Abstract:
The invention relates to methods of evaluating MS severity based on analysis of single nucleotide polymorphisms (SNPs) and to products and kits for use in such methods. The methods include a method of assessing a multiple sclerosis disease severity phenotype in a human subject having multiple sclerosis, by determining the genotype of the subject at one or more positions of single nucleotide polymorphism (SNP) selected from: rs 2107538,  rs 1137933,  rs 1318,  rs 2069763,  rs 423904,  rs 876493,  rs 10243024,  rs 10259085,  rs 1042173,  rs 10492503,  rs 10492972,  rs 12047808,  rs 12202350,  rs 12861247,  rs 13353224,  rs 1350666,  rs 1555322,  rs 1611115,  rs 17641078,  rs 1805009,  rs 2028455,  rs 2032893,  rs 2049306,  rs 2066713,  rs 2074897,  rs 2076530,  rs 2187668,  rs 2213584,  rs 2227139,  rs 2234978,  rs 2239802,  rs 2395182,  rs 260461,  rs 28386840,  rs 3087456,  rs 3135388,  rs 3741981,  rs 3756450,  rs 3781202,  rs 3787283,  rs 3808585,  rs 4128767,  rs 4404254,  rs 4473631,  rs 4680534,  rs 6077690,  rs 6457594,  rs 6570426,  rs 659366,  rs 6917747,  rs 7208257,  rs 7528684,  rs 7577925,  rs 762550,  rs 7956189,  rs 7995215,  rs 8049651,  rs 8702,  rs 9808753  and rs 987107,  and/or a SNP in linkage disequilibrium with any one of said SNPs.

Description:
FIELD OF THE INVENTION 
       [0001]    The invention relates to methods and products, in particular microarrays, for in vitro genotyping of multiple sclerosis (MS) associated genetic variations and to methods for assessment of MS disease severity. 
       BACKGROUND OF THE INVENTION 
       [0002]    Multiple Sclerosis is an autoimmune chronic inflammatory disease, characterized by a progressive demyelination of the central nervous system. While its origin still remains unknown, its multifactorial etiology is well known, consisting of a clear genetic component regulated by several environmental factors. 
         [0003]    Clinical evolution of MS is very heterogeneous, and there are different phenotypes present. These range from a very severe form where patients worsen rapidly (known as primary progressive MS), to a more benign form, where the patient practically recovers completely after each disease relapse (known as relapsing remitting MS). Nowadays, disease diagnostics is clinically based, relying on three main points: clinical history, neurologic exploration and use of several techniques (Magnetic Resonance Imaging, analysis of cerebrospinal fluid and evoked potentials). 
         [0004]    Currently there is no treatment that will cure MS. MS therapies aim at controlling symptoms and maintaining patient&#39;s quality of life. With such treatments, the number of relapses is controlled to a certain level, allowing partial prevention of consequences that may cause such relapses. The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical treatment, medications used in the management of MS have several adverse effects. Disease-modifying treatments reduce the progression rate of the disease, but do not stop it. As multiple sclerosis progresses, the symptomatology tends to increase. The disease is associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and disability. 
         [0005]    Management of these deficits is therefore very important. Both drug therapy and neurorehabilitation have shown to ease the burden of some symptoms, though neither influences disease progression. As for any patient with neurologic deficits, a multidisciplinary approach is key to limiting and overcoming disability; however, there are particular difficulties in specifying a ‘core team’ because people with MS may need help from almost any health profession or service at some point. Similarly, for each symptom there are different treatment options. Treatments should therefore be individualized depending both on the patient and the physician. 
       SUMMARY OF THE INVENTION 
       [0006]    Aspects of the invention relate to methods of analyzing a patient&#39;s genotype, for example through analysis of SNPs, optionally combined with clinical-environmental data, for prognosis and treatment management of MS patients, leading to personalized medicine. 
