               
                 H39 
                 T 
                 A 
                 H42 
                 G 
                 A 
                 G 
                 G 
                 H47 
                 A 
                 A 
                 H49 
                 A 
                 T 
                 C 
                 G 
                 T 
                 G 
                 T 
                 T 
                 T 
               
               
                 H40 
                 C 
                 G 
                 H43 
                 G 
                 A 
                 A 
                 A 
                 H48 
                 G 
                 G 
                 H50 
                 A 
                 T 
                 C 
                 G 
                 T 
                 G 
                 T 
                 T 
                 C 
               
               
                 H41 
                 T 
                 G 
                 H44 
                 A 
                 G 
                 G 
                 A 
                 . . . 
                   
                   
                 H51 
                 A 
                 T 
                 A 
                 C 
                 C 
                 G 
                 T 
                 C 
                 C 
               
               
                 . . . 
                   
                   
                 H45 
                 G 
                 A 
                 G 
                 A 
                   
                   
                   
                 H52 
                 C 
                 T 
                 A 
                 C 
                 T 
                 T 
                 C 
                 T 
                 C 
               
               
                   
                   
                   
                 H46 
                 G 
                 G 
                 G 
                 A 
                   
                   
                   
                 H53 
                 C 
                 T 
                 A 
                 C 
                 T 
                 G 
                 C 
                 T 
                 C 
               
               
                   
                   
                   
                 . . . 
                   
                   
                   
                   
                   
                   
                   
                 H54 
                 A 
                 C 
                 C 
                 G 
                 T 
                 G 
                 T 
                 T 
                 T 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 H55 
                 A 
                 T 
                 A 
                 G 
                 T 
                 G 
                 T 
                 T 
                 C 
               
            
           
           
               
               
            
               
                   
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 33 
                   
                 35 
                   
                 40 
               
            
           
           
               
               
            
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 51 
                 52 
                 53 
                 54 
                   
                   
                   
                 57 
                 58 
                   
                 59 
                   
                   
                   
                   
                   
               
               
                 Haplotype (H) No. 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 55 
                 56 
                 H No 
                 Tag 
                 Tag 
                 H No. 
                 Tag 
                 60 
                 61 
                 62 
                 63 
                 64 
               
               
                   
               
               
                 H56 
                 T 
                 G 
                 G 
                 C 
                 A 
                 A 
                 H61 
                 C 
                 T 
                 H64 
                 G 
                 G 
                 C 
                 T 
                 T 
                 C 
               
               
                 H57 
                 T 
                 A 
                 A 
                 T 
                 G 
                 C 
                 H62 
                 T 
                 C 
                 H65 
                 A 
                 A 
                 T 
                 C 
                 C 
                 A 
               
               
                 H58 
                 G 
                 A 
                 A 
                 C 
                 G 
                 C 
                 H63 
                 T 
                 T 
                 . . . 
               
               
                 H59 
                 T 
                 A 
                 G 
                 C 
                 A 
                 A 
                 . . . 
               
               
                 H60 
                 T 
                 A 
                 A 
                 C 
                 G 
                 C 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
               
                 () 1~64: (in this order)rs4722778, rs177479, rs177480, rs11981754, rs177486, rs177498, rs10229500, rs10243659, rs4722785, rs16874503, rs11772815, rs6958133, rs16874525, rs17715174, rs6953524, rs10239810, rs17156649, rs1811248, rs887623, rs740988, rs6952227, rs42695, rs1029897, rs10233653, rs6955105, rs17156699, rs177572, rs177573, rs177580, rs177581, rs12666636, rs177584, rs177585, rs1008262, rs310353, rs41273, rs1637457, rs17156919, rs41276, rs160375, rs917275, rs17157048, rs6462098, rs10951201, rs13311248, rs12540480, rs10265166, rs7798774, rs7799246, rs6972081, rs12533079, rs7806547, rs6462100, rs6979352, rs6950574, rs4722835, rs721993, rs2237351, rs3735566, rs11975539, rs6462107, rs2190306, rs4719955 and rs10228137 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14  
               
               
                   
               
               
                 Gene name ATF2 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
            
               
                   
                 1 
                 2 
               
            
           
           
               
               
            
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 1 
                 2 
                 3 
                 4 
                 5 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Haplotype No. 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
                 15 
                 16 
               
               
                   
               
               
                 H1 
                 T 
                 C 
                 A 
                 A 
                 G 
                 C 
                 C 
                 A 
                 G 
                 C 
                 G 
                 T 
                 C 
                 A 
                 A 
                 A 
               
               
                 H2 
                 G 
                 C 
                 A 
                 G 
                 G 
                 T 
                 T 
                 G 
                 A 
                 T 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
               
               
                 H3 
                 T 
                 T 
                 C 
                 G 
                 A 
                 T 
                 T 
                 G 
                 A 
                 T 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
               
               
                 H4 
                 T 
                 T 
                 A 
                 G 
                 A 
                 T 
                 T 
                 G 
                 A 
                 T 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
               
               
                   
                   
                   
                   
                 G 
                 G 
                 T 
                 T 
                 G 
                 A 
                 T 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
               
                   
                 Linkage disequilibrium block No. 
               
               
                   
                 2 
               
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 21 
                   
                   
                   
                   
                   
                   
                 28 
                   
                   
                   
               
               
                 Haplotype No. 
                 17 
                 18 
                 19 
                 20 
                 Tag 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 Tag 
                 29 
                 30 
                 31 
               
               
                   
               
               
                 H5 
                 C 
                 T 
                 T 
                 C 
                 C 
                 C 
                 G 
                 A 
                 C 
                 A 
                 C 
                 T 
                 T 
                 G 
                 T 
               
               
                 H6 
                 T 
                 C 
                 C 
                 T 
                 T 
                 T 
                 A 
                 G 
                 A 
                 C 
                 T 
                 G 
                 C 
                 G 
                 C 
               
               
                 H7 
                 T 
                 C 
                 C 
                 T 
                 T 
                 T 
                 A 
                 G 
                 A 
                 C 
                 T 
                 T 
                 C 
                 G 
                 C 
               
               
                 H8 
                 T 
                 C 
                 C 
                 T 
                 T 
                 T 
                 A 
                 G 
                 A 
                 C 
                 T 
                 G 
                 C 
                 G 
                 C 
               
               
                 H9 
                 T 
                 C 
                 C 
                 T 
                 C 
                 C 
                 G 
                 A 
                 C 
                 A 
                 C 
                 T 
                 T 
                 G 
                 T 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
               
                   
               
               
                 () 1~31: (in this order)rs1153711, rs1153702, rs7583431, rs2302663, rs3845744, s212349, rs212347, rs12693057, rs1153685, rs212360, rs212361, rs2072538, rs1205399, rs1153676, rs7566401, rs7578569, rs3755490, rs13388308, rs11888507, rs10497434, rs268214, rs166531, rs268228, rs268229, rs268230, rs268231, rs10497435, rs1982235, rs268237, rs13030474 and rs268174 
               
            
           
         
       
     
     Further, from the genotype information of cyclic AMP responsive element binding protein (CREB) genes of the respective individuals in a population, a haplotype frequency in the population is calculated, and a linkage disequilibrium analysis can be carried out based on the thus obtained haplotype frequency. The D′ value and r2 value, which indicate measures of linkage disequilibrium, can be calculated based on the following definition. 
     Definition 
     It is assumed that there are SNP A and SNP B, and the respective alleles are represented by A and a, and B and b. The four haplotypes formed by SNP A and SNP B are represented by AB, Ab, aB and ab, and the respective haplotype frequencies are represented by PAB, PAb, PaB and Pab. 
         D=P   AB   ×P   ab   −P   Ab   ×P   aB  (In the case of  D&gt; 0) 
         D ′=( P   AB   ×P   ab   −P   Ab   ×P   aB )/Minimum((( P   AB   +P   aB )×( P   aB   +P   ab )),(( P   AB   +P   Ab )×( P   Ab   +P   ab ))) (In the case of  D&lt; 0)
 
         D ′=( P   AB   ×P   ab   −P   Ab   ×P   aB )/Minimum((( P   AB   +P   aB )×( P   AB   +P   Ab )),(( P   aB   +P   ab )×( P   Ab   +P   ab )))
 
         r   2 =( P   AB   ×P   ab   −P   Ab   ×P   aB ) 2 /[( P   AB   +P   Ab )( P   AB   +P   aB )( P   aB   +P   ab )( P   Ab   +P   ab )] 
     [However, Minimum (((P AB +P aB )×(P aB +P ab )), ((P AB +P Ab )×(P Ab +P ab ))) means that a smaller value among (P AB +P aB )×(P aB +P ab ) and (P AB +P Ab )×(P Ab +P ab ) is adopted.] 
     Further, a haplotype block can be estimated from the results of the linkage disequilibrium analysis. As for the haplotype block, a linkage block can be estimated from the results of the haplotype analysis by using, for example, Haploview. 
     When a specific SNP in the estimated haplotype blocks is examined, the information of SNPs indirectly linked to each other in the same block can be obtained. That is, when a gene polymorphism of the cyclic AMP responsive element binding protein gene (specifically, a CREB1 subtype gene, a CREB3 subtype gene, a CREB5 subtype gene, or an ATF2 subtype gene) is examined, it is not necessary to analyze all the SNPs, and it is only necessary to perform typing for several specific SNPs, for example, representative SNPs such as a Tag SNP. 
     4. Correlation of Cyclic AMP Responsive Element Binding Protein Gene Polymorphism with Drug Sensitivity and Disease Vulnerability 
     It is considered that when a gene polymorphism occurs in the cyclic AMP responsive element binding protein gene, the function or expression level of the cyclic AMP responsive element binding protein might change. Therefore, there is a correlation between a cyclic AMP responsive element binding protein gene polymorphism and various phenotypes associated with the cyclic AMP responsive element binding protein in some cases. 
     Here, as the phenotype, a phenotype associated with sensitivity to drugs (drug sensitivity) and a phenotype associated with occurrence of a disease (disease vulnerability) can be exemplified. As the drug sensitivity, an efficacy of drugs, a side effect of drugs, duration of efficacy of drugs and the like can be exemplified. As the disease vulnerability, pain sensitivity, vulnerability to substance dependence (in particular, vulnerability to drug dependence) and the like can be exemplified. 
     In the present invention, the type of the aforementioned drug is not particularly limited, and preferred examples of the drug include opioid receptor function modulators and cyclic AMP responsive element binding protein function modulators. Examples of such modulators include various drugs acting directly or indirectly on the opioid receptor or the cyclic AMP responsive element binding protein. Specific examples of various drugs acting directly or indirectly on the opioid receptor include a stimulant such as methamphetamine, a dopamine receptor agonist, a dopamine receptor antagonist, a m-, κ-, or δ-opioid receptor agonist, a m-, κ-, or δ-opioid receptor antagonist, and the like. Specific examples of various drugs acting directly or indirectly on the cyclic AMP responsive element binding protein include phosphorylated enzyme, a coactivator, a PDE4 inhibitor, dephosphorylated enzyme, an agonist for each subtypes of the cyclic AMP responsive element binding protein, an antagonist for each subtypes of the cyclic AMP responsive element binding protein, and the like. 
     Examples of the opioid receptor function modulator include morphine, DAMGO, codeine, methadone, carfentanil, fentanyl, heroin, cocaine, naloxone, naltrexone, nalorphine, levallorphan, pentazocine, pethidine, buprenorphine, oxycodone, hydrocodone, levorphanol, etorphine, dihydroetorphine, hydromorphone, oxymorphone, tramadol, diclofenac, indomethacin, flurbiprofen axetil, marcain, ethanol, methanol, diethyl ether, propanol, butanol, flupirtine, laughing gas, F3 (1-chloro-1,2,2-trifluorocyclobutane), halothane, estradiol, dithiothreitol, thioridazine, pimozide, fluoxetine, paroxetine, desipramine, imipramine, clomipramine, tetramide, isoflurane, ginsenoside, ifenprodil, bupivacaine, tertiapine, clozapine, haloperidol, SCH23390, cocaine, and the like. In particular, morphine, pentazocine, pethidine, buprenorphine, diclofenac, indomethacin, flurbiprofen axetil and marcain are preferred, and morphine, fentanyl and pentazocine are more preferred. 
     Preferred examples of the cyclic AMP responsive element binding protein function modulator include phosphodiesterase 4 (PDE4), calcineurin, protein kinase A, protein kinase C, p90 ribosome S6 kinase 1 (RSK1), calmodulin kinase, glycogen synthase kinase 3β, and CREB-regulated transcription coactivator 1 (CRTC1). 
     The correlation between a cyclic AMP responsive element binding protein gene polymorphism and a phenotype can be examined as described in the following (1) to (4), for example. 
     (1) A gene polymorphism in a linkage disequilibrium block estimated as a result of a linkage disequilibrium analysis and a haplotype analysis in healthy subjects is selected. For example, a Tag SNP which is a typical gene polymorphism is selected as a cyclic AMP responsive element binding protein gene polymorphism for analyzing a correlation with a phenotype.
 
(2) Then, a gene polymorphism frequency of the gene polymorphism in test subjects (patients) is analyzed. In the case where a correlation between a gene polymorphism and disease vulnerability is examined, a comparison is made in terms of gene polymorphisms between the test subjects and the healthy subjects. It is effective to use a statistical technique such as a chi-square test in the comparison.
 
     Here, the test subjects are classified into groups depending on the difference in phenotypes, and a comparison may be made in terms of gene polymorphism frequencies or genotypes between healthy subjects and test subjects in each group. In the case where the phenotype associated with the occurrence of a disease is a stimulant-induced psychotic-like symptom, it can be classified, for example, according to a period of time from the start of the use of a stimulant to the occurrence of delusion or hallucination, a period of duration of delusion or hallucination after termination of the use thereof, the presence or absence of the relapse, and the presence or absence of multiple drug abuse. 
     (3) If there is a gene polymorphism significantly linked to drug sensitivity in the test subjects, the gene polymorphism can be used for evaluating the genetic predisposition to drug sensitivity. Further, if there is a gene polymorphism with a significant difference in the gene polymorphism frequency between the healthy subjects and the test subjects, the gene polymorphism can be used for evaluating the genetic predisposition to disease vulnerability. 
     However, it is suggested that a tendency to gene polymorphism would be affected by the race, birthplace or the like, therefore, it is preferred that in a group showing a similar gene polymorphism to that of a population used for finding an associated gene polymorphism (such as SNP), the above-mentioned evaluation using the gene polymorphism is carried out. 
     Specific examples of the correlation between a cyclic AMP responsive element binding protein gene polymorphism and a phenotype will be shown in the following (1) to (4). 
     (1) In the correlation with the measurement results of the required total administration amount of analgesic in 24 hours after surgery, in the case of patients who had a minor allele (C) of the CREB1 subtype gene polymorphism (rs10932200) and underwent the surgery, the required administration amount (logarithmic transformation) of analgesic after the surgery was statistically significantly high in correlation with the number of alleles which they had. Thus, by analyzing the CREB1 subtype gene polymorphism (rs10932200), the sensitivity to analgesic can be more easily predicted.
 
(2) In the correlation with the measurement results of pain perception latency due to finger immersion in ice water before surgery, the presence or absence of a minor allele (C) of the CREB1 subtype gene polymorphism (rs10932200) and pain perception latency (logarithmic transformation) showed a significant correlation. Thus, by analyzing the CREB1 subtype gene polymorphism (rs10932200), the sensitivity to pain can be more easily predicted.
 
(3) In the correlation with the measurement results of the scale of the intensity of pain (VAS: on visual analogue scale) 24 hours after surgery, in the case of patients who had a minor allele (C) of the CREB1 subtype gene polymorphism (rs10932200) and underwent the surgery, the value of VAS (logarithmic transformation) was statistically significantly high in correlation with the number of alleles which they had. Thus, by analyzing the CREB1 subtype gene polymorphism (rs10932200), the sensitivity to pain or analgesic after the surgery can be more easily predicted.
 
(4) In the correlation with the measurement results of a difference in threshold of pain perception latency due to finger immersion in ice water before surgery, in the case of patients who had a minor allele (C) of the ATF2 subtype gene polymorphism (rs7583431) and underwent the surgery, a difference in threshold of pain perception latency (logarithmic transformation) due to finger immersion in ice water was statistically significantly short in correlation with the number of alleles which they had. Thus, by analyzing the ATF2 subtype gene polymorphism (rs7583431), the sensitivity to analgesic before the surgery can be more easily predicted.
 