         [0007]    Accordingly, in a first aspect the present invention provides a method of assessing a MS disease severity phenotype in a human subject having or suspected of having MS, the method comprising determining the genotype of the subject at one or more positions of single nucleotide polymorphism (SNP) selected from those listed in Table 10 and/or a SNP in linkage disequilibrium with any one of said SNPs. The SNPs may be as disclosed in the NCBI dbSNP build 131,  Homo sapiens  genome build 37.1 and/or NCBI dbSNP build 129,  Homo sapiens  build 36.3. The presence of one or more “risk alleles” as identified in Table 10 at one or more of the SNPs indicates that the subject has a higher probability of having a greater severity of MS. In some cases, the method of this and other aspects of the invention comprises determining that the subject does have at least one risk allele at at least one of said 
         [0008]    SNPs. In other cases, the subject may be determined to be free from said risk alleles at at least one of said SNPs. In some cases, the method of this and other aspects of the invention, the presence of:
   the TT genotype at rs2107538;   the GG genotype at rs1137933;   the AA genotype at rs1318;   the GG genotype at rs2069763;   the CC genotype at rs423904;   the AA genotype at rs876493;   the GG genotype at rs10243024;   the GG genotype at rs10259085;   the AA genotype at rs1042173;   the TT genotype at rs10492503;   the GG genotype at rs10492972;   the GG genotype at rs12047808;   the AA genotype at rs12202350;   the GG genotype at rs12861247;   the AA genotype at rs13353224;   the GG genotype at rs1350666;   the AA genotype at rs1555322;   the AA genotype at rs1611115;   the GG genotype at rs17641078;   the GG genotype at rs1805009;   the GG genotype at rs2028455;   the AA genotype at rs2032893;   the AA genotype at rs2049306;   the AA genotype at rs2066713;   the AA genotype at rs2074897;   the GG genotype at rs2076530;   the AA genotype at rs2187668;   the AA genotype at rs2213584;   the CC genotype at rs2227139;   the TT genotype at rs2234978;   the GG genotype at rs2239802;   the GG genotype at rs2395182;   the AA genotype at rs260461;   the AA genotype at rs28386840;   the GG genotype at rs3087456;   the AA genotype at rs3135388;   the AA genotype at rs3741981;   the AA genotype at rs3756450;   the CT genotype at rs3781202;   the AA genotype at rs3787283;   the AA genotype at rs3808585;   the GG genotype at rs4128767;   the GG genotype at rs4404254;   the CC genotype at rs4473631;   the AA genotype at rs4680534;   the TT genotype at rs6077690;   the AA genotype at rs6457594;   the TT genotype at rs6570426;   the CC genotype at rs659366;   the GG genotype at rs6917747;   the AA genotype at rs7208257;   the GG genotype at rs7528684;   the AA genotype at rs7577925;   the AA genotype at rs762550;   the GG genotype at rs7956189;   the GG genotype at rs7995215;   the AA genotype at rs8049651;   the GG genotype at rs8702;   the GG genotype at rs9808753; and/or   the AA genotype at rs987107 is indicative of the subject having, or having a high probability of having, a more severe multiple sclerosis disease phenotype.   
 
         [0069]    In some cases, a more severe multiple sclerosis disease phenotype may be a phenotype selected from: a multiple sclerosis severity score (MSSS) of 2.5 or greater; an increase in size and/or distribution of T2 brain lesions; an increased number of focal lesions in the spinal cord; an increased T2 lesion load in the brain; and the presence of diffuse abnormalities in the spinal cord. Optionally, the method of this and other aspects of the invention may comprise determining the genotype of the subject at 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55 or more of said SNPs. Optionally, the method of the invention further comprises the measurement of at least one clinical variable, such as a clinical variable is selected from: age of the subject at onset of multiple sclerosis, gender of the subject and type of multiple sclerosis at onset of multiple sclerosis. The method of the invention may, in some cases, comprise determining the genotype of the subject at a specific combination or sub-set of SNPs selected from those listed in Table 10, such as the first 2, first 3, first 4, first 5 or first 6. Accordingly, in some cases, the method of the invention comprises determining the genotype of the subject at: at least rs2107538, rs1137933 and rs1318; at least rs2107538, rs1137933, rs1318, rs2069763, rs423904 and rs876493. In some cases, the method of the invention comprises determining the genotype of the subject at substantially all of the SNPs listed in Table 10. In some cases, the method of the invention comprises determining the genotype of the subject at only the SNPs listed in Table 10 and/or only SNPs in linkage disequilibrium with one or more of the SNPs listed in Table 10. 
         [0070]    In certain cases, the method of the invention comprises determining the genotype of the subject at a sub-set of SNPs of those listed in Table 10, which sub-set is indicative of a particular MS disease severity phenotype. Methods for assessing particular MS disease severity phenotypes, such as a multiple sclerosis severity score (MSSS) of 2.5 or greater; an increase in size and/or distribution of T2 brain lesions; an increased number of focal lesions in the spinal cord; an increased T2 lesion load in the brain; and the presence of diffuse abnormalities in the spinal cord, may be combined to yield assessment of multiple specific MS disease severity phenotypes or performed independently. 
         [0071]    In particular, the method of the invention may be for assessing multiple sclerosis severity score (MSSS), such as whether or not the subject has an MSSS score of 2.5 or greater, wherein the method comprises determining the genotype of the subject at at least 2 of the following positions of SNP: rs423904, rs876493, rs1137933, rs1318, rs2069763, rs2107538, rs3756450, rs12047808, rs10259085, rs1042173, rs6077690, rs1611115, rs4473631, rs2032893, rs2066713, rs260461, rs3787283, rs6917747, rs2049306, rs12861247, rs4404254, rs4680534, rs17641078, rs2187668, rs7528684, rs7577925, rs1805009, rs3741981, rs12202350, rs28386840, rs2028455, rs10492503, rs8049651, rs13353224, rs1555322, rs10243024 and rs6570426, wherein the presence of one or more of the risk alleles shown in Table 10 at one or more of said SNPs is indicative of having an MSSS score of 2.5 or greater. For example, the method may comprise determining the genotype of the subject at at least the following positions of SNP: rs2107538, rs1137933, rs1318, rs2069763, rs423904 and rs876493. Methods for assessing multiple sclerosis severity score (MSSS) of a subject may advantageously combine genotyping SNPs as specified above with determining at least 1, 2 or 3 clinical variables selected from: age of the subject at onset of multiple sclerosis, gender of the subject and type of multiple sclerosis at onset of multiple sclerosis. Thus, the method of the invention may comprise assessment of MSSS score utilising a model which combines the SNPs and clinical variables shown in Table 3, Table 3B and/or Table 3C, optionally employing the respective coefficient for each SNP and/or clinical variable shown in column “B” of said table or tables 
         [0072]    In certain cases, the method of this and other aspects of the invention may be for assessing the probability of increased size and/or distribution of T2 brain lesions in the subject, wherein the method comprises determining the genotype of the subject at at least 2, 3 or 4 of the following positions of SNP: rs2213584, rs2227139, rs2076530 rs876493, rs9808753, rs2074897, rs762550, rs2234978, rs3781202. 
         [0073]    In certain cases, the method of this and other aspects of the invention may be for assessing the probability of increased T2 lesion load in the brain, wherein the method comprises determining the genotype of the subject at at least 1, 2, 3 or 4 of the following positions of SNP: rs2107538, rs12861247, rs2074897 and rs7995215, such as determining the genotype of the subject at: rs12861247, rs2074897 and rs7995215. 
         [0074]    In certain cases, the method of this and other aspects of the invention may be for assessing an increased number of focal lesions in the spinal cord, wherein the method comprises determining the genotype of the subject at at least 1, 2, 3 or 4 of the following positions of SNP: rs3135388, rs2395182, rs2239802, rs2227139, rs2213584, rs3087456, rs10492972, rs12202350, rs8049651, rs8702 and rs987107, such as determining the genotype of the subject at: rs3135388, rs3087456 and rs2227139. 
         [0075]    In certain cases, the method of this and other aspects of the invention may be for assessing the presence of diffuse abnormalities in the spinal cord, wherein the method comprises determining the genotype of the subject at at least 1, 2, 3 or 4 of the following positions of SNP: rs1350666, rs3808585, rs4128767, rs6457594, rs7208257 and rs7956189. 
         [0076]    The method in accordance with this and other aspects of the invention may, in some cases, be carried out in vitro using a nucleic acid-containing sample that has been obtained from the subject. In some cases the genotype of the subject at said one or more positions of SNP may be determined indirectly by determining the genotype of the subject at a position of SNP that is in linkage disequilibrium with said one or more positions of SNP, while in some cases the genotype of the subject at said one or more positions of SNP may be determined directly by identifying one or both alleles at said one or more positions of SNP. 
         [0077]    In accordance with the method of this and other aspects of the invention, determining the genotype of the subject at said one or more positions of SNP may comprise:
       (i) extracting and/or amplifying DNA from a sample that has been obtained from the subject;   (ii) contacting the DNA with an array comprising a plurality of probes suitable for determining the identity of at least one allele at a position of SNP as listed in Table 10, for example using one or more probes selected from those listed in Table 7. In some cases, the array may be a DNA array, a DNA microarray or a bead array.       
 
         [0080]    In accordance with the method of this and other aspects of the invention the method may comprise amplifying DNA from a sample that has been obtained from the subject, wherein said amplifying comprises contacting the DNA with at least one forward primer as listed in Table 8 and at least one reverse primer as listed in Table 9. 
         [0081]    In a further aspect, the present invention provides an array of probes for use in a method according to the invention, wherein the array comprises:
       at least 5, 10, 15, 20, 50 or more nucleic acid probes suitable for determining the identity of at least one allele at a position of SNP as listed in Table 10; and   a solid support on which said probes are immobilised,
 
wherein said probes comprise at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99% of the total number of nucleic acid probes in the array, or essentially all of the nucleic acid probes in the array. The probes suitable for determining the identity of at least one allele at a position of SNP may be selected from the probes listed in Table 7.
       
 
         [0084]    In a further aspect, the present invention provides methods of evaluating disease severity in a patient having multiple sclerosis, including obtaining a DNA sample from the patient, and determining the presence or absence of two or more single nucleotide polymorphisms (SNPs) associated with severity of the disease, wherein the presence of two or more SNPs associated with severity of the disease indicates a likelihood of increased disease severity. In some embodiments the two or more SNPs associated with the disease comprise SNPs in PNMT, IL1R, CCL5, IL2, PITPNC1 or NOS2A. In certain embodiments the two or more SNPs are selected from those listed in Table 10. In certain embodiments, the two or more SNPs associated with the disease are selected from the group consisting of 2073 Intron2 C/T (rs423904), rs876493, rs1137933, rs1318, rs2069763 and rs2107538. In certain embodiments the two or more SNPs associated with the disease are selected from the group consisting of rs3135388, rs2395182, rs2239802, rs2227139, rs2213584, rs3087456 and rs2107538. 
         [0085]    The presence or absence of two or more SNPs associated with severity of the disease can be determined by any method known in the art such as a gene chip, bead array, RFLP analysis, and/or sequencing. In some embodiments the two or more SNPs associated with the disease comprise SNPs in PNMT, IL1R, CCL5, IL2, PITPNC1 or NOS2A. In certain embodiments the two or more SNPs associated with the disease are selected from the group consisting of, rs876493, rs1137933, rs1318, rs2069763 and rs2107538. In certain embodiments the two or more SNPs associated with the disease are selected from the group consisting of rs1137933, rs1318, rs2069764 and rs2107538. 