     5. Use of Analysis Results 
     As in the above-mentioned 4, the correlation between a cyclic AMP responsive element binding protein gene polymorphism and a phenotype analyzed can be used as an index in a method of predicting sensitivity to various drugs associated with the opioid receptor and the cyclic AMP responsive element binding protein and also to pain, a method of selecting a method of treating or preventing a disease associated with the opioid receptor and the cyclic AMP responsive element binding protein, a method of determining an appropriate administration amount of therapeutic drugs, a method of predicting side effects, or the like. 
     Further, by using the gene polymorphism or the method of the present invention, it is possible to evaluate drug sensitivity and disease vulnerability in different races. The subjects are not particularly limited, and examples thereof include Japanese, Europeans, Americans and the like. In the present invention, however, they are preferably Japanese or those having a similar gene polymorphism tendency to that of Japanese. 
     6. Detection of Gene Polymorphism 
     A genome sample of a test subject can be extracted from the blood, saliva, skin or the like, however, the origin is not limited to these as long as a genome sample can be collected therefrom. The extraction and purification methods of genomic DNA are publicly well known. For example, genomic DNA is purified from a specimen such as the blood, saliva, skin or the like collected from a human using the phenol method or the like. At this time, a commercially available genomic DNA extraction kit such as GFX Genomic Blood DNA Purification Kit (manufactured by GE Healthcare Bio-Sciences KK) or a device may be used. In the case where SNP to be detected is present in an exon, mRNA or total RNA may be extracted instead of genomic DNA. 
     In the detection of a cyclic AMP responsive element binding protein gene polymorphism in a genome sample, the above-mentioned oligonucleotide of the present invention can be used as a probe or a primer. Hereinafter, an example of the gene polymorphism detection method will be described. 
     (1) Detection of Gene Polymorphism by PCR Method 
     In order to amplify a test sample by PCR, it is preferred that a high fidelity DNA polymerase, for example, KOD Dash polymerase (manufactured by TOYOBO) is used. A primer to be used is designed such that a target SNP in the test sample can be amplified and synthesis is carried out. It is preferred that a gene polymorphism or a strand complementary thereto is contained at a given position between the forward and reverse primers. After completion of the amplification reaction, detection of the amplified products is carried out, and the presence or absence of a gene polymorphism is determined by a sequence method or the like. 
     (2) Detection of Gene Polymorphism by Sequencing Method 
     The gene polymorphism of the present invention can also be detected by a sequencing method based on the dideoxy method. As a sequencer to be used for the sequencing, a commercially available ABI series (Applied Biosystems (Life Technologies)) can be used. 
     (3) Detection of Gene Polymorphism Using DNA Microarray 
     A DNA microarray is a microarray in which oligonucleotide probes have been immobilized on a support, and includes a DNA chip, a Gene chip, a microchip, a bead array and the like. First, a polynucleotide of a test sample is isolated and amplified by PCR, and then labeled with a fluorescent reporter group. Then, a labeled DNA/mRNA, or total RNA is incubated along with an array. 
     Then, this array is inserted in a scanner, and a hybridization pattern is detected. The data of the hybridization is collected as emitted light from the fluorescent reporter group bound to the probe array (i.e., incorporated in a target sequence). A probe which is completely identical with the target sequence generates a stronger signal than those having a region which is not identical with the target sequence. Because the sequence and the position of each probe on the array are known, the sequence of the target polynucleotide reacted with the probe array can be determined based on the complementarity. 
     (4) Detection of Gene Polymorphism by TaqMan PCR Method 
     The TaqMan PCR method is a method utilizing an allele specific oligonucleotide (also referred to as TaqMan probe) labeled with fluorescence and PCR with Taq DNA polymerase. The allele specific oligonucleotide is an oligonucleotide containing a gene polymorphic site. The allele specific oligonucleotide to be used in the TaqMan PCR method can be designed based on the above-mentioned gene polymorphism information. 
     (5) Detection of Gene Polymorphism by Invader Method 
     The invader method is a method of detecting a gene polymorphism by subjecting an allele specific oligonucleotide and a template to hybridization. A kit for carrying out the invader method is commercially available (for example, NanoInvader® Array (manufactured by BML, Inc.)), and it is possible to easily detect a gene polymorphism by this method. 
     7. Kit 
     The present invention provides a kit for evaluating drug sensitivity and disease vulnerability. The kit for detecting a gene polymorphism of the present invention includes one or more components necessary for carrying out the present invention. 
     For example, the kit of the present invention preferably includes a component for storing or supplying an enzyme and/or a reaction component necessary for detecting a gene polymorphism. Such a component is not limited, and examples thereof include the oligonucleotide of the present invention, an enzyme buffer solution, dNTP, a reagent for control (such as a tissue sample or a target oligonucleotide for a positive or negative control), a reagent for labeling and/or detection, a solid phase support, a written instruction manual and the like. Further, the kit of the present invention may be a partial kit including only a part of the necessary components. In this case, a user can prepare the other components. 
     The kit of the present invention can be provided as a microarray in which the above-mentioned oligonucleotide has been immobilized on a support. The microarray is one in which the oligonucleotide of the present invention has been immobilized on a support, and includes a DNA chip, a Gene chip, a microchip, a bead array and the like. 
     The kit of the present invention preferably includes an oligonucleotide which contains a cyclic AMP responsive element binding protein gene polymorphism found in the present invention and is capable of being specifically hybridized to a DNA fragment containing the gene polymorphism. 
     In the case where a gene polymorphism is determined using the kit of the present invention, for example, the blood is collected before drugs are applied to patients or the like (for example, before surgery, at the time of occurrence of cancer pain or the like), and DNA containing a cyclic AMP responsive element binding protein 1 gene is isolated. Then, this gene is reacted with an oligonucleotide in the kit, and thereby a genotype is determined. 
     From the determined genotype and gene polymorphism, a dosage regimen such as the type or administration amount of the drugs can be designed. As a result, an effect of the drugs suitable for an individual can be obtained, which is useful in the personalized medicine. For example, in the case of using morphine, it becomes possible to obtain an analgesic effect suitable for an individual, and also to suppress the side effects to the minimum. 
     Hereinafter, the present invention will be described in more detail with reference to Examples. However, the present invention is not limited to these. 
     Example 1 
     &lt;SNP Analysis and Haplotype Construction&gt; 
     (SNP Analysis) 
     Genomic DNA was extracted from the blood of humans (127 Japanese healthy subjects) by a standard method, and gene polymorphisms were identified in four subtypes (CREB1, CREB3, CREB5, and ATF2) of a human cyclic AMP responsive element binding protein. 
     With regard to the CREB1 subtype gene, an entire exon region, 5′ and 3′ flanking regions, and an intron region were analyzed. In the case of the CREB1 subtype gene, 7 gene polymorphisms in an intron region were identified in the Japanese samples. Further, 4 and 6 gene polymorphisms were found in the 5′ and 3′ flanking regions, respectively (see Table 15). As a result of linkage disequilibrium analysis, 1 linkage disequilibrium block was found in a region ranging from the 5′ flanking region to the 3′ flanking region (see  FIG. 1  and  FIG. 2 ). It was found that rs16839837, rs2360969, rs10932200, rs2551946, rs4234080 and rs7594560 were suitable as Tag SNPs representing this linkage disequilibrium block. 
     Further, in the same manner as above, with regard to the CREB3 subtype gene, an entire exon region, 5′ and 3′ flanking regions, and an intron region were analyzed. In the case of the CREB3 subtype gene, 1 gene polymorphism in an intron region, and 25 and 14 gene polymorphisms in the 5′ and 3′ flanking regions, respectively, were identified in the Japanese samples (see Table 15). As a result of linkage disequilibrium analysis, 1 linkage disequilibrium block was found in the 5′ flanking region, and 1 linkage disequilibrium block was found in a region ranging from the 5′ flanking region to the 3′ flanking region (see  FIG. 3  and  FIG. 4 ). It was found that rs1243872, rs2145925, rs2025126, GA007477, rs11541908, rs3763630, rs10814274, rsGA025684, rs10814275, rs4878628 and rs10758321 were suitable as Tag SNPs representing this linkage disequilibrium block. 
     Further, in the same manner as above, with regard to the CREB5 subtype gene, an entire exon region, 5′ and 3′ flanking regions, and an intron region were analyzed. In the case of the CREB5 subtype gene, 2 gene polymorphisms in a noncoding region of exon, 241 gene polymorphisms in an intron region, and 9 and 5 gene polymorphisms in the 5′ and 3′ flanking regions, respectively, were identified in the Japanese samples (see Table 16). As a result of linkage disequilibrium analysis performed on some of the aforementioned gene polymorphisms, 1 linkage disequilibrium block was found in the 5′ flanking region, 15 linkage disequilibrium blocks were found in the intron region, and 1 linkage disequilibrium block was found in a region ranging from the noncoding region of exon to the 3′ flanking region (see  FIG. 5  and  FIG. 6 ). It was found that rs4722778, rs177479, rs177486, rs177498, rs10229500, rs10243659, rs4722785, rs11772815, rs16874525, rs17715174, rs6953524, rs10239810, rs17156649, rs1811248, rs887623, rs740988, rs6952227, rs42695, rs1029897, rs10233653, rs6955105, rs17156699, rs177572, rs177573, rs177580, rs177581, rs12666636, rs1008262, rs310353, rs41273, rs1637457, rs17156919, rs41276, rs160375, rs17157048, rs6462098, rs10951201, rs13311248, rs10265166, rs6972081, rs12533079, rs7806547, rs6462100, rs6979352, rs721993, rs2237351 and rs3735566 were suitable as Tag SNPs representing this linkage disequilibrium block. 
     Further, in the same manner as above, with regard to the ATF2 subtype gene, an entire exon region, 5′ and 3′ flanking regions, and an intron region were analyzed. In the case of the ATF2 subtype gene, 1 gene polymorphism in a noncoding region of exon 1, 16 gene polymorphisms in an intron region, and 11 and 6 gene polymorphisms in the 5′ and 3′ flanking regions, respectively, were identified in the Japanese samples (see Table 15). As a result of linkage disequilibrium analysis, 1 linkage disequilibrium block was found in a region ranging from the 5′ flanking region to the intron region, and 1 linkage disequilibrium block was found in the 3′ flanking region (see  FIG. 7  and  FIG. 8 ). It was found that rs1153711, rs1153702, rs7583431, rs2302663, rs3845744, rs268214 and rs1982235 were suitable as Tag SNPs representing this linkage disequilibrium block. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 CREB1 gene polymorphism 
                   
                 CREB3 gene polymorphism 
                   
                 ATF2 gene polymorphism 
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Gene 
                 Major 
                 Minor 
                   
                 Gene 
                 Major 
                 Minor 
                   
                 Gene 
                 Major 
                 Minor 
               
               
                   
                 polymorphism 
                 allele:minor 
                 allele 
                   
                 polymorphism 
                 allele:minor 
                 allele 
                   
                 polymorphism 
                 allele:minor 
                 allele 
               
               
                 Position 
                 name 
                 allele 
                 frequency 
                 Position 
                 name 
                 allele 
                 frequency 
                 Position 
                 name 
                 allele 
                 frequency 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 5′ 
                 rs16839837 
                 C:T 
                 0.232 
                 5′ 
                 rs1243872 
                 G:T 
                 0.449 
                 5′ 
                 rs268174 
                 C:T 
                 0.201 
               
               
                 Flanking 
                 rs2360969 
                 C:T 
                 0.126 
                 Flanking 
                 rs2145925 
                 C:T 
                 0.39 
                 Flanking 
                 rs13030474 
                 G:T 
                 0.008 
               
               
                 region 
                 rs10932200 
                 A:C 
                 0.315 
                 region 
                 rs2025126 
                 G:A 
                 0.366 
                 region 
                 rs268237 
                 C:T 
                 0.189 
               
               
                   
                 rs2253206 
                 G:A 
                 0.315 
                   
                 rs1885373 
                 T:C 
                 0.055 
                   
                 rs1982235 
                 T:G 
                 0.398 
               
               
                 Intron 
                 rs2551640 
                 A:G 
                 0.323 
                   
                 rs1885374 
                 A:C 
                 0.051 
                   
                 rs10497435 
                 T:C 
                 0.189 
               
               
                   
                 rs11904814 
                 T:G 
                 0.319 
                   
                 GA007473 
                 T:C 
                 0.051 
                   
                 rs268231 
                 C:A 
                 0.197 
               
               
                   
                 rs16839883 
                 A:G 
                 0.181 
                   
                 rs2295794 
                 T:C 
                 0.453 
                   
                 rs268230 
                 A:C 
                 0.197 
               
               
                   
                 rs6740584 
                 C:T 
                 0.307 
                   
                 rs4879926 
                 T:C 
                 0.051 
                   
                 rs268229 
                 G:A 
                 0.197 
               
               
                   
                 rs3770704 
                 T:C 
                 0.181 
                   
                 GA007477 
                 C:T 
                 0.358 
                   
                 rs268228 
                 A:G 
                 0.205 
               
               
                   
                 rs2254137 
                 A:C 
                 0.323 
                   
                 rs867194 
                 T:C 
                 0.028 
                   
                 rs166531 
                 T:C 
                 0.189 
               
               
                   
                 rs2551645 
                 T:C 
                 0.319 
                   
                 rs11541908 
                 C:T 
                 0.283 
                   
                 rs268214 
                 T:C 
                 0.189 
               
               
                 3′ 
                 rs2551946 
                 C:A 
                 0.02 
                   
                 rs741917 
                 C:T 
                 0.028 
                 Exon 
                 rs10497434 
                 T:C 
                 0.154 
               
               
                 Flanking 
                 rs4234080 
                 C:A 
                 0.193 
                   
                 rs7862485 
                 G:A 
                 0.051 
                 Intron 
                 rs11888507 
                 C:T 
                 0.154 
               
               
                 region 
                 rs2952768 
                 T:C 
                 0.331 
                   
                 rs2756894 
                 C:A 
                 0.445 
                   
                 rs13388308 
                 C:T 
                 0.154 
               
               
                   
                 rs2709386 
                 G:A 
                 0.331 
                   
                 rs2249250 
                 T:G 
                 0.425 
                   
                 rs3755490 
                 T:C 
                 0.146 
               
               
                   
                 rs7591784 
                 G:A 
                 0.331 
                   
                 rs2295795 
                 G:A 
                 0.374 
                   
                 rs7578569 
                 G:A 
                 0.154 
               
               
                   
                 rs7594560 
                 T:C 
                 0.181 
                   
                 rs877365 
                 T:C 
                 0.445 
                   
                 rs7566401 
                 C:A 
                 0.154 
               
               
                   
                   
                   
                   
                   
                 rs2737273 
                 G:A 
                 0.413 
                   
                 rs1153676 
                 C:A 
                 0.154 
               
               
                   
                   
                   
                   
                   
                 rs2295797 
                 T:C 
                 0.374 
                   
                 rs1205399 
                 A:C 
                 0.169 
               
               
                   
                   
                   
                   
                   
                 rs2295798 
                 C:T 
                 0.008 
                   
                 rs2072538 
                 C:T 
                 0.146 
               
               
                   
                   
                   
                   
                   
                 rs1534847 
                 A:G 
                 0.37 
                   
                 rs212361 
                 A:G 
                 0.154 
               
               
                   
                   
                   
                   
                   
                 rs7873822 
                 G:T 
                 0.417 
                   
                 rs212360 
                 T:C 
                 0.154 
               
               
                   
                   
                   
                   
                   
                 rs2737274 
                 G:A 
                 0.051 
                   
                 rs1153685 
                 A:G 
                 0.154 
               
               
                   
                   
                   
                   
                   
                 rs10972567 
                 A:C 
                 0.445 
                   
                 rs12693057 
                 G:A 
                 0.154 
               
               
                   
                   
                   
                   
                   
                 rs3763630 
                 C:T 
                 0.276 
                   
                 rs212347 
                 T:C 
                 0.154 
               
               
                   
                   
                   
                   
                 Intron 
                 rs10814274 
                 C:T 
                 0.409 
                   
                 rs212349 
                 T:C 
                 0.154 
               
               
                   
                   
                   
                   
                 3′ 
                 rs3750434 
                 G:A 
                 0.402 
                   
                 rs3845744 
                 A:G 
                 0.291 
               
               
                   
                   
                   
                   
                 Flanking 
                 rs1570246 
                 G:T 
                 0.385 
                   
                 rs2302663 
                 G:A 
                 0.146 
               
               
                   
                   
                   
                   
                 region 
                 GA025684 
                 G:C 
                 0.323 
                 3′ 
                 rs35507277 
                 T:G 
                 0.008 
               
               
                   
                   
                   
                   
                   
                 rs1570248 
                 T:C 
                 0.268 
                 Flanking 
                 rs1153699 
                 G:T 
                 0.472 
               
               
                   
                   
                   
                   
                   
                 rs1570249 
                 G:A 
                 0.409 
                 region 
                 rs1153700 
                 C:G 
                 0.425 
               
               
                   
                   
                   
                   
                   
                 rs34478611 
                 G:A 
                 0.323 
                   
                 rs7583431 
                 A:C 
                 0.366 
               
               
                   
                   
                   
                   
                   
                 rs1322045 
                 A:G 
                 0.268 
                   
                 rs1153702 
                 T:C 
                 0.476 
               
               
                   
                   
                   
                   
                   
                 rs1951432 
                 G:A 
                 0.26 
                   
                 rs1153711 
                 T:G 
                 0.209 
               
               
                   
                   
                   
                   
                   
                 GA025687 
                 A:T 
                 0.264 
               
               
                   
                   
                   
                   
                   
                 rs10814275 
                 A:G 
                 0.067 
               
               
                   
                   
                   
                   
                   
                 rs10758320 
                 T:C 
                 0.264 
               
               
                   
                   
                   
                   
                   
                 rs4878628 
                 C:T 
                 0.134 
               
               
                   
                   
                   
                   
                   
                 rs10758321 
                 G:A 
                 0.394 
               
               
                   
                   
                   
                   
                   
                 rs10758322 
                 C:T 
                 0.402 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 CREB5 gene polymorphism 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Gene 
                 Major 
                   
               
               
                   
                   
                 polymorphism 
                 allele:minor 
                 Minor allele 
               
               
                   
                 Position 
                 name 
                 allele 
                 frequency 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 5′ Flanking 
                 rs4722778 
                 C:G 
                 0.256 
               
               
                   
                 region 
                 rs177479 
                 T:C 
                 0.252 
               
               
                   
                   
                 rs177480 
                 A:G 
                 0.242 
               
               
                   
                   
                 rs11981754 
                 A:G 
                 0.008 
               
               
                   
                   
                 rs177486 
                 G:A 
                 0.161 
               
               
                   
                   
                 rs177498 
                 C:T 
                 0.248 
               
               
                   
                   
                 rs849322 
                 A:G 
                 0.437 
               
               
                   
                   
                 rs177505 
                 T:G 
                 0.201 
               
               
                   
                   
                 rs2175738 
                 G:A 
                 0.161 
               
               
                   
                 Intron 
                 rs4719932 
                 A:C 
                 0.016 
               
               
                   
                   
                 rs10258745 
                 C:T 
                 0.031 
               
               
                   
                   
                 rs1013900 
                 G:T 
                 0.021 
               
               
                   
                   
                 rs6955393 
                 G:A 
                 0.035 
               
               
                   
                   
                 rs6953880 
                 A:G 
                 0.02 
               
               
                   
                   
                 rs17156573 
                 T:C 
                 0.035 
               
               
                   
                   
                 rs6960209 
                 C:T 
                 0.02 
               
               
                   
                   
                 rs17156577 
                 T:C 
                 0.039 
               
               
                   
                   
                 rs7811922 
                 A:C 
                 0.035 
               
               
                   
                   
                 rs6973453 
                 T:C 
                 0.201 
               
               
                   
                   
                 rs17156579 
                 C:T 
                 0.055 
               
               
                   
                   
                 rs1073298 
                 T:C 
                 0.201 
               
               
                   
                   
                 rs6961801 
                 C:T 
                 0.319 
               
               
                   
                   
                 rs6977728 
                 C:A 
                 0.106 
               
               
                   
                   
                 rs6978238 
                 C:T 
                 0.102 
               
               
                   
                   
                 rs13230543 
                 C:A 
                 0.248 
               
               
                   
                   
                 rs12673465 
                 A:G 
                 0.343 
               
               
                   
                   
                 rs10251129 
                 T:C 
                 0.327 
               
               
                   
                   
                 rs2391656 
                 T:C 
                 0.333 
               
               
                   