         [0086]    Aspects of the invention relate to SNPs associated with increased T2 lesion load in the brain. In some embodiments the SNP is associated with an increased number of focal spinal cord abnormalities. In some embodiments the two or more SNPs are in linkage disequilibrium. In certain embodiments the two or more SNPs are in linkage disequilibrium with SNPs selected from the group consisting of rs2239802, rs2213584, rs3135388, 2213584 rs2227139, rs1137933, rs1318, rs2069764 and rs2107538. 
         [0087]    In some embodiments methods described herein further include the measurement of one or more clinical variables such as age of onset, gender, and/or type of onset of disease. 
         [0088]    In some embodiments disease severity is based on an MS severity scale such as the Multiple Sclerosis Severity Score (MSSS) test, the Kurtzke Expanded Disability Status Scale (EDSS), or the Multiple Sclerosis Functional Composite (MSFC) measure. 
         [0089]    In some embodiments the presence or absence of at least 6 SNPs is determined. In certain embodiments the two or more SNPs are selected from the group consisting of 2073 Intron2 C/T (rs423904), rs876493, rs1137933, rs1318, rs2069763, rs2107538, rs3135388, rs2395182, rs2239802, rs2227139, rs2213584 and rs3087456. In certain embodiments at least one of the SNPs is in linkage disequilibrium with a SNP selected from the group consisting of 2073 Intron2 C/T (rs423904), rs876493, rs1137933, rs1318, rs2069763, rs2107538, rs3135388, rs2395182, rs2239802, rs2227139, rs2213584 and rs3087456. In some embodiments methods described herein include use of one or more probe sets listed in Table 7. In some embodiments methods described herein include at least one forward primer from Table 8 and one reverse primer from Table 9. 
         [0090]    Aspects of the invention relate to methods of designing a treatment regimen for a patient having multiple sclerosis, including obtaining a DNA sample from the patient, determining the presence or absence of two or more single nucleotide polymorphisms (SNPs) associated with severity of the disease, wherein the presence of two or more SNPs associated with severity of the disease indicates a likelihood of increased disease severity, and designing the treatment regimen based on the presence or absence of the SNPs associated with the disease. In some embodiments the treatment regimen comprises early or elevated doses of glatiramer acetate, vitamin D, interferon beta-la or -lb, natalizumab, mitoxantrone, and/or corticosteroids. 
         [0091]    Aspects of the invention relate to methods of treating a patient having a prognosis of increased disease severity, comprising early or elevated doses of glatiramer acetate, vitamin D, interferon beta-1 a or -1 b, natalizumab, mitoxantrone, and/or corticosteroids. 
         [0092]    Aspects of the invention relate to methods of identifying SNPs associated with severity of symptoms in multiple sclerosis, including obtaining a DNA sample from a patient having multiple sclerosis, identifying SNPs in the DNA, wherein the SNPs comprise two or more of the SNPs listed in Table 1, performing an MRI on the patient to determine spatial distribution of T2 brain lesions, T2 lesion load, presence of diffuse abnormalities and/or number of spinal cord lesions, comparing identified SNPs with the spatial distribution of T2 brain lesions, T2 lesion load, presence of diffuse abnormalities and/or number of spinal cord lesions, and identifying the SNPs that correlate with spatial distribution of T2 brain lesion, T2 lesion load, presence of diffuse abnormalities and/or number of spinal cord lesions, wherein the SNPs that correlate with spatial distribution of T2 brain lesions, T2 lesion load, presence of diffuse abnormalities and/or number of spinal cord lesions, are SNPs associated with severity of symptoms in multiple sclerosis. In some embodiments at least one of the SNPs is in linkage disequilibrium with a SNP listed in Table 1. In some embodiments identifying SNPs associated with severity of symptoms in multiple sclerosis further comprises consideration of clinical data. 
         [0093]    Aspects of the invention relate to methods of evaluating disease severity, as measured using the Multiple Sclerosis Severity Score (MSSS) test, the Kurtzke Expanded Disability Status Scale (EDSS), and/or the Multiple Sclerosis Functional Composite measure (MSFC), in a patient having multiple sclerosis, the method including obtaining a DNA sample from the patient, and determining the presence or absence of two or more single nucleotide polymorphisms (SNPs), wherein said SNPs comprise two or more of the SNPs listed in Table 1, and wherein the presence of said two or more SNPs indicates a likelihood of increased disease severity. In some embodiments evaluating disease severity further comprises consideration of clinical data. In some embodiments at least one of the SNPs is in linkage disequilibrium with a SNP listed in Table 1. 
         [0094]    Aspects of the invention relate to methods of evaluating the severity of spinal cord lesions in a patient having multiple sclerosis, the method including obtaining a DNA sample from the patient, and determining the presence or absence of two or more single nucleotide polymorphisms (SNPs) associated with spinal cord lesions, wherein the presence of two or more SNPs associated with spinal cord lesions indicates a likelihood of increased disease severity. In some embodiments the two or more SNPs are selected from the group consisting of rs3135388, rs2395182, rs2239802, rs2227139, rs2213584 and rs3087456. In certain embodiments one of the SNPs is rs3135388. In some embodiments the two or more SNPs are selected from the group consisting of 2073 Intron2 C/T (rs423904), rs876493, rs1137933, rs1318, rs2069763, rs2107538, rs3135388, rs2395182, rs2239802, rs2227139, rs2213584 and rs3087456. In certain embodiments at least one of the SNPs is in linkage disequilibrium with a SNP selected from the group consisting of 2073 Intron2 C/T (rs423904), rs876493, rs1137933, rs1318, rs2069763, rs2107538, rs3135388, rs2395182, rs2239802, rs2227139, rs2213584 and rs3087456. 
         [0095]    Aspects of the invention relate to method of prognosing the likelihood of T2 lesions and/or T2 lesion load in a patient having multiple sclerosis, the method including obtaining a DNA sample from the patient, and determining the presence or absence of SNP rs2107538, wherein the presence of SNP rs2107538 indicates a likelihood of T2 lesions and/or T2 lesion load in the patient. 
         [0096]    Aspects of the invention relate to methods where determining the presence or absence of SNPs includes (a) providing, for each genetic variation to be genotyped, at least 2 oligonucleotide probe pairs, wherein: (i) one pair consists of probes 1 and 2, and the other pair consists of probes 3 and 4; (ii) one probe in each pair is capable of hybridising to genetic variation A and the other probe in each pair is capable of hybridising to genetic variation B; (iii) each probe is provided in replicates; and (iv) the probe replicates are each coupled to a solid support; (c) amplifying and detectably labelling the target DNA; (d) contacting the target DNA with the probes under conditions which allow hybridisation to occur, thereby forming detectably labeled nucleic acid-probe hybridisation complexes, (e) determining the intensity of detectable label at each probe replica position, thereby obtaining a raw intensity value; (f) optionally amending the raw intensity value to take account of background noise, thereby obtaining a clean intensity value for each replica; and (g) applying a suitable algorithm to the intensity data from (e) or (f), thereby determining the genotype with respect to each genetic variation, wherein application of the algorithm comprises calculating an average intensity value from the intensity values for each of the replicas of each probe and wherein the algorithm uses three Fisher linear functions that characterize each of the three possible genotypes AA, AB or BB for the genetic variation. 
         [0097]    Aspects of the invention relate to kits for evaluating severity of disease in a subject having multiple sclerosis, the kit including: (i) at least one set of probes listed in table 7; optionally (ii) instruction for genotyping analysis as described in claim H1; and optionally (iii) instructions for determining the severity MS phenotype from the outcomes. Aspects of the invention relate to PCR amplification kits comprising at least one pair of PCR primers from tables 8 and 9, a thermostable polymerase, dNTPs, a suitable buffer, and optionally instructions for use. 
         [0098]    Further aspects of the invention relate to a computational method of deriving a probability function for use in determining an MS severity phenotype in a subject, including applying a probability function such as stepwise multiple logistic regression analysis to outcome data and phenotype data obtained from a suitable study population of individuals, wherein each individual is of known clinically determined phenotype with respect to the Multiple Sclerosis severity phenotype, thereby deriving a probability function which produces a statistically significant separation between individuals of different phenotype in the population; wherein: (i) the phenotype data comprises the known clinically determined phenotype of each individual; (ii) the outcomes data for each individual comprises the genotype of the individual at each SNP in a set of SNPs; and wherein: (a) the probability function is for distinguishing or differentially diagnosing MS severity phenotype, and the set of SNPs is selected from the set of MS severity phenotype discriminating SNPs in Table 3; (b) the probability function is for prognosing MS disease severity phenotype and the set of SNPs is selected from the set of MS disease severity discriminating SNPs in Table 3; and/or (c) the probability function is for prognosing MS disease severity phenotype and the set of SNPs is selected from the set of MS disease severity discriminating SNPs in Table 10. 
         [0099]    The present invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or is stated to be expressly avoided. These and further aspects and embodiments of the invention are described in further detail below and with reference to the accompanying examples and figures. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0100]      FIG. 1  is a graph showing a ROC (receiver operating characteristic) curve obtained for the model MSSS&lt;2.5 versus≧2.5, showing the relationship between sensitivity (y-axis) and percentage (x-axis). 
           [0101]      FIG. 2  depicts MRI data maps showing mean lesion frequency map of the patient sample (n=208). Lesion frequency across the patient sample is shown for every voxel on axial and sagittal slices. The colour bar indicates lesion frequency; voxels with a lesion frequency &lt;1% are not shown; peak frequency was 32%. 
           [0102]      FIG. 3  depicts MRI data maps showing clusterwise (t=2) associations of lesion presence with genotype, on a background of the common brain image. The cluster colour bar indicates clusterwise p-value, with the range indicated by the colour bar; only clusters with p&lt;0.05 are shown. A: rs2213584 (HLA-DRA gene); B: rs2227139 (HLA-DRA gene); C: rs2076530 (BTNL2 gene); D: rs876493 (PNMT gene). 
           [0103]      FIG. 4  is a graph showing the mean number of focal spinal cord lesions in patients who carry HLA-DRB1*1501 (measured as presence of A-allele of rs3135388). Difference between carriers and non-carriers p&lt;0.001, Maim Whitney U test. Error bars show 95% confidence interval of mean. 
           [0104]      FIG. 5  is a graph showing a ROC (receiver operating characteristic) curve obtained for the model MSSS&lt;2.5 versus≧2.5, showing the relationship between sensitivity (y-axis) and percentage (x-axis), as further described in Table 3B. 