                   
                 rs6971345 
                 A:G 
                 0.327 
               
               
                   
                   
                 rs17156603 
                 A:G 
                 0.398 
               
               
                   
                   
                 rs7806362 
                 C:A 
                 0.173 
               
               
                   
                   
                 rs17642145 
                 T:C 
                 0.008 
               
               
                   
                   
                 rs10229500 
                 C:T 
                 0.138 
               
               
                   
                   
                 rs10243659 
                 C:A 
                 0.476 
               
               
                   
                   
                 rs4722785 
                 G:A 
                 0.488 
               
               
                   
                   
                 rs16874503 
                 C:T 
                 0.004 
               
               
                   
                   
                 rs11772815 
                 G:A 
                 0.331 
               
               
                   
                   
                 rs6958133 
                 G:A 
                 0.13 
               
               
                   
                   
                 rs16874525 
                 C:T 
                 0.461 
               
               
                   
                   
                 rs17715174 
                 G:C 
                 0.354 
               
               
                   
                   
                 rs10242868 
                 T:G 
                 0.205 
               
               
                   
                   
                 rs12700884 
                 G:A 
                 0.476 
               
               
                   
                   
                 rs17156635 
                 G:A 
                 0.189 
               
               
                   
                   
                 rs10239606 
                 C:T 
                 0.374 
               
               
                   
                   
                 rs16874528 
                 G:A 
                 0.008 
               
               
                   
                   
                 rs7799687 
                 C:A 
                 0.189 
               
               
                   
                   
                 rs714218 
                 G:A 
                 0.327 
               
               
                   
                   
                 rs1860759 
                 A:G 
                 0.327 
               
               
                   
                   
                 rs997908 
                 G:A 
                 0.476 
               
               
                   
                   
                 rs12112050 
                 C:T 
                 0.484 
               
               
                   
                   
                 rs2191827 
                 A:G 
                 0.484 
               
               
                   
                   
                 rs4498447 
                 T:C 
                 0.327 
               
               
                   
                   
                 rs10254657 
                 G:A 
                 0.449 
               
               
                   
                   
                 rs6953524 
                 C:T 
                 0.492 
               
               
                   
                   
                 rs10239810 
                 A:G 
                 0.307 
               
               
                   
                   
                 rs17156649 
                 G:A 
                 0.079 
               
               
                   
                   
                 rs1811248 
                 T:G 
                 0.13 
               
               
                   
                   
                 rs887623 
                 T:C 
                 0.252 
               
               
                   
                   
                 rs740988 
                 A:G 
                 0.276 
               
               
                   
                   
                 rs7794304 
                 T:C 
                 0.457 
               
               
                   
                   
                 rs42694 
                 A:G 
                 0.035 
               
               
                   
                   
                 rs6952227 
                 G:A 
                 0.291 
               
               
                   
                   
                 rs42695 
                 C:T 
                 0.244 
               
               
                   
                   
                 rs1029897 
                 T:C 
                 0.409 
               
               
                   
                   
                 rs42699 
                 A:C 
                 0.024 
               
               
                   
                   
                 rs4722793 
                 C:A 
                 0.405 
               
               
                   
                   
                 rs735101 
                 T:C 
                 0.409 
               
               
                   
                   
                 rs10233653 
                 G:A 
                 0.421 
               
               
                   
                   
                 rs6955105 
                 G:A 
                 0.465 
               
               
                   
                   
                 rs2286841 
                 C:A 
                 0.228 
               
               
                   
                   
                 rs979915 
                 C:T 
                 0.012 
               
               
                   
                   
                 rs7794347 
                 C:T 
                 0.248 
               
               
                   
                   
                 rs16874562 
                 G:T 
                 0.283 
               
               
                   
                   
                 rs17156685 
                 A:G 
                 0.087 
               
               
                   
                   
                 rs174024 
                 C:T 
                 0.268 
               
               
                   
                   
                 rs6949786 
                 G:A 
                 0.26 
               
               
                   
                   
                 rs7793437 
                 A:G 
                 0.016 
               
               
                   
                   
                 rs3757677 
                 T:C 
                 0.016 
               
               
                   
                   
                 rs6462085 
                 T:G 
                 0.016 
               
               
                   
                   
                 rs17717216 
                 T:C 
                 0.016 
               
               
                   
                   
                 rs17156694 
                 G:A 
                 0.441 
               
               
                   
                   
                 rs17156699 
                 A:G 
                 0.268 
               
               
                   
                   
                 rs177572 
                 T:C 
                 0.331 
               
               
                   
                   
                 rs177573 
                 T:C 
                 0.417 
               
               
                   
                   
                 rs6977204 
                 A:G 
                 0.48 
               
               
                   
                   
                 rs177574 
                 A:G 
                 0.047 
               
               
                   
                   
                 rs177576 
                 T:C 
                 0.327 
               
               
                   
                   
                 rs177578 
                 G:A 
                 0.012 
               
               
                   
                   
                 rs13437706 
                 C:T 
                 0.374 
               
               
                   
                   
                 rs177580 
                 C:T 
                 0.382 
               
               
                   
                   
                 rs177581 
                 C:T 
                 0.169 
               
               
                   
                   
                 rs12666636 
                 C:A 
                 0.224 
               
               
                   
                   
                 rs177584 
                 G:A 
                 0.169 
               
               
                   
                   
                 rs177585 
                 C:T 
                 0.169 
               
               
                   
                   
                 rs177588 
                 G:A 
                 0.098 
               
               
                   
                   
                 rs6462088 
                 G:A 
                 0.437 
               
               
                   
                   
                 rs7796539 
                 C:T 
                 0.004 
               
               
                   
                   
                 rs1859020 
                 A:G 
                 0.378 
               
               
                   
                   
                 rs1011384 
                 A:G 
                 0.236 
               
               
                   
                   
                 rs6462090 
                 G:T 
                 0.004 
               
               
                   
                   
                 rs12671247 
                 T:C 
                 0.154 
               
               
                   
                   
                 rs217508 
                 T:C 
                 0.398 
               
               
                   
                   
                 rs4719936 
                 G:T 
                 0.004 
               
               
                   
                   
                 rs217509 
                 G:T 
                 0.197 
               
               
                   
                   
                 rs217510 
                 T:C 
                 0.193 
               
               
                   
                   
                 rs17718257 
                 G:A 
                 0.004 
               
               
                   
                   
                 rs149591 
                 C:A 
                 0.051 
               
               
                   
                   
                 rs1910553 
                 C:A 
                 0.22 
               
               
                   
                   
                 rs217517 
                 G:A 
                 0.193 
               
               
                   
                   
                 rs217519 
                 G:A 
                 0.173 
               
               
                   
                   
                 rs2391668 
                 T:G 
                 0.382 
               
               
                   
                   
                 rs4722804 
                 G:T 
                 0.189 
               
               
                   
                   
                 rs618776 
                 A:G 
                 0.378 
               
               
                   
                   
                 rs217503 
                 C:T 
                 0.382 
               
               
                   
                   
                 rs217513 
                 C:T 
                 0.236 
               
               
                   
                   
                 rs65264 
                 C:T 
                 0.394 
               
               
                   
                   
                 rs441355 
                 G:T 
                 0.189 
               
               
                   
                   
                 rs2391670 
                 C:T 
                 0.362 
               
               
                   
                   
                 rs2391671 
                 A:G 
                 0.362 
               
               
                   
                   
                 rs216708 
                 A:G 
                 0.425 
               
               
                   
                   
                 rs11980665 
                 C:T 
                 0.173 
               
               
                   
                   
                 rs11980669 
                 C:T 
                 0.173 
               
               
                   
                   
                 rs11984308 
                 T:C 
                 0.173 
               
               
                   
                   
                 rs160346 
                 G:A 
                 0.37 
               
               
                   
                   
                 rs150607 
                 A:G 
                 0.276 
               
               
                   
                   
                 rs177594 
                 G:A 
                 0.106 
               
               
                   
                   
                 rs6969064 
                 A:G 
                 0.169 
               
               
                   
                   
                 rs150610 
                 A:G 
                 0.094 
               
               
                   
                   
                 rs216715 
                 T:C 
                 0.287 
               
               
                   
                   
                 rs10951197 
                 T:C 
                 0.39 
               
               
                   
                   
                 rs12539927 
                 A:G 
                 0.185 
               
               
                   
                   
                 rs216720 
                 A:G 
                 0.051 
               
               
                   
                   
                 rs17156823 
                 G:A 
                 0.252 
               
               
                   
                   
                 rs2078980 
                 G:A 
                 0.492 
               
               
                   
                   
                 rs216730 
                 T:G 
                 0.236 
               
               
                   
                   
                 rs13228899 
                 G:T 
                 0.201 
               
               
                   
                   
                 rs160335 
                 G:A 
                 0.496 
               
               
                   
                   
                 rs10951200 
                 G:A 
                 0.047 
               
               
                   
                   
                 rs10486588 
                 G:A 
                 0.461 
               
               
                   
                   
                 rs216735 
                 G:A 
                 0.287 
               
               
                   
                   
                 rs216737 
                 C:T 
                 0.031 
               
               
                   
                   
                 rs216743 
                 G:A 
                 0.055 
               
               
                   
                   
                 rs216744 
                 A:G 
                 0.055 
               
               
                   
                   
                 rs216747 
                 C:T 
                 0.031 
               
               
                   
                   
                 rs1976489 
                 A:G 
                 0.496 
               
               
                   
                   
                 rs150613 
                 C:T 
                 0.169 
               
               
                   
                   
                 rs17156878 
                 G:A 
                 0.232 
               
               
                   
                   
                 rs767834 
                 C:G 
                 0.437 
               
               
                   
                   
                 rs4722820 
                 G:A 
                 0.177 
               
               
                   
                   
                 rs160337 
                 C:A 
                 0.047 
               
               
                   
                   
                 rs160338 
                 G:A 
                 0.075 
               
               
                   
                   
                 rs1008262 
                 T:C 
                 0.323 
               
               
                   
                   
                 rs310353 
                 G:A 
                 0.299 
               
               
                   
                   
                 rs310359 
                 T:C 
                 0.217 
               
               
                   
                   
                 rs310361 
                 C:T 
                 0.169 
               
               
                   
                   
                 rs13233942 
                 A:G 
                 0.339 
               
               
                   
                   
                 rs310338 
                 T:C 
                 0.323 
               
               
                   
                   
                 rs41273 
                 G:A 
                 0.169 
               
               
                   
                   
                 rs1637457 
                 A:G 
                 0.22 
               
               
                   
                   
                 rs17156919 
                 G:A 
                 0.299 
               
               
                   
                   
                 rs41276 
                 A:G 
                 0.417 
               
               
                   
                   
                 rs160375 
                 A:G 
                 0.067 
               
               
                   
                   
                 rs917275 
                 A:G 
                 0.067 
               
               
                   
                   
                 rs160342 
                 A:G 
                 0.264 
               
               
                   
                   
                 rs160343 
                 T:C 
                 0.083 
               
               
                   
                   
                 rs41295 
                 C:T 
                 0.094 
               
               
                   
                   
                 rs160357 
                 A:G 
                 0.492 
               
               
                   
                   
                 rs41298 
                 G:A 
                 0.236 
               
               
                   
                   
                 rs41305 
                 G:A 
                 0.402 
               
               
                   
                   
                 rs41307 
                 C:T 
                 0.425 
               
               
                   
                   
                 rs10228740 
                 A:G 
                 0.126 
               
               
                   
                   
                 rs3888613 
                 G:A 
                 0.205 
               
               
                   
                   
                 rs41320 
                 C:T 
                 0.323 
               
               
                   
                   
                 rs41321 
                 A:G 
                 0.402 
               
               
                   
                   
                 rs41322 
                 A:G 
                 0.335 
               
               
                   
                   
                 rs7780656 
                 G:T 
                 0.063 
               
               
                   
                   
                 rs41327 
                 A:G 
                 0.343 
               
               
                   
                   
                 rs42322 
                 T:C 
                 0.331 
               
               
                   
                   
                 rs41333 
                 A:G 
                 0.331 
               
               
                   
                   
                 rs9655280 
                 A:G 
                 0.063 
               
               
                   
                   
                 rs9655281 
                 G:A 
                 0.063 
               
               
                   
                   
                 rs4719945 
                 A:G 
                 0.307 
               
               
                   
                   
                 rs6945988 
                 A:G 
                 0.413 
               
               
                   
                   
                 rs10258405 
                 T:G 
                 0.185 
               
               
                   
                   
                 rs10243376 
                 G:A 
                 0.185 
               
               
                   
                   
                 rs41334 
                 T:C 
                 0.429 
               
               
                   
                   
                 rs10245004 
                 C:T 
                 0.189 
               
               
                   
                   
                 rs41339 
                 G:T 
                 0.317 
               
               
                   
                   
                 rs982947 
                 C:T 
                 0.181 
               
               
                   
                   
                 rs982950 
                 A:G 
                 0.181 
               
               
                   
                   
                 rs16874653 
                 A:G 
                 0.28 
               
               
                   
                   
                 rs41346 
                 G:T 
                 0.02 
               
               
                   
                   
                 rs41348 
                 A:G 
                 0.386 
               
               
                   
                   
                 rs9969149 
                 C:T 
                 0.339 
               
               
                   
                   
                 rs6968464 
                 G:A 
                 0.02 
               
               
                   
                   
                 rs886816 
                 G:A 
                 0.181 
               
               
                   
                   
                 rs757980 
                 A:G 
                 0.035 
               
               
                   
                   
                 rs41351 
                 G:A 
                 0.083 
               
               
                   
                   
                 rs9691873 
                 A:C 
                 0.098 
               
               
                   
                   
                 rs17157048 
                 A:C 
                 0.087 
               
               
                   
                   
                 rs6462098 
                 T:C 
                 0.122 
               
               
                   
                   
                 rs10951201 
                 C:A 
                 0.154 
               
               
                   
                   
                 rs13311248 
                 G:C 
                 0.146 
               
               
                   
                   
                 rs12540480 
                 T:C 
                 0.063 
               
               
                   
                   
                 rs10265166 
                 G:T 
                 0.043 
               
               
                   
                   
                 rs7798774 
                 T:C 
                 0.087 
               
               
                   
                   
                 rs7799246 
                 T:C 
                 0.059 
               
               
                   
                   
                 rs6972081 
                 T:C 
                 0.287 
               
               
                   
                   
                 rs7777929 
                 T:C 
                 0.037 
               
               
                   
                   
                 rs12533079 
                 T:G 
                 0.079 
               
               
                   
                   
                 rs7806547 
                 G:A 
                 0.157 
               
               
                   
                   
                 rs6462100 
                 G:A 
                 0.134 
               
               
                   
                   
                 rs6979352 
                 C:T 
                 0.012 
               
               
                   
                   
                 rs6950574 
                 A:G 
                 0.13 
               
               
                   
                   
                 rs4722835 
                 A:C 
                 0.13 
               
               
                   
                   
                 rs9648352 
                 A:G 
                 0.028 
               
               
                   
                   
                 rs879593 
                 A:C 
                 0.138 
               
               
                   
                   
                 rs879591 
                 G:T 
                 0.15 
               
               
                   
                   
                 rs2299110 
                 C:T 
                 0.228 
               
               
                   
                   
                 rs2237349 
                 C:T 
                 0.272 
               
               
                   
                   
                 rs2066979 
                 T:C 
                 0.276 
               
               
                   
                   
                 rs10486589 
                 A:G 
                 0.039 
               
               
                   
                   
                 rs10486591 
                 G:A 
                 0.272 
               
               
                   
                   
                 rs6462103 
                 C:T 
                 0.118 
               
               
                   
                   
                 rs721993 
                 C:T 
                 0.154 
               
               
                   
                   
                 rs2237351 
                 T:C 
                 0.091 
               
               
                   
                   
                 rs740315 
                 G:A 
                 0.004 
               
               
                   
                   
                 rs2237353 
                 A:C 
                 0.238 
               
               
                   
                   
                 rs2073537 
                 T:C 
                 0.217 
               
               
                   
                   
                 rs4722844 
                 G:T 
                 0.181 
               
               
                   
                   
                 rs17730621 
                 C:T 
                 0.327 
               
               
                   
                   
                 rs2282907 
                 G:A 
                 0.24 
               
               
                   
                   
                 rs10238623 
                 G:A 
                 0.193 
               
               
                   
                   
                 rs2299116 
                 C:A 
                 0.091 
               
               
                   
                   
                 rs2299117 
                 T:C 
                 0.154 
               
               
                   
                   
                 rs2237355 
                 A:G 
                 0.366 
               
               
                   
                   
                 rs2237360 
                 T:G 
                 0.268 
               
               
                   
                   
                 rs2237361 
                 T:C 
                 0.217 
               
               
                   
                   
                 rs2237362 
                 T:C 
                 0.106 
               
               
                   
                   
                 rs7791555 
                 G:T 
                 0.272 
               
               
                   
                   
                 rs2237364 
                 A:G 
                 0.26 
               
               
                   
                   
                 rs2282909 
                 T:G 
                 0.366 
               
               
                   
                   
                 rs2282910 
                 C:T 
                 0.366 
               
               
                   
                   
                 rs2282911 
                 T:C 
                 0.366 
               
               
                   
                   
                 rs1544470 
                 A:G 
                 0.362 
               
               
                   
                   
                 rs1964240 
                 A:C 
                 0.293 
               
               
                   
                   
                 rs17669844 
                 T:C 
                 0.008 
               
               
                   
                   
                 rs886750 
                 A:G 
                 0.354 
               
               
                   
                   
                 rs12531253 
                 G:A 
                 0.272 
               
               
                   
                   
                 rs10951205 
                 A:G 
                 0.374 
               
               
                   
                 Exon 
                 rs2190305 
                 A:G 
                 0.374 
               
               
                   
                   
                 rs3735566 
                 G:A 
                 0.039 
               
               
                   
                 3′ Flanking 
                 rs11975539 
                 G:A 
                 0.039 
               
               
                   
                 region 
                 rs6462107 
                 C:T 
                 0.039 
               
               
                   
                   
                 rs2190306 
                 T:C 
                 0.043 
               
               
                   
                   
                 rs4719955 
                 T:C 
                 0.047 
               
               
                   
                   
                 rs10228137 
                 C:A 
                 0.051 
               
               
                   
                   
               
            
           
         
       
     
     In Table 15 and Table 16, there is not found any polymorphism causing amino acid substitution, namely, a polymorphism in which the type of amino acid after translation is changed depending on the gene polymorphism allele. 
     Moreover, in Table 15 and Table 16, “minor allele frequency” means the ratio of a minor allele. It is to be noted that the number of healthy subjects used as test subjects was 127. 
     (Haplotype Construction) 
     As some examples of haplotype analysis, with regard to the 17 sites of SNPs which are CREB1 subtype gene polymorphisms, the 40 sites of SNPs which are CREB3 subtype gene polymorphisms, the 83 sites of SNPs which are CREB5 subtype gene polymorphisms, and the 23 sites of SNPs which are ATF2 subtype gene polymorphisms, as shown in Table 15 and Table 16, among the cyclic AMP responsive element binding protein gene polymorphisms in Japanese healthy subjects, a haplotype was estimated for each linkage disequilibrium block (haplotype block), using Haploview. The estimated haplotypes are shown in Tables 17, 18, 19 and 20. It is to be noted that the “Tag” used in each table means a Tag SNP that is a representative gene polymorphism in the linkage disequilibrium block. 
     