           [0105]      FIG. 6  is a graph showing a ROC (receiver operating characteristic) curve obtained for the model MSSS&lt;2.5 versus≧2.5, showing the relationship between sensitivity (y-axis) and percentage (x-axis), as further described in Table 3B. 
           [0106]      FIG. 7  is a graph showing a ROC (receiver operating characteristic) curve obtained for the model MSSS&lt;2.5 versus≧2.5, showing the relationship between sensitivity (y-axis) and percentage (x-axis), as further described in Table 3C. 
       
    
    
     DETAILED DESCRIPTION 
       [0107]    Multiple Sclerosis (MS) is a multifocal inflammatory demyelinating disease of the central nervous system (CNS), characterized by inflammation, demyelination and axonal loss resulting in a highly variable clinical presentation. Most patients suffer from relapsing-remitting (RR) MS, experiencing waves of inflammation leading to alternating periods of disability (relapses) and stable disease (remissions). The RRMS phase usually leads to progressive and irreversible disability (the secondary progressive [SP] phase). For a subset of patients, the disease is progressive from onset (primary progressive [PP] MS). Treatment decisions are based on the occurrence of relapses, and the development of white matter lesions visible on MRI. Brain lesion volume and distribution however are highly variable among MS patients, and correlate only moderately with disability. As treatment guidelines would strongly benefit from a better understanding of this variability, the present invention is drawn to methods of genetic screening and predicting severity of disease using genetic information that correlates with increased numbers of lesions in the brain, optic nerve, or spinal cord. 
         [0108]    Aspects of the invention relate at least in part to the surprising discovery that MS severity can be associated (e.g., statistically) with one or more genetic markers. As used herein, a genetic marker refers to a DNA sequence that has a known location on a chromosome. Several non-limiting examples of classes of genetic markers include RFLP (restriction fragment length polymorphism), AFLP (amplified fragment length polymorphism), RAPD (random amplification of polymorphic DNA), VNTR (variable number tandem repeat), microsatellite polymorphism, SNP (single nucleotide polymorphism), STR (short tandem repeat), and SFP (single feature polymorphism). 
         [0109]    In some embodiments, genetic markers associated with the invention are SNPs. As used herein a SNP or “single nucleotide polymorphism” refers to a specific site in the genome where there is a difference in DNA base between individuals. In some embodiments the SNP is located in a coding region of a gene. In other embodiments the SNP is located in a noncoding region of a gene. In still other embodiments the SNP is located in an intergenic region. It should be appreciated that SNPs exhibit variability in different populations. In some embodiments, a SNP associated with the invention may occur at higher frequencies in some ethnic populations than in others. In some embodiments, SNPs associated with the invention are SNPs that are linked to MS. In certain embodiments a SNP associated with the invention is a SNP associated with a gene that is linked to MS. A SNP that is linked to MS may be identified experimentally. In other embodiments a SNP that is linked to MS may be identified through accessing a database containing information regarding SNPs. Several non-limiting examples of databases from which information on SNPs or genes that are associated with human disease can be retrieved include: NCBI resources, The SNP Consortium LTD, NCBI dbSNP database, International HapMap Project, 1000 Genomes Project, Glovar Variation Browser, SNPStats, PharmGKB, GEN-SniP, and SNPedia. In some embodiments, SNPs associated with the invention comprise two or more of the SNPs listed in Table 1 and/or Table 10. In some embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more than 30 SNPs are evaluated in a patient sample. In some embodiments, multiple SNPs are evaluated simultaneously while in other embodiments SNPS are evaluated separately. 
         [0110]    SNPs are identified herein using the rs identifier numbers in accordance with the 
         [0111]    NCBI dbSNP database, which is publically available at: http://www.ncbi.nlm.nih.gov/projects/SNP/. As used herein, rs numbers refer to the dbSNP build 129,  Homo sapiens  build 36.3 available from 14 Apr. 2008 and/or dbSNP build 131,  Homo sapiens  build 37.1 available from 2 February 2010. Except where indicated otherwise, the rs identifiers are identical for dbSNP build 129,  Homo sapiens  build 36.3 and dbSNP build 131,  Homo sapiens  build 37.1. 
         [0112]    In some embodiments, SNPs in linkage disequilibrium with the SNPs associated with the invention are useful for obtaining similar results. As used herein, linkage disequilibrium refers to the non-random association of SNPs at two or more loci. Techniques for the measurement of linkage disequilibrium are known in the art. As two SNPs are in linkage disequilibrium if they are inherited together, the information they provide is correlated to a certain extent. SNPs in linkage disequilibrium with the SNPs included in the models can be obtained from databases such as HapMap or other related databases, from experimental setups run in laboratories or from computer-aided in-silico experiments. Determining the genotype of a subject at a position of SNP as specified herein, e.g. as specified by NCBI dbSNP rs identifier, may comprise directly genotyping, e.g. by determining the identity of the nucleotide of each allele at the locus of SNP, and/or indirectly genotyping, e.g. by determining the identity of each allele at one or more loci that are in linkage disequilibrium with the SNP in question and which allow one to infer the identity of each allele at the locus of SNP in question with a substantial degree of confidence. In some cases, indirect genotyping may comprise determining the identity of each allele at one or more loci that are in sufficiently high linkage disequilibrium with the SNP in question so as to allow one to infer the identity of each allele at the locus of SNP in question with a probability of at least 90%, at least 95% or at least 99% certainty. 