       
         
           
               
             
               
                 TABLE 17  
               
             
            
               
                   
               
               
                 Gene name CREB1 
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
               
                   
                 1 
               
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                 1 
                 2 
                 3 
                   
                   
                   
                   
                   
                   
                   
                   
                 12 
                 13 
                   
                   
                   
                 17 
               
               
                 Haplotype No. 
                 Frequency (%) 
                 Tag 
                 Tag 
                 Tag 
                 4 
                 5 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 Tag 
                 Tag 
                 14 
                 15 
                 16 
                 Tag 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 H1 
                 16.9 
                 C 
                 C 
                 C 
                 A 
                 G 
                 G 
                 G 
                 T 
                 C 
                 C 
                 C 
                 C 
                 C 
                 C 
                 A 
                 A 
                 T 
               
               
                 H2 
                 42.5 
                 C 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 C 
                 C 
                 T 
                 G 
                 G 
                 T 
               
               
                 H3 
                 12.2 
                 C 
                 T 
                 C 
                 A 
                 G 
                 G 
                 A 
                 T 
                 T 
                 C 
                 C 
                 C 
                 C 
                 C 
                 A 
                 A 
                 T 
               
               
                 H4 
                 17.7 
                 T 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 C 
                 A 
                 T 
                 G 
                 G 
                 C 
               
               
                 H5 
                 1.6 
                 C 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 A 
                 C 
                 C 
                 A 
                 A 
                 T 
               
               
                 H6 
                 3.5 
                 T 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 C 
                 C 
                 T 
                 G 
                 G 
                 T 
               
               
                 H7 
                 1.2 
                 T 
                 C 
                 A 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 A 
                 T 
                 C 
                 A 
                 T 
                 G 
                 G 
                 T 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 
                   
                 
                 100.0% 
               
               
                   
               
               
                 () 1~17: (in this order)rs16839837, rs2360969, rs10932200, rs2253206, rs2551640, rs11904814, rs16839883, rs6740584, rs3770704, rs2254137, rs2551645, rs2551946, rs4234080, rs2952768, rs2709386, rs7591784 and rs7594560 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18  
               
               
                   
               
               
                 Gene name CREB3 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                   
                 Linkage disequilibrium block No. 
               
               
                   
                   
                 1 
               
               
                 Hap- 
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 lotype 
                 Frequen- 
                 1 
                 2 
                 3 
                   
                   
                   
                   
                   
                 9 
                   
                 11 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
                 Tag 
                 4 
                 5 
                 6 
                 7 
                 8 
                 Tag 
                 10 
                 Tag 
                 12 
                 13 
                 14 
                 15 
                 16 
                 17 
                 18 
                 19 
                 20 
                 21 
                 22 
                 23 
                 24 
               
               
                   
               
               
                 H1 
                 18.9 
                 G 
                 C 
                 G 
                 T 
                 A 
                 T 
                 T 
                 T 
                 C 
                 T 
                 C 
                 C 
                 G 
                 C 
                 T 
                 G 
                 T 
                 G 
                 T 
                 C 
                 A 
                 G 
                 G 
                 A 
               
               
                 H2 
                 35.4 
                 G 
                 C 
                 G 
                 T 
                 A 
                 T 
                 T 
                 T 
                 T 
                 T 
                 C 
                 C 
                 G 
                 C 
                 T 
                 G 
                 T 
                 G 
                 T 
                 C 
                 A 
                 G 
                 G 
                 A 
               
               
                 H3 
                 25.6 
                 T 
                 T 
                 A 
                 T 
                 A 
                 T 
                 C 
                 T 
                 C 
                 T 
                 T 
                 C 
                 G 
                 A 
                 G 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
                 T 
                 G 
                 C 
               
               
                 H4 
                 8.3 
                 T 
                 T 
                 A 
                 T 
                 A 
                 T 
                 C 
                 T 
                 C 
                 T 
                 C 
                 C 
                 G 
                 A 
                 G 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
                 T 
                 G 
                 C 
               
               
                 H5 
                 4.3 
                 T 
                 C 
                 G 
                 C 
                 C 
                 C 
                 C 
                 C 
                 C 
                 T 
                 C 
                 C 
                 A 
                 A 
                 G 
                 G 
                 C 
                 A 
                 T 
                 C 
                 A 
                 T 
                 A 
                 C 
               
               
                 H6 
                 2.8 
                 T 
                 T 
                 G 
                 T 
                 A 
                 T 
                 C 
                 T 
                 C 
                 C 
                 C 
                 T 
                 G 
                 A 
                 T 
                 G 
                 C 
                 G 
                 T 
                 C 
                 A 
                 G 
                 G 
                 C 
               
               
                 H7 
                 1.2 
                 T 
                 C 
                 A 
                 T 
                 A 
                 T 
                 C 
                 T 
                 C 
                 T 
                 T 
                 C 
                 G 
                 A 
                 G 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
                 T 
                 G 
                 C 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 
                   
                 
                 100.0% 
               
               
                   
               
            
           
           
               
               
               
            
               
                   
                   
                 Linkage disequilibrium block No. 
               
               
                   
                   
                 2 
               
               
                 Hap- 
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 lotype 
                 Frequen- 
                 25 
                 26 
                   
                   
                 29 
                   
                   
                   
                   
                   
                   
                 36 
                   
                 38 
                 39 
                   
               
               
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
                 27 
                 28 
                 Tag 
                 30 
                 31 
                 32 
                 33 
                 34 
                 35 
                 Tag 
                 37 
                 Tag 
                 Tag 
                 40 
               
               
                   
               
               
                 H8 
                 12.6 
                 C 
                 C 
                 G 
                 G 
                 G 
                 C 
                 G 
                 G 
                 G 
                 A 
                 T 
                 A 
                 C 
                 C 
                 G 
                 C 
               
               
                 H9 
                 29.8 
                 C 
                 T 
                 A 
                 T 
                 G 
                 T 
                 A 
                 G 
                 A 
                 G 
                 A 
                 A 
                 T 
                 C 
                 A 
                 T 
               
               
                 H10 
                 25.9 
                 T 
                 C 
                 G 
                 G 
                 C 
                 T 
                 G 
                 A 
                 A 
                 G 
                 A 
                 A 
                 T 
                 C 
                 G 
                 C 
               
               
                 H11 
                 2.0 
                 C 
                 T 
                 A 
                 G 
                 G 
                 T 
                 A 
                 G 
                 A 
                 G 
                 A 
                 A 
                 T 
                 C 
                 G 
                 T 
               
               
                 H12 
                 6.4 
                 C 
                 C 
                 G 
                 G 
                 C 
                 T 
                 G 
                 A 
                 A 
                 G 
                 A 
                 A 
                 T 
                 C 
                 G 
                 C 
               
               
                 H13 
                 6.7 
                 C 
                 T 
                 A 
                 T 
                 G 
                 T 
                 A 
                 G 
                 A 
                 G 
                 A 
                 G 
                 T 
                 C 
                 A 
                 T 
               
               
                 H14 
                 12.2 
                 C 
                 C 
                 G 
                 G 
                 G 
                 C 
                 G 
                 G 
                 G 
                 A 
                 T 
                 A 
                 C 
                 T 
                 G 
                 C 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 
                   
                 
                 100.0% 
               
               
                   
               
               
                 () 1~40: (in this order)rs1243872, rs2145925, rs2025126, rs1885373, rs1885374, GA007473, rs2295794, rs4879926, GA007477, rs867194, rs11541908, rs741917, rs7862485, rs2756894, rs2249250, rs2295795, rs877365, rs2737273, rs2295797, rs2295798, rs1534847, rs7873822, rs2737274, rs10972567, rs3763630, rs10814274, rs3750434, rs1570246, GA025684, rs1570248, rs1570249, rs34478611, rs1322045, rs1951432, GA025687, rs10814275, rs10758320, rs4878628, rs10758321 and rs10758322 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 19  
               
               
                   
               
               
                 Gene name CREB5 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 1 
                   
                 5 
                   
                 6 
                   
                 9 
                   
                 10 
               
            
           
           
               
               
            
               
                 Hap- 
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 lotype 
                 Frequen- 
                 1 
                 2 
                   
                   
                 5 
                 6 
                 H 
                 Frequen- 
                 7 
                 8 
                 9 
                   
                 11 
                   
                 H 
                 Frequen- 
                 13 
                 14 
                 H 
                 Frequen- 
                 15 
                 16 
                 H 
                 Frequen- 
                 17 
                 18 
               
               
                 (H) No. 
                 cy (%) 
                 Tag 
                 Tag 
                 3 
                 4 
                 Tag 
                 Tag 
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
                 Tag 
                 10 
                 Tag 
                 12 
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
               
               
                   
               
               
                 H1 
                 73.2 
                 C 
                 T 
                 A 
                 A 
                 G 
                 C 
                 H6 
                 33.1 
                 C 
                 C 
                 G 
                 C 
                 A 
                 G 
                 H11 
                 46.1 
                 T 
                 G 
                 H14 
                 49.2 
                 T 
                 A 
                 H17 
                 87.0 
                 G 
                 T 
               
               
                 H2 
                 6.7 
                 G 
                 C 
                 G 
                 A 
                 G 
                 T 
                 H7 
                 33.8 
                 C 
                 A 
                 A 
                 C 
                 G 
                 G 
                 H12 
                 35.4 
                 C 
                 C 
                 H15 
                 20.1 
                 C 
                 A 
                 H18 
                 5.1 
                 G 
                 G 
               
               
                 H3 
                 16.1 
                 G 
                 C 
                 G 
                 A 
                 A 
                 T 
                 H8 
                 16.5 
                 C 
                 C 
                 G 
                 C 
                 G 
                 G 
                 H13 
                 18.5 
                 C 
                 G 
                 H16 
                 30.7 
                 C 
                 G 
                 H19 
                 7.9 
                 A 
                 G 
               
               
                 H4 
                 1.2 
                 C 
                 C 
                 G 
                 A 
                 G 
                 T 
                 H9 
                 12.6 
                 T 
                 A 
                 A 
                 C 
                 G 
                 A 
                 . . . 
                   
                   
                   
                 . . . 
                   
                   
                   
                 . . . 
               
               
                 H5 
                 1.2 
                 G 
                 C 
                 G 
                 A 
                 G 
                 C 
                 H10 
                 2.0 
                 C 
                 C 
                 A 
                 C 
                 G 
                 G 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 
                   
                 
                 100.0% 
                   
                   
                   
                   
                   
                   
                   
                 100.0% 
                   
                   
                   
                   
                   
                   
                   
                 100.0% 
                   
                   
                   
                 100.0% 
                   
                   
                   
                 100.0% 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 11 
                   
                 12 
                   
                 13 
                   
                 15 
                   
                 16 
               
            
           
           
               
               
            
               
                 Hap- 
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 lotype 
                 Frequen- 
                 19 
                 20 
                 H 
                 Frequen- 
                 21 
                 22 
                 23 
                 H 
                 Frequen- 
                 24 
                 25 
                 H 
                 Frequen- 
                 26 
                 27 
                 28 
                 H 
                 Frequen- 
                 29 
                 30 
                 31 
                   
                   
               
               
                 (H) No. 
                 cy (%) 
                 Tag 
                 Tag 
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
                 Tag 
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
                 Tag 
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
                 Tag 
                 32 
                 33 
               
               
                   
               
               
                 H20 
                 71.2 
                 T 
                 A 
                 H24 
                 40.1 
                 G 
                 C 
                 C 
                 H28 
                 42.1 
                 A 
                 A 
                 H31 
                 26.8 
                 G 
                 T 
                 C 
                 H35 
                 60.6 
                 C 
                 C 
                 C 
                 G 
                 C 
               
               
                 H21 
                 3.6 
                 T 
                 G 
                 H25 
                 6.4 
                 G 
                 C 
                 T 
                 H29 
                 4.3 
                 G 
                 A 
                 H32 
                 33.1 
                 A 
                 C 
                 T 
                 H36 
                 21.3 
                 T 
                 C 
                 A 
                 G 
                 C 
               
               
                 H22 
                 24.0 
                 C 
                 G 
                 H26 
                 28.7 
                 A 
                 C 
                 T 
                 H30 
                 53.5 
                 G 
                 G 
                 H33 
                 25.2 
                 A 
                 T 
                 T 
                 H37 
                 1.2 
                 C 
                 C 
                 A 
                 G 
                 C 
               
               
                 H23 
                 1.2 
                 C 
                 A 
                 H27 
                 24.0 
                 G 
                 T 
                 T 
                 . . . 
                   
                   
                   
                 H34 
                 15.0 
                 A 
                 T 
                 C 
                 H38 
                 16.9 
                 T 
                 T 
                 C 
                 A 
                 T 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 
                   
                 
                 100.0% 
                   
                   
                   
                 100.0% 
                   
                   
                   
                   
                 100.0% 
                   
                   
                   
                 100.0% 
                   
                   
                   
                   
                 100.0% 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 25 
                   
                 26 
                   
                 27 
                   
                 32 
               
            
           
           
               
               
            
               
                 Hap- 
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 lotype 
                 Frequen- 
                 34 
                 35 
                 H 
                 Frequen- 
                 36 
                 37 
                 38 
                 39 
                 H 
                 Frequen- 
                 40 
                   
                 H 
                 Frequen- 
                 42 
                 43 
                 44 
                 45 
                   
                 47 
                   
                   
                 50 
               
               
                 (H) No. 
                 cy (%) 
                 Tag 
                 Tag 
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 No. 
                 cy (%) 
                 Tag 
                 41 
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 46 
                 Tag 
                 48 
                 49 
                 Tag 
               
               
                   
               
               
                 H39 
                 29.9 
                 T 
                 A 
                 H42 
                 41.7 
                 G 
                 A 
                 G 
                 G 
                 H47 
                 93.3 
                 A 
                 A 
                 H49 
                 58.7 
                 A 
                 T 
                 C 
                 G 
                 T 
                 G 
                 T 
                 T 
                 T 
               
               
                 H40 
                 32.3 
                 C 
                 G 
                 H43 
                 29.9 
                 G 
                 A 
                 A 
                 A 
                 H48 
                 6.7 
                 G 
                 G 
                 H50 
                 13.0 
                 A 
                 T 
                 C 
                 G 
                 T 
                 G 
                 T 
                 T 
                 C 
               
               
                 H41 
                 37.8 
                 T 
                 G 
                 H44 
                 16.9 
                 A 
                 G 
                 G 
                 A 
                 . . . 
                   
                   
                   
                 H51 
                 5.4 
                 A 
                 T 
                 A 
                 C 
                 C 
                 G 
                 T 
                 C 
                 C 
               
               
                 . . . 
                   
                   
                   
                 H45 
                 6.3 
                 G 
                 A 
                 G 
                 A 
                   
                   
                   
                   
                 H52 
                 4.3 
                 C 
                 T 
                 A 
                 C 
                 T 
                 T 
                 C 
                 T 
                 C 
               
               
                   
                   
                   
                   
                 H46 
                 5.1 
                 G 
                 G 
                 G 
                 A 
                   
                   
                   
                   
                 H53 
                 4.3 
                 C 
                 T 
                 A 
                 C 
                 T 
                 G 
                 C 
                 T 
                 C 
               
               
                   
                   
                   
                   
                 . . . 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 H54 
                 12.2 
                 A 
                 C 
                 C 
                 G 
                 T 
                 G 
                 T 
                 T 
                 T 
               
               
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                 H55 
                 1.2 
                 A 
                 T 
                 A 
                 G 
                 T 
                 G 
                 T 
                 T 
                 C 
               
            
           
           
               
               
            
               
                   
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 
                   
                 
                 100.0% 
                   
                   
                   
                 100.0% 
                   
                   
                   
                   
                   
                 100.0% 
                   
                   
                   
                 100.0% 
               
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 33 
                   
                 35 
                   
                 40 
               
            
           
           
               
               
            
               
                 Hap- 
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 lotype 
                 Frequen- 
                 51 
                 52 
                 53 
                 54 
                   
                   
                 H 
                 Frequen- 
                 57 
                 58 
                 H 
                 Frequen- 
                 59 
                   
                   
                   
                   
                   
               
               
                 (H) No. 
                 cy (%) 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 55 
                 56 
                 No. 
                 cy (%) 
                 Tag 
                 Tag 
                 No. 
                 cy (%) 
                 Tag 
                 60 
                 61 
                 62 
                 63 
                 64 
               
               
                   
               
               
                 H56 
                 83.4 
                 T 
                 G 
                 G 
                 C 
                 A 
                 A 
                 H61 
                 84.6 
                 C 
                 T 
                 H64 
                 94.5 
                 G 
                 G 
                 C 
                 T 
                 T 
                 C 
               
               
                 H57 
                 1.2 
                 T 
                 A 
                 A 
                 T 
                 G 
                 C 
                 H62 
                 9.1 
                 T 
                 C 
                 H65 
                 3.9 
                 A 
                 A 
                 T 
                 C 
                 C 
                 A 
               
               
                 H58 
                 7.5 
                 G 
                 A 
                 A 
                 C 
                 G 
                 C 
                 H63 
                 6.3 
                 T 
                 T 
                 . . . 
               
               
                 H59 
                 2.8 
                 T 
                 A 
                 G 
                 C 
                 A 
                 A 
                 . . . 
               