         [0113]    As used herein MS or multiple sclerosis refers to a progressive neurodegenerative disease involving demyelination of nerve cells. Several non-limiting classifications of MS include: relapsing-remitting (RRMS) (typically characterized by partial or total recovery after attacks (also called exacerbations, relapses, or flares)), secondary progressive MS (SPMS) (generally characterized by fewer relapses, with an increase in disability and symptoms), and primary progressive MS (PPMS) (generally characterized by progression of symptoms and disability without remission). 
         [0114]    Some non-limiting examples of symptoms of MS include: fatigue (also referred to as MS lassitude), muscle fatigue, paresthesias, difficulty in walking and/or balance problems, abnormal sensations such as numbness, prickling, or “pins and needles”, pain, bladder dysfunction, bowel dysfunction, changes in cognitive function (including problems with memory, attention, concentration, judgment, and problem-solving), dizziness and vertigo, emotional problems (e.g., depression), sexual dysfunction, and vision problems. In some embodiments, symptoms of MS can include partial or complete paralysis (such as blurred or double vision, red-green color distortion, or blindness in one eye), headache, hearing loss, itching, seizures, spasticity, speech and swallowing disorders, and tremors. In some embodiments, clinical symptoms of MS can include increased CD4:CD8 cell ratio compared to normal, decreased number of CD 14+ cells compared to normal, increased expression of HLA-DR on CD14+ cells compared to normal CD14+ cells, increased levels of activated monocytes or macrophages compared to normal, the presence of proliferating macrophages, and decreased serum IgG and/or IgM compared to normal, where “normal” as used in this context refers to a subject who does not have MS. 
         [0115]    Previous studies have explored patterns of spatial lesion distribution in MS patients. Without wishing to be bound by any theory, one potential factor underlying differences in lesion burden and spatial lesion distribution among MS patients may be found in pathological and immunological heterogeneity: studies on spatial lesion distribution throughout the brain demonstrated differences in lesion distribution across disease types and across lesion types. These findings of distinct lesion distributions across patient subgroups and lesion types suggest that different subtypes of pathology exist in MS based at least in part on different immunological mechanisms. For example, periventricular predilection of MS lesions may be caused at least in part by differences in the vasculature compared to other regions, making this location vulnerable to pathological changes. Without wishing to be bound by any theory, enhanced lesions in peripheral as opposed to central brain regions may be caused, at least in part, by central lesions developing from progressive gliosis and peripheral lesions being more inflammatory. As lesions in different locations may have different immunological backgrounds, they may warrant different treatment mechanisms. Results described herein suggest that differences in immunological backgrounds of lesion formation among MS patients may be driven by genetic predisposition. 
         [0116]    Aspects of the invention relate to a large-scale study investigating the genetic influences on different phenotypes of MS (disease severity, subtype, MRI characteristics, response to treatment). Described herein is an investigation into the correlation between genetic background and spatial lesion distribution in a large cohort of MS patients using a variety of SNPs. 
         [0117]    Aspects of the invention relate to evaluating the severity of MS in a patient. One symptom associated with MS is the presence of demyelination (lesions or plaques) in the brain and/or spinal cord of a patient. It should be appreciated that regions of demyelination may be detected through any means known to one of ordinary skill in the art. In some embodiments, lesions are detected through MRI. In some embodiments treatment decisions regarding a patient with MS, are based on the occurrence of relapses and the development of white matter lesions visible on MRI. Brain lesion volume and distribution, however, are highly variable among MS patients and correlate only moderately with disability. Treatment guidelines would benefit from a better understanding of this variability. Differences in genetic background may lead to different lesion distribution, which in turn may lead to a different clinical expression of the disease. Thus, the correlations revealed herein, between the presence of specific genetic markers and the presence of lesions offer important applications for screening of patients who have or are at risk of MS, diagnostic and prognostics for MS patients, as well as development of appropriate therapeutic approaches. As used herein, the term disease severity refers to the evaluation of a patient&#39;s disability using the tests listed above or other similar tests known in the art. An assessment of disease severity in some embodiments includes determining rapidity of development of disability, disease duration, rate of progression or relapse of symptoms, and symptoms such as changes in sensation, fatigue, pain, muscle weakness and/or spasm, problems in speech, visual problems, difficulty in moving, difficulties with coordination and balance, bladder and bowel difficulties and cognitive impairment. 
         [0118]    Several methods have been established for assessing the severity of MS based on analysis of clinical factors such as those in Table 2, below. Non-limiting examples of tests used to assess the severity of MS include the Kurtzke Expanded Disability Status Scale (EDSS), the Multiple Sclerosis Functional Composite measure (MSFC), and the Multiple Sclerosis Severity Score (MSSS). The MSSS test relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations. Effectively the MSSS assigns to each EDSS its median decile score within this distribution. For example, an MSSS of 5.0 indicates the disease is progressing at the median rate. A patient whose MSSS is 9.0 is a fast progressor, progressing faster than 90% of patients. A patient whose MSSS is 1.0 is a slow progressor, progressing faster than just 10% of patients. In some embodiments, based on the MSSS test a patient may be assigned a median docile score of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 9.5, including any intermediate values. In some embodiments, based on a test such as the MSSS test, MS patients are allocated into severe and benign subgroups. In some embodiments, MS patients are classified into different categories of severity based on a test such as MSSS. In some embodiments MS patient may be classified as relapsing-remitting (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). 