               
                 H60 
                 4.3 
                 T 
                 A 
                 A 
                 C 
                 G 
                 C 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 
                   
                 
                 100.0% 
                   
                   
                   
                   
                   
                   
                   
                 100.0% 
                   
                   
                   
                 100.0% 
               
               
                   
               
               
                 () 1~64: (in this order)rs4722778, rs177479, rs177480, rs11981754, rs177486, rs177498, rs10229500, rs10243659, rs4722785, rs16874503, rs11772815, rs6958133, rs16874525, rs17715174, rs6953524, rs10239810, rs17156649, rs1811248, rs887623, rs740988, rs6952227, rs42695, rs1029897, rs10233653, rs6955105, rs17156699, rs177572, rs177573, rs177580, rs177581, rs12666636, rs177584, rs177585, rs1008262, rs310353, rs41273, rs1637457, rs17156919, rs41276, rs160375, rs917275, rs17157048, rs6462098, rs10951201, rs13311248, rs12540480, rs10265166, rs7798774, rs7799246, rs6972081, rs12533079, rs7806547, rs6462100, rs6979352, rs6950574, rs4722835, rs721993, rs2237351, rs3735566, rs11975539, rs6462107, rs2190306, rs4719955 and rs10228137 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 20  
               
               
                   
               
               
                 Gene name ATF2 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                   
                 Linkage disequilibrium block No. 
               
            
           
           
               
               
               
            
               
                   
                 1 
                 2 
               
            
           
           
               
               
            
               
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                 1 
                 2 
                 3 
                 4 
                 5 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 Haplotype No. 
                 Frequency (%) 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 Tag 
                 6 
                 7 
                 8 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
                 15 
                 16 
               
               
                   
               
               
                 H1 
                 26.3 
                 T 
                 C 
                 A 
                 A 
                 G 
                 C 
                 C 
                 A 
                 G 
                 C 
                 G 
                 T 
                 C 
                 A 
                 A 
                 A 
               
               
                 H2 
                 20.9 
                 G 
                 C 
                 A 
                 G 
                 G 
                 T 
                 T 
                 G 
                 A 
                 T 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
               
               
                 H3 
                 36.2 
                 T 
                 T 
                 C 
                 G 
                 A 
                 T 
                 T 
                 G 
                 A 
                 T 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
               
               
                 H4 
                 16.2 
                 T 
                 T 
                 A 
                 G 
                 A 
                 T 
                 T 
                 G 
                 A 
                 T 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
               
               
                   
                   
                   
                   
                   
                 G 
                 G 
                 T 
                 T 
                 G 
                 A 
                 T 
                 A 
                 C 
                 A 
                 C 
                 C 
                 G 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 
                   
                 
                 100.0% 
               
               
                   
               
            
           
           
               
               
               
            
               
                   
                   
                 Linkage disequilibrium block No. 
               
               
                   
                   
                 2 
               
               
                   
                   
                 Gene polymorphism name () 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                   
                 21 
                   
                   
                   
                   
                   
                   
                 28 
                   
                   
                   
               
               
                 Haplotype No. 
                 Frequency (%) 
                 17 
                 18 
                 19 
                 20 
                 Tag 
                 22 
                 23 
                 24 
                 25 
                 26 
                 27 
                 Tag 
                 29 
                 30 
                 31 
               
               
                   
               
               
                 H5 
                 14.6 
                 C 
                 T 
                 T 
                 C 
                 C 
                 C 
                 G 
                 A 
                 C 
                 A 
                 C 
                 T 
                 T 
                 G 
                 T 
               
               
                 H6 
                 8.8 
                 T 
                 C 
                 C 
                 T 
                 T 
                 T 
                 A 
                 G 
                 A 
                 C 
                 T 
                 G 
                 C 
                 G 
                 C 
               
               
                 H7 
                 40.3 
                 T 
                 C 
                 C 
                 T 
                 T 
                 T 
                 A 
                 G 
                 A 
                 C 
                 T 
                 T 
                 C 
                 G 
                 C 
               
               
                 H8 
                 28.3 
                 T 
                 C 
                 C 
                 T 
                 T 
                 T 
                 A 
                 G 
                 A 
                 C 
                 T 
                 G 
                 C 
                 G 
                 C 
               
               
                 H9 
                 4.3 
                 T 
                 C 
                 C 
                 T 
                 C 
                 C 
                 G 
                 A 
                 C 
                 A 
                 C 
                 T 
                 T 
                 G 
                 T 
               
            
           
           
               
               
            
               
                 . . . 
                 Haplotypes which are estimated to occur at a frequency of less than 1% 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 
                   
                 
                 100.0% 
               
               
                   
               
               
                 () 1~31: (in this order)rs1153711, rs1153702, rs7583431, rs2302663, rs3845744, s212349, rs212347, rs12693057, rs1153685, rs212360, rs212361, rs2072538, rs1205399, rs1153676, rs7566401, rs7578569, rs3755490, rs13388308, rs11888507, rs10497434, rs268214, rs166531, rs268228, rs268229, rs268230, rs268231, rs10497435, rs1982235, rs268237, rs13030474 and rs268174 
               
            
           
         
       
     
     As shown in Table 17, at least 7 haplotypes were estimated as the haplotype of CREB1 subtype gene polymorphism in the Japanese healthy subjects, and among these, there were 6 haplotypes observed at a high frequency of 3% or higher (haplotype Nos. H1 to H6). Incidentally, specific description regarding haplotypes which are estimated to occur at a frequency of less than 1% was omitted from Table 17. 
     In addition, as shown in Table 18, at least 14 haplotypes were estimated as the haplotype of CREB3 subtype gene polymorphism in the Japanese healthy subjects, and among these, there were 11 haplotypes observed at a high frequency of 3% or higher (haplotype Nos. H1 to H5, H8 to H10, and H12 to H14). Incidentally, specific description regarding haplotypes which are estimated to occur at a frequency of less than 1% was omitted from Table 18. 
     Moreover, as shown in Table 19, at least 65 haplotypes were estimated as the haplotype of CREB5 subtype gene polymorphism in the Japanese healthy subjects, and among these, there were 57 haplotypes observed at a high frequency of 3% or higher (haplotype Nos. H1 to H3, H6 to H9, H11 to H22, H24 to H36, H38 to H54, H56, H58, and H60 to H65). Incidentally, specific description regarding haplotypes which are estimated to occur at a frequency of less than 1% was omitted from Table 19. 
     Furthermore, as shown in Table 20, at least 9 haplotypes were estimated as the haplotype of ATF2 subtype gene polymorphism in the Japanese healthy subjects, and among these, there were 9 haplotypes observed at a high frequency of 3% or higher (haplotype Nos. H1 to H9). Incidentally, specific description regarding haplotypes which are estimated to occur at a frequency of less than 1% was omitted from Table 20. 
     As well as an analysis of the haplotype frequencies in the haplotype analysis shown in Tables 17, 18, 19 and 20, a linkage disequilibrium analysis was carried out. The results are shown in  FIG. 1  to  FIG. 8 . The linkage disequilibrium among the CREB1 subtype gene polymorphisms in the Japanese healthy subjects is shown in  FIG. 1  and  FIG. 2 . In addition, the linkage disequilibrium among the CREB3 subtype gene polymorphisms in the Japanese healthy subjects is shown in  FIG. 3  and  FIG. 4 . Moreover, the linkage disequilibrium among the CREB5 subtype gene polymorphisms in the Japanese healthy subjects is shown in  FIG. 5  and  FIG. 6 . Furthermore, the linkage disequilibrium among the ATF2 subtype gene polymorphisms in the Japanese healthy subjects is shown in  FIG. 7  and  FIG. 8 . 
     A linkage disequilibrium block was estimated from the results of the linkage disequilibrium analysis ( FIG. 1  to  FIG. 8 ) using Haploview. 
     In  FIG. 1 , a D′ value, which is an index of a linkage disequilibrium between SNP and SNP, is calculated, and the resulting value (two places of decimals) is written in the square at the intersection of squares continued from each SNP to the lower left direction or the lower right direction. Further, an r 2  value, which is a more stringent index of the linkage disequilibrium, is calculated in the same manner, and the resulting value is written in the same square as defined above in  FIG. 2 . It is to be noted that the square in which no numbers are written indicates that the D′ or r 2  value is 1. Also, the same shall apply to  FIGS. 3 and 4 ,  FIGS. 5 and 6 , and  FIGS. 7 and 8 . 
     When focusing attention on the D′ values in  FIG. 1 , a complete linkage disequilibrium (D′=1) was observed in many combinations of gene polymorphisms. Further, when focusing attention on the r 2  values in  FIG. 2 , it was found that several gene polymorphisms showed a strong linkage disequilibrium (r 2 =1). It was found that suitable Tag SNPs representing these linkage disequilibrium blocks are rs16839837, rs2360969, rs10932200, rs2551946, rs4234080 and rs7594560. 
     In addition, when focusing attention on the D′ values in  FIG. 3 , a complete linkage disequilibrium (D′=1) was observed in many combinations of gene polymorphisms. Further, when focusing attention on the r 2  values in  FIG. 4 , it was found that several gene polymorphisms showed a strong linkage disequilibrium (r 2 =1). It was found that suitable Tag SNPs representing these linkage disequilibrium blocks are rs1243872, rs2145925, rs2025126, GA007477, rs11541908, rs3763630, rs10814274, rsGA025684, rs10814275, rs4878628 and rs10758321. 
     When focusing attention on the D′ values in  FIG. 5 , a complete linkage disequilibrium (D′=1) was observed in many combinations of gene polymorphisms. Further, when focusing attention on the r 2  values in  FIG. 6 , it was found that several gene polymorphisms showed a strong linkage disequilibrium (r 2 =1). It was found that suitable Tag SNPs representing these linkage disequilibrium blocks are rs4722778, rs177479, rs177486, rs177498, rs10229500, rs10243659, rs4722785, rs11772815, rs16874525, rs17715174, rs6953524, rs10239810, rs17156649, rs1811248, rs887623, rs740988, rs6952227, rs42695, rs1029897, rs10233653, rs6955105, rs17156699, rs177572, rs177573, rs177580, rs177581, rs12666636, rs1008262, rs310353, rs41273, rs1637457, rs17156919, rs41276, rs160375, rs17157048, rs6462098, rs10951201, rs13311248, rs10265166, rs6972081, rs12533079, rs7806547, rs6462100, rs6979352, rs721993, rs2237351 and rs3735566. 
     In addition, when focusing attention on the D′ values in  FIG. 7 , a complete linkage disequilibrium (D′=1) was observed in many combinations of gene polymorphisms. Further, when focusing attention on the r 2  values in  FIG. 8 , it was found that several gene polymorphisms showed a strong linkage disequilibrium (r 2 =1). It was found that suitable Tag SNPs representing these linkage disequilibrium blocks are rs1153711, rs1153702, rs7583431, rs2302663, rs3845744, rs268214 and rs1982235. 
     Further, a linkage disequilibrium block was estimated from the results of the linkage disequilibrium analysis ( FIG. 1  to  FIG. 8 ) using Haploview. As a result, with regard to SNP in the CREB1 subtype gene shown in  FIG. 1  and  FIG. 2 , one linkage disequilibrium block was confirmed in a region ranging from the 5′ flanking region to the 3′ flanking region. In a similar manner, with regard to SNP in the CREB3 subtype gene shown in  FIG. 3  and  FIG. 4 , one linkage disequilibrium block was confirmed in the 5′ flanking region, and one linkage disequilibrium block was confirmed in a region ranging from the 5′ flanking region to the 3′ flanking region. In a similar manner, with regard to SNP in the CREB5 subtype gene shown in  FIG. 5  and  FIG. 6 , one linkage disequilibrium block was confirmed in the 5′ flanking region, 15 linkage disequilibrium blocks were confirmed in the intron region, and one linkage disequilibrium block was confirmed in a region ranging from the noncoding region of exon to the 3′ flanking region. In a similar manner, with regard to SNP in the ATF2 subtype gene shown in  FIG. 7  and  FIG. 8 , one linkage disequilibrium block was confirmed in a region ranging from the 5′ flanking region to the intron region, and one linkage disequilibrium block was confirmed in the 3′ flanking region. 
     Example 2 
     &lt;Correlation Between CREB1 Subtype Gene Polymorphism (rs10932200) and Required Administration Amount of Analgesic&gt; 
     A correlation between a cyclic AMP responsive element binding protein gene polymorphism and the required administration amount of analgesic was examined. Genomic DNA was extracted from the blood of 247 patients undergoing surgery (orthognathic surgery), and one gene polymorphism (rs10932200) in the CREB1 subtype gene was determined. Then, a correlation between these results of determination of the gene polymorphism and the required administration amount of analgesic after the surgery was analyzed. 
     Incidentally, as the analgesic, fentanyl, which is mainly administered intravenously through a PCA (patient-controlled analgesia) pump, was used. 
     As a result, as shown in the following Table 21 and  FIG. 9 , in the case of patients who had a minor allele (C) of the CREB1 subtype gene polymorphism (rs10932200) and underwent the surgery, the required administration amount (logarithmic transformation) of analgesic after the surgery was statistically significantly high in correlation with the number of alleles which they had. Accordingly, by analyzing the CREB1 subtype gene polymorphism (rs10932200), the sensitivity to analgesic can be predicted. 
     Using the median (2.222 (μg/kg)) of the required administration amounts of fentanyl in 24 hours after the surgery as a reference, a patient group with a value smaller than the reference and a patient group with a value larger than the reference were defined as a “high analgesic sensitivity group” and a “low analgesic sensitivity group,” respectively, and the groups were then stratified in terms of the rs10932200 polymorphism of the CREB1 gene. As a result, in terms of this polymorphism, 54% and 46% of patients were determined to belong to the high analgesic sensitivity group and the low analgesic sensitivity group, respectively, in the A/A patient group. In contrast, in the C/C patient group, 23% and 77% of patients were determined to belong to the high analgesic sensitivity group and the low analgesic sensitivity group, respectively. 
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 Effect of CREB1 rs10932200 polymorphism on required amount 
               
               
                 of analgesic administered in 24 hours after surgery in 
               
               
                 patients treated with analgesic in surgery (orthognathic surgery) 
               
               
                 (descriptive statistics by gender) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Number of test 
               
               
                 CREB1 
                   
                 Average 
                   
                 subjects 
               
               
                 rs10932200 
                 Gender 
                  
                 Standard deviation 
                 (subjects) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 A/A 
                 F 
                 2.47 
                 2.06 
                 77 
               
               
                   
                 M 
                 2.42 
                 2.57 
                 36 
               
               
                   
                 Total 
                 2.46 
                 2.23 
                 113 
               
               
                 A/C 
                 F 
                 3.23 
                 2.65 
                 75 
               
               
                   
                 M 
                 2.05 
                 1.97 
                 33 
               
               
                   
                 Total 
                 2.87 
                 2.51 
                 108 
               
               
                 C/C 
                 F 
                 4.37 
                 3.32 
                 13 
               
               
                   
                 M 
                 4.94 
                 2.70 
                 13 
               
               
                   
                 Total 
                 4.65 
                 2.98 
                 26 
               
               
                 Total 
                 F 
                 2.96 
                 2.50 
                 165 
               
               
                   
                 M 
                 2.67 
                 2.54 
                 82 
               
               
                   
                 Total 
                 2.87 
                 2.51 
                 247 
               
               
                   
               
               
                  Required administration amount (μg/kg) of analgesic in 24 hours after surgery 
               
            
           
         
       
     
     Example 3 
     &lt;Correlation Between CREB1 Subtype Gene Polymorphism (rs10932200) and Pain Sensitivity&gt; 
     A correlation between a cyclic AMP responsive element binding protein gene polymorphism and pain sensitivity was examined. Genomic DNA was extracted from the blood of 247 patients undergoing surgery (orthognathic surgery), and one gene polymorphism (rs10932200) in the CREB1 subtype gene was determined. Then, a correlation between these results of determination of the gene polymorphism and the measurement of pain perception latency due to finger immersion in ice water before the surgery was analyzed. 
     As a result, as shown in the following Table 22 and  FIG. 10 , in the case of patients who had a minor allele (C) of the CREB1 subtype gene polymorphism (rs10932200) and underwent the surgery, the measurement result (logarithmic transformation) of pain perception latency was statistically significantly low in correlation with the number of alleles which they had. Accordingly, by analyzing the CREB1 subtype gene polymorphism (rs10932200), the sensitivity to pain can be predicted. 
     Using the median (15 sec) of the measurement results of pain perception latency due to finger immersion in ice water before the surgery as a reference, a patient group with a value smaller than the reference and a patient group with a value larger than the reference were defined as a “high pain sensitivity group” and a “low pain sensitivity group,” respectively, and the groups were then stratified in terms of the rs10932200 polymorphism of the CREB1 gene. As a result, in terms of this polymorphism, 45% and 55% of patients were determined to belong to the high pain sensitivity group and the low pain sensitivity group, respectively, in the A/A patient group. In contrast, in the A/C or C/C patient group, 55% and 45% of patients were determined to belong to the high pain sensitivity group and the low pain sensitivity group, respectively. 
     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 Effect of CREB1 rs10932200 polymorphism on 
               
               
                 measurement results of pain sensitivity before surgery in 
               
               
                 patients treated with analgesic in surgery (orthognathic surgery) 
               
               
                 (descriptive statistics by gender) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Number of test 
               
               
                 CREB1 
                   
                 Average 
                   
                 subjects 
               
               
                 rs10932200 
                 Gender 
                  
                 Standard deviation 
                 (subjects) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 A/A 
                 F 
                 20.95 
                 18.21 
                 76 
               
               
                   
                 M 
                 27.96 
                 32.07 
                 36 
               
               
                   
                 Total 
                 23.20 
                 23.65 
                 112 
               
               
                 A/C 
                 F 
                 17.83 
                 15.13 
                 75 
               
               
                   
                 M 
                 21.91 
                 17.12 
                 33 
               
               
                   
                 Total 
                 19.07 
                 15.80 
                 108 
               
               
                 C/C 
                 F 
                 12.07 
                 8.03 
                 14 
               
               
                   
                 M 
                 17.73 
                 9.86 
                 13 
               
               
                   
                 Total 
                 14.80 
                 9.24 
                 27 
               
               
                 Total 
                 F 
                 18.78 
                 16.33 
                 165 
               
               
                   
                 M 
                 23.90 
                 24.28 
                 82 
               
               
                   
                 Total 
                 20.48 
                 19.43 
                 247 
               
               
                   
               
               
                  Measurement (sec) of pain perception latency due to finger immersion in ice water before surgery 
               
            
           
         
       
     
     Example 4 
     &lt;Correlation Between CREB1 Subtype Gene Polymorphism (rs10932200) and Pain Sensitivity&gt; 
     A correlation between a cyclic AMP responsive element binding protein gene polymorphism and pain sensitivity was examined. Genomic DNA was extracted from the blood of 247 patients undergoing surgery (orthognathic surgery), and one gene polymorphism (rs10932200) in the CREB1 subtype gene was determined. Then, a correlation between these results of determination of the gene polymorphism and the measurement of the scale of the intensity of pain (VAS: on visual analogue scale) 24 hours after the surgery was analyzed. 
     As a result, as shown in the following Table 23 and  FIG. 11 , in correlation with the measurement result (logarithmic transformation) of the scale of the intensity of pain (VAS) 24 hours after the surgery, patients who had a minor allele (T) of the CREB1 subtype gene polymorphism (rs10932200) and underwent the surgery had a value of VAS (logarithmic transformation) that was statistically significantly high in correlation with the number of alleles which they had. Accordingly, by analyzing the CREB1 subtype gene polymorphism (rs10932200), the sensitivity to pain or analgesic after the surgery can be more easily predicted. 
     Using the median (24 mm) of the VAS values 24 hours after the surgery as a reference, a patient group with a value smaller than the reference and a patient group with a value larger than the reference were defined as a “low pain sensitivity group” and a “high pain sensitivity group,” respectively, and the groups were then stratified in terms of the rs10932200 polymorphism of the CREB1 gene. As a result, in terms of this polymorphism, 54% and 46% of patients were determined to belong to the low pain sensitivity group and the high pain sensitivity group, respectively, in the A/A patient group. In contrast, in the A/C or C/C patient group, 47% and 53% of patients were determined to belong to the low pain sensitivity group and the high pain sensitivity group, respectively. 
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 Effect of CREB1 rs10932200 polymorphism on measurement results 
               
               
                 of VAS (intensity of pain on visual analogue scale) after surgery 
               
               
                 in patients administered with analgesic in surgery (orthognathic surgery) 
               
               
                 (descriptive statistics by gender) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Number of test 
               
               
                   
                   
                   
                 Standard 
                 subjects 
               
               
                 CREB1 rs10932200 
                 Gender 
                 Average  
                 deviation 
                 (subjects) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 A/A 
                 F 
                 24.17 
                 19.35 
                 77 
               
               
                   
                 M 
                 21.94 
                 18.59 
                 36 
               
               
                   
                 Total 
                 23.46 
                 19.06 
                 113 
               
               
                 A/C 
                 F 
                 28.51 
                 24.49 
                 75 
               
               
                   
                 M 
                 26.33 
                 20.06 
                 33 
               
               
                   
                 Total 
                 27.84 
                 23.15 
                 108 
               
               
                 C/C 
                 F 
                 37.31 
                 17.78 
                 13 
               
               
                   
                 M 
                 34.31 
                 21.78 
                 13 
               
               
                   
                 Total 
                 35.81 
                 19.54 
                 26 
               
               
                 Total 
                 F 
                 27.18 
                 21.92 
                 165 
               
               
                   
                 M 
                 25.67 
                 19.92 
                 82 
               
               
                   
                 Total 
                 26.68 
                 21.25 
                 247 
               
               
                   
               
               
                  Measurement (mm) of scale of intensity of pain by VAS after surgery 
               
            
           
         
       
     
     Example 5 
     &lt;Correlation Between ATF2 Subtype Gene Polymorphism (rs7583431) and Analgesic Effect of Fentanyl&gt; 
     A correlation between a cyclic AMP responsive element binding protein gene polymorphism and pain sensitivity was examined. Genomic DNA was extracted from the blood of 247 patients undergoing surgery (orthognathic surgery), and one gene polymorphism (rs7583431) in the ATF2 subtype gene was determined. Then, a correlation between these results of determination of the gene polymorphism and the analgesic effect of fentanyl that was evaluated based on the measurement of a difference in threshold of pain perception latency due to finger immersion in ice water after administration of an analgesic before the surgery was analyzed. 
     As a result, as shown in the following Table 24 and  FIG. 12 , in correlation with the measurement result (logarithmic transformation) of a difference in threshold of pain perception latency due to finger immersion in ice water before the surgery, patients who had a minor allele (C) of the ATF2 subtype gene polymorphism (rs7583431) and underwent the surgery had a difference in threshold of pain perception latency (logarithmic transformation) due to finger immersion in ice water before the surgery that was statistically significantly low in correlation with the number of alleles which they had. Accordingly, by analyzing the ATF2 subtype gene polymorphism (rs7583431), the sensitivity to analgesic before surgery can be more easily predicted. 
     Using the median (13 sec) of the measurement results of a difference in threshold of pain perception due to finger immersion in ice water before the surgery as a reference, a patient group with a value smaller than the reference and a patient group with a value larger than the reference were defined as a “low analgesic sensitivity group” and a “high analgesic sensitivity group,” respectively, and the groups were then stratified in terms of the rs7583431 polymorphism of the ATF2 gene. As a result, in terms of this polymorphism, 40% and 60% of patients were determined to belong to the low analgesic sensitivity group and the high analgesic sensitivity group, respectively, in the A/A patient group. In contrast, in the C/C patient group, 71% and 29% of patients were determined to belong to the low analgesic sensitivity group and the high analgesic sensitivity group, respectively. 
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 Effect of ATF2 rs7583431 polymorphism on measurement results of 
               
               
                 difference in threshold of pain sensitivity before surgery in patients 
               
               
                 treated with analgesic in surgery (orthognathic surgery) 
               
               
                 (descriptive statistics by gender) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Number of test 
               
               
                 ATF2 
                   
                   
                   
                 subjects 
               
               
                 rs7583431 
                 Gender 
                 Average  
                 Standard deviation 
                 (subjects) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 A/A 
                 F 
                 26.69 
                 32.69 
                 64 
               
               
                   
                 M 
                 34.78 
                 36.28 
                 32 
               
               
                   
                 Total 
                 29.39 
                 33.96 
                 96 
               
               
                 A/C 
                 F 
                 26.97 
                 36.11 
                 76 
               
               
                   
                 M 
                 28.73 
                 42.97 
                 44 
               
               
                   
                 Total 
                 27.62 
                 38.60 
                 120 
               
               
                 C/C 
                 F 
                 14.24 
                 25.36 
                 25 
               
               
                   
                 M 
                 12.00 
                 19.07 
                 6 
               
               
                   
                 Total 
                 13.81 
                 24.00 
                 31 
               
               
                 Total 
                 F 
                 24.93 
                 33.49 
                 165 
               
               
                   
                 M 
                 29.87 
                 39.24 
                 82 
               
               
                   
                 Total 
                 26.57 
                 35.50 
                 247 
               
               
                   
               
               
                  Measurement (sec) of difference in threshold of pain perception latency due to finger immersion in ice water before surgery 
               
            
           
         
       
     
     Example 6 
     &lt;Correlation Between Each of CREB1, CREB3, CREB5 and ATF2 Subtype Gene Polymorphisms, and Each of Required Administration Amount of Analgesic, Pain Sensitivity, and Analgesic Effect of Fentanyl&gt; 
     In the same manner as Examples 2 to 5 above, a correlation between each gene polymorphism of the cyclic AMP responsive element binding protein gene, and each of the required administration amount of analgesic, pain sensitivity, and the analgesic effect of fentanyl was examined. Genomic DNA was extracted from the blood of 355 patients undergoing surgery (orthognathic surgery), and gene polymorphisms in the CREB1, CREB3, CREB5 and ATF2 subtype genes (Tag SNPs in linkage disequilibrium blocks and individual SNPs outside of the linkage disequilibrium blocks) were determined. Then, a correlation between these results of determination of the gene polymorphisms, and each of the required administration amount of analgesic in 24 hours after the surgery, pain sensitivity before the surgery, pain sensitivity (VAS) 24 hours after the surgery and before the surgery, and the analgesic effect of fentanyl, was analyzed. 
     Incidentally, as the analgesic, fentanyl, which is mainly administered intravenously through a PCA (patient-controlled analgesia) pump, was used. 
     As a result, the gene polymorphisms of the CREB1, CREB3, CREB5 and ATF2 subtype genes showed a statistically significant correlation with any phenotype of the required administration amount of analgesic in 24 hours after the surgery, pain sensitivity before the surgery, pain sensitivity (VAS) 24 hours after the surgery and before the surgery, and the analgesic effect of fentanyl. Accordingly, by analyzing these gene polymorphisms, the sensitivity to analgesic, pain sensitivity, and the analgesic effect of fentanyl can be predicted. 
     The results of the present example, as well as the results of Examples 2 to 5, are collectively shown in the following Table 25. 
     
       
         
           
               
             
               
                 TABLE 25 
               
             
            
               
                   
               
               
                 Tag SNPs in linkage disequilibrium (LD) blocks and SNPs outside of LD blocks found to have significant association with phenotypes 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Gene 
                 Chromosome 
                   
                 Minor allele 
                   
                 Statistics 
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 region 
                 No. 
                 LD block No. 
                 Tag SNP 
                 Position 
                 frequency 
                 Phenotype 
                 N 
                 BETA 
                 SE 
                 R 2   
                 P 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 CREB1 
                 2 
                 1 
                 rs16839837 
                 208079256 
                 0.232 
                 Required amount of fentanyl 
                 247 
                 −0.1347 
                 0.06718 
                 0.01613 
                 0.04613 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB1 
                 2 
                 1 
                 rs2360969 
                 208081241 
                 0.126 
                 Required amount of fentanyl 
                 353 
                 0.1453 
                 0.07182 
                 0.01153 
                 0.04377 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB1 
                 2 
                 1 
                 rs10932200 
                 208095930 
                 0.315 
                 Required amount of fentanyl 
                 247 
                 0.2211 
                 0.0597 
                 0.05301 
                 0.000263 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB1 
                 2 
                 1 
                 rs10932200 
                 208095930 
                 0.315 
                 VAS 24 hours after surgery 
                 247 
                 0.3084 
                 0.1305 
                 0.02228 
                 0.01891 
               
               
                 CREB1 
                 2 
                 1 
                 rs10932200 
                 208095930 
                 0.315 
                 pain perception latency before 
                 247 
                 −0.14 
                 0.06043 
                 0.02145 
                 0.02129 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB1 
                 2 
                 1 
                 rs4234080 
                 208197346 
                 0.193 
                 Required amount of fentanyl 
                 247 
                 −0.2078 
                 0.07133 
                 0.03348 
                 0.003906 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB3 
                 9 
                 1 
                 rs2145925 
                 35679373 
                 0.39 
                 Required amount of fentanyl 
                 246 
                 −0.1258 
                 0.05884 
                 0.01838 
                 0.03358 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB3 
                 9 
                 1 
                 rs2025126 
                 35686625 
                 0.366 
                 Required amount of fentanyl 
                 247 
                 −0.1281 
                 0.06011 
                 0.01821 
                 0.03402 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB3 
                 9 
                 2 
                 rs4878628 
                 35756561 
                 0.134 
                 VAS 24 hours after surgery 
                 253 
                 −0.4888 
                 0.1739 
                 0.0305 
                 0.005343 
               
               
                 CREB5 
                 7 
                 1 
                 rs4722778 
                 28278588 
                 0.256 
                 Required amount of fentanyl 
                 126 
                 −0.2062 
                 0.09913 
                 0.03371 
                 0.03961 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs2175738 
                 28304605 
                 0.161 
                 Required amount of fentanyl 
                 126 
                 −0.3309 
                 0.1141 
                 0.06356 
                 0.0044 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs2175738 
                 28304605 
                 0.161 
                 VAS 24 hours after surgery 
                 126 
                 −0.5459 
                 0.2322 
                 0.04267 
                 0.0203 
               
               
                 CREB5 
                 7 
                 — 
                 rs17156579 
                 28327642 
                 0.055 
                 Required amount of fentanyl 
                 253 
                 −0.306 
                 0.1293 
                 0.02184 
                 0.01868 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs17156603 
                 28348671 
                 0.398 
                 pain perception latency before 
                 253 
                 −0.1105 
                 0.05533 
                 0.01564 
                 0.04692 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs17642145 
                 28355789 
                 0.008 
                 pain perception latency before 
                 247 
                 −0.7505 
                 0.319 
                 0.02209 
                 0.01943 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 5 
                 rs4722785 
                 28356666 
                 0.488 
                 Required amount of fentanyl 
                 253 
                 −0.1142 
                 0.05564 
                 0.01651 
                 0.04114 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 6 
                 rs16874525 
                 28357707 
                 0.461 
                 VAS 24 hours after surgery 
                 252 
                 0.2455 
                 0.121 
                 0.01621 
                 0.04345 
               
               
                 CREB5 
                 7 
                 10 
                 rs17156649 
                 28386945 
                 0.079 
                 Analgesic effect of fentanyl 
                 247 
                 −0.6983 
                 0.2917 
                 0.02285 
                 0.01743 
               
               
                   
                   
                   
                   
                   
                   
                 before surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs7794304 
                 28394916 
                 0.457 
                 pain perception latency before 
                 354 
                 −0.1154 
                 0.05005 
                 0.01487 
                 0.02175 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 12 
                 rs1029897 
                 28400928 
                 0.409 
                 pain perception latency before 
                 353 
                 −0.09985 
                 0.04979 
                 0.01133 
                 0.04568 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs4722793 
                 28404054 
                 0.405 
                 pain perception latency before 
                 252 
                 −0.1225 
                 0.05698 
                 0.01817 
                 0.03246 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 13 
                 rs10233653 
                 28406845 
                 0.421 
                 pain perception latency before 
                 354 
                 −0.119 
                 0.05004 
                 0.0158 
                 0.01796 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 13 
                 rs6955105 
                 28409814 
                 0.465 
                 pain perception latency before 
                 354 
                 −0.1222 
                 0.0481 
                 0.01802 
                 0.01147 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs17156685 
                 28431959 
                 0.087 
                 pain perception latency before 
                 247 
                 −0.2359 
                 0.1053 
                 0.02007 
                 0.02598 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs17156694 
                 28451480 
                 0.441 
                 pain perception latency before 
                 253 
                 −0.1379 
                 0.05492 
                 0.02449 
                 0.0127 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 15 
                 rs177572 
                 28460820 
                 0.331 
                 pain perception latency before 
                 253 
                 0.1454 
                 0.06446 
                 0.01988 
                 0.02492 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs177574 
                 28461566 
                 0.047 
                 Analgesic effect of fentanyl 
                 247 
                 0.7803 
                 0.3685 
                 0.01798 
                 0.03521 
               
               
                   
                   
                   
                   
                   
                   
                 before surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs177576 
                 28463632 
                 0.327 
                 Analgesic effect of fentanyl 
                 247 
                 0.4179 
                 0.1582 
                 0.02771 
                 0.008764 
               
               
                   
                   
                   
                   
                   
                   
                 before surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs13437706 
                 28465016 
                 0.374 
                 Analgesic effect of fentanyl 
                 253 
                 0.3854 
                 0.1501 
                 0.02559 
                 0.01083 
               
               
                   
                   
                   
                   
                   
                   
                 before surgery 
               
               
                 CREB5 
                 7 
                 16 
                 rs177580 
                 28465195 
                 0.382 
                 Analgesic effect of fentanyl 
                 253 
                 −0.3177 
                 0.1503 
                 0.01749 
                 0.03554 
               
               
                   
                   
                   
                   
                   
                   
                 before surgery 
               
               
                 CREB5 
                 7 
                 16 
                 rs12666636 
                 28465748 
                 0.224 
                 VAS 24 hours after surgery 
                 354 
                 −0.2569 
                 0.1182 
                 0.01325 
                 0.03036 
               
               
                 CREB5 
                 7 
                 — 
                 rs216715 
                 28539407 
                 0.287 
                 VAS 24 hours after surgery 
                 354 
                 −0.2213 
                 0.1069 
                 0.01202 
                 0.03923 
               
               
                 CREB5 
                 7 
                 — 
                 rs10951197 
                 28540048 
                 0.39 
                 VAS 24 hours after surgery 
                 253 
                 −0.248 
                 0.1181 
                 0.01726 
                 0.03676 
               
               
                 CREB5 
                 7 
                 — 
                 rs160335 
                 28554342 
                 0.496 
                 VAS 24 hours after surgery 
                 247 
                 0.2437 
                 0.122 
                 0.01602 
                 0.04693 
               
               
                 CREB5 
                 7 
                 25 
                 rs310353 
                 28603649 
                 0.299 
                 VAS 24 hours after surgery 
                 247 
                 −0.2846 
                 0.1258 
                 0.02047 
                 0.02451 
               
               
                 CREB5 
                 7 
                 — 
                 rs310359 
                 28606311 
                 0.217 
                 Required amount of fentanyl 
                 126 
                 0.2233 
                 0.1071 
                 0.0339 
                 0.03904 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 26 
                 rs1637457 
                 28615963 
                 0.22 
                 pain perception latency before 
                 253 
                 −0.1327 
                 0.06564 
                 0.01603 
                 0.04422 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs41348 
                 28683373 
                 0.386 
                 pain perception latency before 
                 354 
                 −0.1254 
                 0.04985 
                 0.01765 
                 0.01235 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs886816 
                 28689932 
                 0.181 
                 Required amount of fentanyl 
                 354 
                 0.1596 
                 0.06074 
                 0.01924 
                 0.008961 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 32 
                 rs17157048 
                 28703823 
                 0.087 
                 Required amount of fentanyl 
                 354 
                 −0.2175 
                 0.09867 
                 0.01361 
                 0.02816 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 32 
                 rs10951201 
                 28711867 
                 0.154 
                 Required amount of fentanyl 
                 354 
                 −0.2078 
                 0.07776 
                 0.01988 
                 0.007896 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 32 
                 rs10265166 
                 28713821 
                 0.043 
                 Analgesic effect of fentanyl 
                 253 
                 0.9373 
                 0.4605 
                 0.01624 
                 0.04285 
               
               
                   
                   
                   
                   
                   
                   
                 before surgery 
               
               
                 CREB5 
                 7 
                 32 
                 rs6972081 
                 28715571 
                 0.287 
                 pain perception latency before 
                 354 
                 −0.1289 
                 0.05762 
                 0.01402 
                 0.02588 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 33 
                 rs6462100 
                 28720620 
                 0.134 
                 Required amount of fentanyl 
                 354 
                 −0.2022 
                 0.08 
                 0.01782 
                 0.01194 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs2066979 
                 28730634 
                 0.276 
                 pain perception latency before 
                 250 
                 −0.1395 
                 0.06557 
                 0.01792 
                 0.0344 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 — 
                 rs10486591 
                 28733403 
                 0.272 
                 pain perception latency before 
                 354 
                 −0.1231 
                 0.05973 
                 0.01192 
                 0.04007 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 35 
                 rs721993 
                 28745985 
                 0.154 
                 Required amount of fentanyl 
                 354 
                 −0.1698 
                 0.07741 
                 0.01348 
                 0.02898 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 CREB5 
                 7 
                 40 
                 rs3735566 
                 28831314 
                 0.039 
                 Required amount of fentanyl 
                 247 
                 −0.2901 
                 0.1445 
                 0.01618 
                 0.04582 
               
               
                   
                   
                   
                   
                   
                   
                 administered in 24 hours after 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 ATF2 
                 2 
                 1 
                 rs1153702 
                 175629003 
                 0.476 
                 Analgesic effect of fentanyl 
                 354 
                 0.2496 
                 0.1214 
                 0.01188 
                 0.04044 
               
               
                   
                   
                   
                   
                   
                   
                 before surgery 
               
               
                 ATF2 
                 2 
                 1 
                 rs7583431 
                 175630628 
                 0.366 
                 Analgesic effect of fentanyl 
                 247 
                 −0.5442 
                 0.1582 
                 0.04606 
                 0.000685 
               
               
                   
                   
                   
                   
                   
                   
                 before surgery 
               
               
                 ATF2 
                 2 
                 — 
                 rs1153699 
                 175631032 
                 0.472 
                 Analgesic effect of fentanyl 
                 247 
                 0.3865 
                 0.1524 
                 0.02558 
                 0.01184 
               
               
                   
                   
                   
                   
                   
                   
                 before surgery 
               
               
                 ATF2 
                 2 
                 — 
                 rs1153699 
                 175631032 
                 0.472 
                 pain perception latency before 
                 247 
                 0.1173 
                 0.0577 
                 0.01659 
                 0.04312 
               
               
                   
                   
                   
                   
                   
                   
                 surgery 
               
               
                 ATF2 
                 2 
                 2 
                 rs268214 
                 175741461 
                 0.189 
                 Analgesic effect of fentanyl 
                 247 
                 0.4065 
                 0.1863 
                 0.01907 
                 0.03004 
               
               
                   
                   
                   
                   
                   
                   
                 before surgery 
               
               
                   
               
            
           
         
       
     
     Example 7 
     &lt;Correlation Between CREB1 Subtype Gene Polymorphism (rs2952768) and Required Administration Amount of Analgesic&gt; 
     A correlation between a cyclic AMP responsive element binding protein gene polymorphism and the required administration amount of analgesic was examined. Genomic DNA was extracted from the blood of 354 patients undergoing surgery (orthognathic surgery), and one gene polymorphism (rs2952768) in the CREB1 subtype gene was determined. Then, a correlation between these results of determination of the gene polymorphism and the required administration amount of analgesic after the surgery was analyzed. 
     Incidentally, as the analgesic, fentanyl, which is mainly administered intravenously through a PCA (patient-controlled analgesia) pump, was used. 
     As a result, as shown in the following Table 26 and  FIG. 13 , in the case of patients who had a minor allele (C) of the CREB1 subtype gene polymorphism (rs2952768) and underwent the surgery, the required administration amount (logarithmic transformation) of analgesic after the surgery was statistically significantly high in correlation with the number of alleles which they had. Accordingly, by analyzing the CREB1 subtype gene polymorphism (rs2952768), the sensitivity to analgesic can be predicted. 
     Using the median (2.268 (μg/kg)) of the required administration amount of fentanyl in 24 hours after the surgery as a reference, a patient group with a value smaller than the reference and a patient group with a value larger than the reference were defined as a “high analgesic sensitivity group” and a “low analgesic sensitivity group,” respectively, and the groups were then stratified in terms of the rs2952768 polymorphism of the CREB1 gene. As a result, in terms of this polymorphism, 53% and 47% of patients were determined to belong to the high analgesic sensitivity group and the low analgesic sensitivity group, respectively, in the T/T or T/C patient group. In contrast, in the C/C patient group, 22% and 78% of patients were determined to belong to the high analgesic sensitivity group and the low analgesic sensitivity group, respectively. 
     
       
         
           
               
             
               
                 TABLE 26 
               
             
            
               
                   
               
               
                 Effect of CREB1 rs2952768 polymorphism on required amount 
               
               
                 of analgesic administered in 24 hours after surgery in patients 
               
               
                 treated with analgesic in surgery (orthognathic surgery) 
               
               
                 (descriptive statistics by gender) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Number of test 
               
               
                 CREB1 
                   
                   
                   
                 subjects 
               
               
                 rs2952768 
                 Gender 
                 Average  
                 Standard deviation 
                 (subjects) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 T/T 
                 F 
                 2.78 
                 2.43 
                 101 
               
               
                   
                 M 
                 2.38 
                 2.46 
                 58 
               
               
                   
                 Total 
                 2.64 
                 2.44 
                 159 
               
               
                 T/C 
                 F 
                 2.99 
                 2.42 
                 108 
               
               
                   
                 M 
                 2.38 
                 2.50 
                 52 
               
               
                   
                 Total 
                 2.79 
                 2.46 
                 160 
               
               
                 C/C 
                 F 
                 4.80 
                 3.05 
                 20 
               
               
                   
                 M 
                 5.08 
                 2.55 
                 15 
               
               
                   
                 Total 
                 4.92 
                 2.81 
                 35 
               
               
                 Total 
                 F 
                 3.05 
                 2.53 
                 229 
               
               
                   
                 M 
                 2.71 
                 2.62 
                 125 
               
               
                   
                 Total 
                 2.93 
                 2.57 
                 354 
               
               
                   
               
               
                  Required amount (μg/kg) of analgesic administered in 24 hours after surgery 
               
            
           
         
       
     
     Example 8 
     &lt;Correlation Between CREB1 Subtype Gene Polymorphism (rs2952768) and Required Administration Amount of Analgesic&gt; 
     A correlation between a cyclic AMP responsive element binding protein gene polymorphism and the required administration amount of analgesic was examined. Genomic DNA was extracted from the blood or the oral mucosa of 112 patients undergoing surgery (abdominal surgery), and one gene polymorphism (rs2952768) in the CREB1 subtype gene was determined. Then, a correlation between these results of determination of the gene polymorphism and the required administration amount of analgesic after the surgery was analyzed. 
     Incidentally, as the analgesic, analgesics such as pentazocine and pethidine, which are mainly administered intravenously, buprenorphine, diclofenac and indomethacin, which are mainly administered as a suppository, flurbiprofen axetil, which is injected by intravenous infusion, as well as epidural morphine and marcain were used. 
     Incidentally, the total amount of each analgesic in terms of fentanyl means the total amount of analgesic (mg) in the case where the amount of each administered analgesic is converted to a value corresponding to the potency equivalent to fentanyl. The conversion of the amount of each analgesic to a value corresponding to the potency of fentanyl was carried out by setting a potency equivalent to 0.3 mg of fentanyl at 90 mg of pentazocine, 360 mg in the case of pethidine (Opystan), 1 mg in the case of buprenorphine (Lepetan), 300 mg in the case of diclofenac (Voltaren), 300 mg in the case of flurbiprofen axetil (Ropion), and 6 mg in the case of epidural morphine. 
     As a result, as shown in the following Table 27 and  FIG. 14 , in the case of patients who did not have a major allele (T) of the CREB1 subtype gene polymorphism (rs2952768) and underwent the surgery, the required administration amount (logarithmic transformation) of analgesic after the surgery was statistically significantly higher compared with patients having the aforementioned allele (T). Accordingly, by analyzing the CREB1 subtype gene polymorphism (rs2952768), the sensitivity to each analgesic can be predicted. 
     Using the median (2.453 (μg/kg)) of the required total administration amount of each analgesic in terms of fentanyl in 24 hours after the surgery as a reference, a patient group with a value smaller than the reference and a patient group with a value larger than the reference were defined as a “high analgesic sensitivity group” and a “low analgesic sensitivity group,” respectively, and the groups were then stratified in terms of the rs2952768 polymorphism of the CREB1 gene. As a result, in terms of this polymorphism, 52% and 48% of patients were determined to belong to the high analgesic sensitivity group and the low analgesic sensitivity group, respectively, in the T/T or T/C patient group. In contrast, in the C/C patient group, 33% and 67% of patients were determined to belong to the high analgesic sensitivity group and the low analgesic sensitivity group, respectively. 
     
       
         
           
               
             
               
                 TABLE 27 
               
             
            
               
                   
               
               
                 Effect of CREB1 rs2952768 polymorphism on required amount 
               
               
                 of analgesic administered in 24 hours after surgery in patients 
               
               
                 treated with analgesic in surgery (abdominal surgery) 
               
               
                 (descriptive statistics by gender) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Number of test 
               
               
                 CREB1 
                   
                   
                   
                 subjects 
               
               
                 rs2952768 
                 Gender 
                 Average  
                 Standard deviation 
                 (subjects) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 T/T 
                 F 
                 0.93 
                 1.35 
                 18 
               
               
                   
                 M 
                 0.43 
                 0.63 
                 26 
               
               
                   
                 Total 
                 0.63 
                 1.01 
                 44 
               
               
                 T/C 
                 F 
                 0.67 
                 1.32 
                 28 
               
               
                   
                 M 
                 0.78 
                 1.01 
                 28 
               
               
                   
                 Total 
                 0.72 
                 1.17 
                 56 
               
               
                 C/C 
                 F 
                 1.12 
                 1.34 
                 6 
               
               
                   
                 M 
                 1.78 
                 1.61 
                 6 
               
               
                   
                 Total 
                 1.45 
                 1.45 
                 12 
               
               
                 Total 
                 F 
                 0.81 
                 1.32 
                 52 
               
               
                   
                 M 
                 0.73 
                 1.00 
                 60 
               
               
                   
                 Total 
                 0.77 
                 1.15 
                 112 
               
               
                   
               
               
                  Required total amount (μg/kg) of analgesic administered in terms of fentanyl in 24 hours after surgery 
               
            
           
         
       
     
     Example 9 
     &lt;Correlation Between CREB1 Subtype Gene Polymorphism (rs2952768) and Severity of Drug Dependence in Methamphetamine-Dependent Patients&gt; 
     A correlation between a cyclic AMP responsive element binding protein gene polymorphism and vulnerability to drug dependence associated with the severity of drug dependence was examined. Genomic DNA was extracted from the blood of 194 methamphetamine-dependent patients, and one gene polymorphism (rs2952768) in the CREB1 subtype gene was determined. The patients were classified based on the presence or absence of the abuse of many drugs, and a comparison was made among them. The results are shown in the following Table 28. Here, the methamphetamine-dependent patients were classified into two groups, namely, a patient group involving the abuse of drugs other than stimulants (two or more types) and a patient group involving the abuse of a single drug (only one type). 
     As a result, as is clear from the following Table 28, a significant difference in genotype frequency was observed in terms of the gene polymorphism (rs2952768), and in methamphetamine-dependent patients having a major allele (T), the number of patients who abused many drugs was statistically significantly higher compared with patient who did not have the aforementioned allele T. 
     From the above results, it was demonstrated that drug sensitivity associated with the severity of stimulant dependence can be easily predicted by determining genotype frequency in the cyclic AMP responsive element binding protein gene polymorphism. 
     
       
         
           
               
             
               
                 TABLE 28 
               
             
            
               
                   
               
               
                 Comparison of genotype and allele frequencies in rs2952768 polymorphism in methamphetamine-dependent patients 
               
               
                 classified based on presence or absence of abuse of many drugs 
               
               
                 Gene polymorphism name: CREB1 rs2952768 
               
            
           
           
               
               
               
               
            
               
                   
                 (Number of samples) 
                 Genotype frequency (%) 
                 Allele frequency 
               
               
                 Sample name 
                 Abuse of many drugs 
                   T/T   T/C   C/C 
                  T   C 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Methamphetamine- dependent patients 
                 No (53)   Yes (141)  
                 
                   
                     
                       
                         
                           
                             
                               
                                 
                                   
                                     
                                       
                                         19 
                                       
                                       
                                         22 
                                       
                                       
                                         12 
                                       
                                     
                                     
                                       
                                         
                                           ( 
                                           
                                             35.8 
                                              
                                             % 
                                           
                                           ) 
                                         
                                       
                                       
                                         
                                           ( 
                                           
                                             41.5 
                                              
                                             % 
                                           
                                           ) 
                                         
                                       
                                       
                                         
                                           ( 
                                           
                                             22.6 
                                              
                                             % 
                                           
                                           ) 
                                         
                                       
                                     
                                     
                                       
                                         58 
                                       
                                       
                                         67 
                                       
                                       
                                         16 
                                       
                                     
                                   
                                   ) 
                                 
                                  
                                 
                                     
                                 
                                  
                                 
                                   
                                     
                                       
                                             
                                          
                                         
                                           ( 
                                           
                                             
                                               P 
                                               = 
                                               0.137 
                                             
                                             ; 
                                             genotype 
                                           
                                           ) 
                                         
                                       
                                     
                                   
                                   
                                     
                                       
                                             
                                          
                                         
                                           ( 
                                           
                                             
                                               P 
                                               = 
                                               0.503 
                                             
                                             ; 
                                             
                                               dominant 
                                                
                                               
                                                   
                                               
                                                
                                               model 
                                             
                                           
                                           ) 
                                         
                                       
                                     
                                   
                                   
                                     
                                       
                                         * 
                                         
                                           ( 
                                           
                                             
                                               P 
                                               = 
                                               0.046 
                                             
                                             ; 
                                             
                                               recessive 
                                                
                                               
                                                   
                                               
                                                
                                               model 
                                             
                                           
                                           ) 
                                         
                                       
                                     
                                   
                                 
                               
                             
                           
                           
                             
                               
                                   
                                  
                                 
                                   
                                     ( 
                                     
                                       41.1 
                                        
                                       % 
                                     
                                     ) 
                                   
                                    
                                   
                                       
                                   
                                    
                                   
                                     ( 
                                     
                                       47.5 
                                        
                                       % 
                                     
                                     ) 
                                   
                                    
                                   
                                       
                                   
                                    
                                   
                                     ( 
                                     
                                       11.3 
                                        
                                       % 
                                     
                                     ) 
                                   
                                 
                               
                             
                           
                         
                           
                       
                     
                   
                 
                 
                   
                     
                       
                         
                           
                             
                               
                                 0.556 
                               
                               
                                 0.444 
                               
                             
                             
                               
                                 
                                     
                                 
                               
                               
                                 
                                     
                                 
                               
                             
                             
                               
                                 0.644 
                               
                               
                                 0.356 
                               
                             
                           
                           ) 
                         
                          
                         
                             
                         
                          
                         
                           ( 
                           
                             
                               P 
                               = 
                               0.133 
                             
                             ; 
                             allele 
                           
                           ) 
                         
                       
                     
                   
                 
               
               
                   
               
               
                 Each model indicates hereditary mode regarding minor allele (C); 
               
               
                 *. P &lt; 0.05. 
               
            
           
         
       
     
     Example 10 
     &lt;Correlation Between CREB1 Subtype Gene Polymorphism (rs2952768) and Severity of Drug Dependence in Alcohol-Dependent Patients&gt; 
     A correlation between a cyclic AMP responsive element binding protein gene polymorphism and vulnerability to drug dependence associated with the severity of drug dependence was examined. Genomic DNA was extracted from the blood of 436 alcohol-dependent patients, and one gene polymorphism (rs2952768) in the CREB1 subtype gene was determined. The patients were classified based on the presence or absence of drug abuse, and a comparison was made among them. The results are shown in the following Table 29. Here, the alcohol-dependent patients were classified into two groups, namely, a patient group with drug abuse (one or more types) and a patient group without drug abuse (only alcohol ingestion). 
     As a result, as is clear from the following Table 29, a significant difference in genotype and allele frequencies was observed in terms of the gene polymorphism (rs2952768), and it was demonstrated that the frequency of major allele (T) was statistically significantly higher in the patient group with drug abuse than in the patient group without drug abuse. 
     From the above results, it was demonstrated that vulnerability to drug dependence associated with the severity of drug dependence can be easily predicted by determining genotype and allele frequencies in the cyclic AMP responsive element binding protein gene polymorphism. 
     
       
         
           
               
             
               
                 TABLE 29 
               
             
            
               
                   
               
               
                 Comparison of genotype and allele frequencies in rs2952768 polymorphism in alcohol-dependent patients 
               
               
                 classified based on presence or absence of drug abuse 
               
               
                 Gene polymorphism name: CREB1 rs2952768 
               
            
           
           
               
               
               
               
            
               
                   
                 (Number of samples) 
                 Genotype frequency (%) 
                 Allele frequency 
               
               
                 Sample name 
                 Drug abuse 
                   T/T   T/C   C/C 
                  T   C 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Alcohol- dependent patients 
                 No (391)   Yes (45)  
                 
                   
                     
                       
                         
                           
                             
                               
                                 
                                   
                                     
                                       
                                         172 
                                       
                                       
                                         166 
                                       
                                       
                                         53 
                                       
                                     
                                     
                                       
                                         
                                           ( 
                                           
                                             44.0 
                                              
                                             % 
                                           
                                           ) 
                                         
                                       
                                       
                                         
                                           ( 
                                           
                                             42.5 
                                              
                                             % 
                                           
                                           ) 
                                         
                                       
                                       
                                         
                                           ( 
                                           
                                             13.6 
                                              
                                             % 
                                           
                                           ) 
                                         
                                       
                                     
                                     
                                       
                                         25 
                                       
                                       
                                         18 
                                       
                                       
                                         2 
                                       
                                     
                                   
                                   ) 
                                 
                                  
                                 
                                     
                                 
                                  
                                 
                                   
                                     
                                       
                                            
                                          
                                         
                                           ( 
                                           
                                             
                                               P 
                                               = 
                                               0.142 
                                             
                                             ; 
                                             genotype 
                                           
                                           ) 
                                         
                                       
                                     
                                   
                                   
                                     
                                       
                                            
                                          
                                         
                                           ( 
                                           
                                             
                                               P 
                                               = 
                                               0.140 
                                             
                                             ; 
                                             
                                               dominant 
                                                
                                               
                                                   
                                               
                                                
                                               model 
                                             
                                           
                                           ) 
                                         
                                       
                                     
                                   
                                   
                                     
                                       
                                         † 
                                          
                                         
                                           ( 
                                           
                                             
                                               P 
                                               = 
                                               0.097 
                                             
                                             ; 
                                             
                                               recessive 
                                                
                                               
                                                   
                                               
                                                
                                               model 
                                             
                                           
                                           ) 
                                         
                                       
                                     
                                   
                                 
                               
                             
                           
                           
                             
                               
                                   
                                  
                                 
                                   
                                     ( 
                                     
                                       55.6 
                                        
                                       % 
                                     
                                     ) 
                                   
                                    
                                   
                                       
                                   
                                    
                                   
                                     ( 
                                     
                                       40.0 
                                        
                                       % 
                                     
                                     ) 
                                   
                                    
                                   
                                       
                                   
                                    
                                   
                                     ( 
                                     
                                       4.4 
                                        
                                       % 
                                     
                                     ) 
                                   
                                 
                               
                             
                           
                         
                           
                       
                     
                   
                 
                 
                   
                     
                       
                         
                           
                             
                               
                                 0.652 
                               
                               
                                 0.348 
                               
                             
                             
                               
                                 
                                     
                                 
                               
                               
                                 
                                     
                                 
                               
                             
                             
                               
                                 0.756 
                               
                               
                                 0.244 
                               
                             
                           
                           ) 
                         
                         * 
                         
                           ( 
                           
                             
                               P 
                               = 
                               0.049 
                             
                             ; 
                             allele 
                           
                           ) 
                         
                       
                     
                   
                 
               
               
                   
               
               
                 Each model indicates hereditary mode regarding minor allele (C); 
               
               
                 *. P &lt; 0.05. 
               
               
                 †. 0.05 ≦ P &lt; 0.1. 
               
            
           
         
       
     
     Example 11 
     &lt;Correlation Between CREB1 Subtype Gene Polymorphism (rs2952768) and Severity of Drug Dependence in Eating Disorder Patients&gt; 
     A correlation between a cyclic AMP responsive element binding protein gene polymorphism and vulnerability to drug dependence associated with the severity of drug dependence was examined. Genomic DNA was extracted from the blood of 221 patients with eating disorder, and one gene polymorphism (rs2952768) in the CREB1 subtype gene was determined. The patients were classified based on the presence or absence of drug dependence, and a comparison was made among them. The results are shown in the following Table 30. Here, the eating disorder patients were classified into two groups, namely, a patient group with a complication of drug dependence and a patient group without a complication of drug dependence. 
     As a result, as is clear from the following Table 30, a significant difference in genotype and allele frequencies was observed in terms of the gene polymorphism (rs2952768), and it was demonstrated that the frequency of major allele (T) was statistically significantly higher in the patient group with a complication of drug dependence than in the patient group without a complication of drug dependence. 
     From the above results, it was demonstrated that vulnerability to drug dependence associated with the severity of drug dependence can be easily predicted by determining genotype and allele frequencies in the cyclic AMP responsive element binding protein gene polymorphism. 
     
       
         
           
               
             
               
                 TABLE 30 
               
             
            
               
                   
               
               
                 Comparison of genotype and allele frequencies in rs2952768 polymorphism in patients with eating disorder 
               
               
                 classified based on presence or absence of complication of drug dependence 
               
               
                 Gene polymorphism name: CREB1 rs2952768 
               
            
           
           
               
               
               
               
            
               
                   
                 (Number of samples) 
                 Genotype frequency (%) 
                 Allele frequency 
               
               
                 Sample name 
                 Complication of drug 
                   T/T   T/C   C/C 
                  T   C 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Eating disorder patients 
                 No (200)   Yes (21)  
                 
                   
                     
                       
                         
                           
                             
                               
                                 
                                   
                                     
                                       
                                         85 
                                       
                                       
                                         93 
                                       
                                       
                                         22 
                                       
                                     
                                     
                                       
                                         
                                           ( 
                                           
                                             42.5 
                                              
                                             % 
                                           
                                           ) 
                                         
                                       
                                       
                                         
                                           ( 
                                           
                                             46.5 
                                              
                                             % 
                                           
                                           ) 
                                         
                                       
                                       
                                         
                                           ( 
                                           
                                             11.0 
                                              
                                             % 
                                           
                                           ) 
                                         
                                       
                                     
                                     
                                       
                                         14 
                                       
                                       
                                         6 
                                       
                                       
                                         1 
                                       
                                     
                                   
                                   ) 
                                 
                                  
                                 
                                     
                                 
                                  
                                 
                                   
                                     
                                       
                                             
                                          
                                         
                                           ( 
                                           
                                             
                                               P 
                                               = 
                                               0.103 
                                             
                                             ; 
                                             genotype 
                                           
                                           ) 
                                         
                                       
                                     
                                   
                                   
                                     
                                       
                                         * 
                                         
                                           ( 
                                           
                                             
                                               P 
                                               = 
                                               0.034 
                                             
                                             ; 
                                             
                                               dominant 
                                                
                                               
                                                   
                                               
                                                
                                               model 
                                             
                                           
                                           ) 
                                         
                                       
                                     
                                   
                                   
                                     
                                       
                                             
                                          
                                         
                                           ( 
                                           
                                             
                                               P 
                                               = 
                                               0.705 
                                             
                                             ; 
                                             
                                               recessive 
                                                
                                               
                                                   
                                               
                                                
                                               model 
                                             
                                           
                                           ) 
                                         
                                       
                                     
                                   
                                 
                               
                             
                           
                           
                             
                               
                                   
                                  
                                 
                                   
                                     ( 
                                     
                                       66.7 
                                        
                                       % 
                                     
                                     ) 
                                   
                                    
                                   
                                       
                                   
                                    
                                   
                                     ( 
                                     
                                       28.6 
                                        
                                       % 
                                     
                                     ) 
                                   
                                    
                                   
                                       
                                   
                                    
                                   
                                     ( 
                                     
                                       4.8 
                                        
                                       % 
                                     
                                     ) 
                                   
                                 
                               
                             
                           
                         
                           
                       
                     
                   
                 
                 
                   
                     
                       
                         
                           
                             
                               
                                 0.658 
                               
                               
                                 0.343 
                               
                             
                             
                               
                                 
                                     
                                 
                               
                               
                                 
                                     
                                 
                               
                             
                             
                               
                                 0.810 
                               
                               
                                 0.190 
                               
                             
                           
                           ) 
                         
                         * 
                         
                           ( 
                           
                             
                               P 
                               = 
                               0.046 
                             
                             ; 
                             allele 
                           
                           ) 
                         
                       
                     
                   
                 
               
               
                   
               
               
                 Each model indicates hereditary mode regarding minor allele (C); 
               
               
                 *. P &lt; 0.05. 
               
            
           
         
       
     
     Example 12 
     &lt;Correlation Between CREB1 Subtype Gene Polymorphism (rs2952768) and Severity of Substance Dependence in Eating Disorder Patients&gt; 
     A correlation between a cyclic AMP responsive element binding protein gene polymorphism and vulnerability to substance (alcohol) dependence associated with the severity of substance (alcohol) dependence was examined. Genomic DNA was extracted from the blood of 221 patients with eating disorder, and one gene polymorphism (rs2952768) in the CREB1 subtype gene was determined. The patients were classified based on the presence or absence of alcohol dependence, and a comparison was made among them. The results are shown in the following Table 31. Here, the eating disorder patients were classified into two groups, namely, a patient group with a complication of alcohol dependence and a patient group without a complication of alcohol dependence. 
     As a result, as is clear from the following Table 31, a significant difference in genotype and allele frequencies was observed in terms of the gene polymorphism (rs2952768), and it was demonstrated that the frequency of major allele (T) was statistically significantly higher in the patient group with a complication of alcohol dependence than in the patient group without a complication of alcohol dependence. 
     From the above results, it was demonstrated that vulnerability to substance (alcohol) dependence associated with the severity of substance (alcohol) dependence can be easily predicted by determining genotype and allele frequencies in the cyclic AMP responsive element binding protein gene polymorphism. 
     
       
         
           
               
             
               
                 TABLE 31 
               
             
            
               
                   
               
               
                 Comparison of genotype and allele frequencies in rs2952768 polymorphism in patients with eating disorder 
               
               
                 classified based on presence or absence of complication of alcohol dependence 
               
               
                 Gene polymorphism name: CREB1 rs2952768 
               
            
           
           
               
               
               
               
            
               
                   
                 (Number of samples) 
                 Genotype frequency (%) 
                 Allele frequency 
               
               
                 Sample name 
                 Complication of alcohol 
                   T/T   T/C   C/C 
                  T   C 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Eating disorder patients 
                 No (151)   Yes (70)  
                 
                   
                     
                       
                         
                           
                             
                               
                                 
                                   
                                     
                                       
                                         61 
                                       
                                       
                                         72 
                                       
                                       
                                         18 
                                       
                                     
                                     
                                       
                                         
                                           ( 
                                           
                                             40.4 
                                              
                                             % 
                                           
                                           ) 
                                         
                                       
                                       
                                         
                                           ( 
                                           
                                             47.7 
                                              
                                             % 
                                           
                                           ) 
                                         
                                       
                                       
                                         
                                           ( 
                                           
                                             11.9 
                                              
                                             % 
                                           
                                           ) 
                                         
                                       
                                     
                                     
                                       
                                         38 
                                       
                                       
                                         27 
                                       
                                       
                                         5 
                                       
                                     
                                   
                                   ) 
                                 
                                  
                                 
                                     
                                 
                                  
                                 
                                   
                                     
                                       
                                            
                                          
                                         
                                           ( 
                                           
                                             
                                               P 
                                               = 
                                               0.136 
                                             
                                             ; 
                                             genotype 
                                           
                                           ) 
                                         
                                       
                                     
                                   
                                   
                                     
                                       
                                         † 
                                          
                                         
                                           ( 
                                           
                                             
                                               P 
                                               = 
                                               0.053 
                                             
                                             ; 
                                             
                                               dominant 
                                                
                                               
                                                   
                                               
                                                
                                               model 
                                             
                                           
                                           ) 
                                         
                                       
                                     
                                   
                                   
                                     
                                       
                                            
                                          
                                         
                                           ( 
                                           
                                             
                                               P 
                                               = 
                                               0.279 
                                             
                                             ; 
                                             
                                               recessive 
                                                
                                               
                                                   
                                               
                                                
                                               model 
                                             
                                           
                                           ) 
                                         
                                       
                                     
                                   
                                 
                               
                             
                           
                           
                             
                               
                                   
                                  
                                 
                                   
                                     ( 
                                     
                                       54.3 
                                        
                                       % 
                                     
                                     ) 
                                   
                                    
                                   
                                       
                                   
                                    
                                   
                                     ( 
                                     
                                       38.6 
                                        
                                       % 
                                     
                                     ) 
                                   
                                    
                                   
                                       
                                   
                                    
                                   
                                     ( 
                                     
                                       7.1 
                                        
                                       % 
                                     
                                     ) 
                                   
                                 
                               
                             
                           
                         
                           
                       
                     
                   
                 
                 
                   
                     
                       
                         
                           
                             
                               
                                 0.642 
                               
                               
                                 0.358 
                               
                             
                             
                               
                                 
                                     
                                 
                               
                               
                                 
                                     
                                 
                               
                             
                             
                               
                                 0.736 
                               
                               
                                 0.264 
                               
                             
                           
                           ) 
                         
                          
                         
                             
                         
                          
                         
                           † 
                            
                           
                             ( 
                             
                               
                                 P 
                                 = 
                                 0.052 
                               
                               ; 
                               allele 
                             
                             ) 
                           
                         
                       
                     
                   
                 
               
               
                   
               
               
                 Each model indicates hereditary mode regarding minor allele (C); 
               
               
                 †. 0.05 ≦ P &lt; 0.1. 
               
            
           
         
       
     
     Example 13 
     &lt;Correlation Between CREB1 Subtype Gene Polymorphism (rs2952768) and Reward Dependence&gt; 
     A correlation between a cyclic AMP responsive element binding protein gene polymorphism and dependence-prone personality associated with reward dependence was examined. Genomic DNA was extracted from the oral mucosa of 495 healthy subjects, and one gene polymorphism (rs2952768) in the CREB1 subtype gene was determined. Then, a correlation between these results of determination of the gene polymorphism and dependence-prone personality was analyzed. 
     It is to be noted that, as a test of dependence-prone personality, a reward dependence (RD) score (average) in the Temperament and Character Inventory (TCI) was used. 
     As a result, as is shown in the following Table 32 and  FIG. 15 , healthy subjects having a minor allele (C) in the CREB1 subtype gene polymorphism (rs2952768) had an RD score (logarithmic transformation) that was statistically significantly low in correlation with the number of alleles which they had. Accordingly, by analyzing the CREB1 subtype gene polymorphism (rs2952768), dependence-prone personality can be predicted. 
     Using the median (0.667) of the RD score as a reference, a patient group with a value smaller than the reference and a patient group with a value larger than the reference were defined as a “low reward dependence group” and a “high reward dependence group,” respectively, and the groups were then stratified in terms of the rs2952768 polymorphism of the CREB1 gene. As a result, in terms of this polymorphism, 43% and 57% of healthy subjects were determined to belong to the low reward dependence group and the high reward dependence group, respectively, in the T/T patient group. In contrast, in the C/C patient group, 58% and 42% of healthy subjects were determined to belong to the low reward dependence group and the high reward dependence group, respectively. 
     From the above results, it was demonstrated that dependence-prone personality associated with reward dependence can be easily predicted by determining genotype and allele frequencies in the cyclic AMP responsive element binding protein gene polymorphism. 
     
       
         
           
               
             
               
                 TABLE 32 
               
             
            
               
                   
               
               
                 Effect of CREB1 rs2952768 polymorphism on 
               
               
                 reward dependence (RD) score (average) 
               
               
                 (descriptive statistics by gender) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Number of test 
               
               
                 CREB1 
                   
                 Average 
                   
                 subjects 
               
               
                 rs2952768 
                 Gender 
                  
                 Standard deviation 
                 (subjects) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 T/T 
                 F 
                 0.72 
                 0.18 
                 98 
               
               
                   
                 M 
                 0.66 
                 0.18 
                 122 
               
               
                   
                 Unknown 
                 0.60 
                 0.09 
                 2 
               
               
                   
                 Total 
                 0.68 
                 0.18 
                 222 
               
               
                 T/C 
                 F 
                 0.70 
                 0.18 
                 103 
               
               
                   
                 M 
                 0.62 
                 0.20 
                 98 
               
               
                   
                 Unknown 
                 0.78 
                 0.08 
                 3 
               
               
                   
                 Total 
                 0.66 
                 0.19 
                 204 
               
               
                 C/C 
                 F 
                 0.68 
                 0.22 
                 37 
               
               
                   
                 M 
                 0.58 
                 0.18 
                 32 
               
               
                   
                 Total 
                 0.63 
                 0.21 
                 69 
               
               
                 
                   
                 
                 F 
                 0.70 
                 0.19 
                 238 
               
               
                   
                 M 
                 0.63 
                 0.19 
                 252 
               
               
                   
                 Unknown 
                 0.71 
                 0.12 
                 5 
               
               
                   
                 Total 
                 0.67 
                 0.19 
                 495 
               
               
                   
               
               
                  Average in dimension of average score in each subscale 
               
            
           
         
       
     
     Example 14 
     &lt;Correlation Between CREB1 Subtype Gene Polymorphism (rs2952768) and Expression Level of CREB1 Gene&gt; 
     A correlation between a cyclic AMP responsive element binding protein gene polymorphism and a gene expression level was examined. Genomic DNA was extracted from the blood of 100 postmortem brain tissue donors at the Stanley Foundation Brain Bank, and one gene polymorphism (rs2952768) in the CREB1 subtype gene was determined. Then, a correlation between these results of determination of the gene polymorphism and a gene expression level was analyzed. 
     Incidentally, as the gene expression level, the value of the relative mRNA expression level of CREB1, which was standardized with the value of the mRNA expression level of a β-actin gene (ACTB), was used. 
     As a result, as shown in the following Table 33 and  FIG. 16 , in the case of subjects who did not have a major allele (T) of the CREB1 subtype gene polymorphism (rs2952768), the mRNA expression level (logarithmic transformation) of CREB1 was statistically significantly higher compared with subjects having the aforementioned allele (T). Accordingly, by analyzing the CREB1 subtype gene polymorphism (rs2952768), the gene expression level can be predicted. 
     Using the median (0.0145) of the relative mRNA expression level as a reference, a subject group with a value smaller than the reference and a subject group with a value larger than the reference were defined as a “low gene expression group” and a “high gene expression group,” respectively, and the groups were then stratified in terms of the rs2952768 polymorphism of the CREB1 gene. As a result, in terms of this polymorphism, 52% and 48% of subjects were determined to belong to the low gene expression group and the high gene expression group, respectively, in the T/T or T/C subject group. In contrast, in the C/C subject group, 30% and 70% of subjects were determined to belong to the low gene expression group and the high gene expression group, respectively. 
     From the above results, it was demonstrated that the tendency of the expression level of a CREB1 gene (whether the gene tends to be expressed at a high level or at a low level) can be easily predicted by determining genotype and allele frequencies in the cyclic AMP responsive element binding protein gene polymorphism. 
     
       
         
           
               
             
               
                 TABLE 33 
               
             
            
               
                   
               
               
                 Effect of CREB1 rs2952768 polymorphism on gene expression level 
               
               
                 in postmortem brain tissue donors at Stanley Foundation Brain Bank 
               
               
                 (descriptive statistics) 
               
            
           
           
               
               
               
               
            
               
                   
                   
                   
                 Number of test 
               
               
                   
                   
                   
                 subjects 
               
               
                 CREB1 rs2952768 
                 Average  
                 Standard deviation 
                 (subjects) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 T/T 
                 0.015345 
                 0.006618 
                 48 
               
               
                 T/C 
                 0.015667 
                 0.005267 
                 42 
               
               
                 C/C 
                 0.023360 
                 0.023537 
                 10 
               
               
                 Total 
                 0.016282 
                 0.009396 
                 100 
               
               
                   
               
               
                  Relative mRNA expression level value of CREB1 standardized with mRNA expression level value of β-actin gene (ACTB) 
               
            
           
         
       
     
     INDUSTRIAL APPLICABILITY 
     According to the present invention, it becomes possible to provide: a gene polymorphism of a cyclic AMP responsive element binding protein gene or a haplotype constituted by the gene polymorphism, which can evaluate an individual difference in terms of drug sensitivity and disease vulnerability; a method for evaluating drug sensitivity and disease vulnerability using the gene polymorphism or the haplotype; and the like. According to this evaluation method, it becomes possible to readily know or predict a proper prescribed amount, a proper prescribed schedule associated with a narcotic drug such as morphine, and the like, and hence the method is extremely useful for personalized pain therapy, drug dependence therapy and the like.