         [0119]    The invention in one aspect presents a model for assessing the strength of the disability, or the severity of the form of MS, according to the MSSS scale, using SNP analysis, thus allowing differential treatment management for a given patient. Results described herein generate a model from the analysis of 605 MS patients and 700 MS patients (see Example section). In some aspects, the invention evaluates differences between patients that have an MSSS score of less than 2.5 versus patients that have an MSSS score 2.5 or greater. Aspects of the invention relate to using genetic markers that are correlated to certain degrees of MS severity as predictive of MS severity and as indicators of recommended therapeutic approaches. In some embodiments, methods described herein relate to screening a patient for one or more risk factors associated with MS. In some embodiments the presence of two or more of the SNPs described herein indicate a more severe form of MS. 
         [0120]    The invention in one aspect relates to correlating specific SNPs or combinations of SNPs with the presence and/or severity of lesions in the brain and/or spinal cord. The SNPs or combinations of SNPs that are correlated to the presence and/or severity of lesions in the brain and/or spinal cord can be used as predictive, diagnostic or prognostic indicators of the presence and/or severity of lesions in the brain and/or spinal cord. The detection of such SNPs, indicating the presence of lesions in the brain and/or spinal cord may in some embodiments be used as an indicator of the severity of MS. 
         [0121]    Aspects of the invention relate to determining the presence of SNPs through obtaining a patient DNA sample and evaluating the patient sample for the presence of two or more SNPs. It should be appreciated that a patient DNA sample can be extracted, and a SNP can be detected in the sample, through any means known to one of ordinary skill in art. Some non-limiting examples of known techniques include detection via restriction fragment length polymorphism (RFLP) analysis, planar microarrays, bead arrays, sequencing, single strand conformation polymorphism analysis (SSCP), chemical cleavage of mismatch (CCM), and denaturing high performance liquid chromatography (DHPLC). 
         [0122]    In some embodiments, a SNP is detected through PCR amplification and sequencing of the DNA region comprising the SNP. In some embodiments SNPs are detected using microarrays. Microarrays for detection of genetic polymorphisms, changes or mutations (in general, genetic variations) such as a SNP in a DNA sequence, comprise a solid surface, typically glass, on which a high number of genetic sequences are deposited (the probes), complementary to the genetic variations to be studied. Using standard robotic printers to apply probes to the array a high density of individual probe features can be obtained, for example probe densities of 600 features per cm 2  or more can be typically achieved. The positioning of probes on an array is precisely controlled by the printing device (robot, inkjet printer, photolithographic mask etc) and probes are aligned in a grid. The organisation of probes on the array facilitates the subsequent identification of specific probe-target interactions. Additionally it is common, but not necessary, to divide the array features into smaller sectors, also grid-shaped, that are subsequently referred to as sub-arrays. Sub-arrays typically comprise 32 individual probe features although lower (e.g. 16) or higher (e.g. 64 or more) features can comprise each subarray. 
         [0123]    In some embodiments, detection of genetic variation such as the presence of a SNP involves hybridization to sequences which specifically recognize the normal and the mutant allele in a fragment of DNA derived from a test sample. Typically, the fragment has been amplified, e.g. by using the polymerase chain reaction (PCR), and labelled e.g. with a fluorescent molecule. A laser can be used to detect bound labelled fragments on the chip and thus an individual who is homozygous for the normal allele can be specifically distinguished from heterozygous individuals (in the case of autosomal dominant conditions then these individuals are referred to as carriers) or those who are homozygous for the mutant allele. In some embodiments, the amplification reaction and/or extension reaction is carried out on the microarray or bead itself. 
         [0124]    In some embodiments, methods described herein may involve hybridization. For differential hybridization based methods there are a number of methods for analysing hybridization data for genotyping: 
         [0125]    Increase in hybridization level: The hybridization levels of probes complementary to the normal and mutant alleles are compared. 
         [0126]    Decrease in hybridization level: Differences in the sequence between a control sample and a test sample can be identified by a decrease in the hybridization level of the totally complementary oligonucleotides with a reference sequence. A loss approximating 100% is produced in mutant homozygous individuals while there is only an approximately 50% loss in heterozygotes. In Microarrays for examining all the bases of a sequence of “n” nucleotides (“oligonucleotide”) of length in both strands, a minimum of “2n” oligonucleotides that overlap with the previous oligonucleotide in all the sequence except in the nucleotide are necessary. Typically the size of the oligonucleotides is about 25 nucleotides. However it should be appreciated that the oligonucleotide can be any length that is appropriate as would be understood by one of ordinary skill in the art. The increased number of oligonucleotides used to reconstruct the sequence reduces errors derived from fluctuation of the hybridization level. However, the exact change in sequence cannot be identified with this method; in some embodiments this method is combined with sequencing to identify the mutation. 
         [0127]    Where amplification or extension is carried out on the microarray or bead itself, three methods are presented by way of example: 
         [0128]    In the Minisequencing strategy, a mutation specific primer is fixed on the slide and after an extension reaction with fluorescent dideoxynucleotides, the image of the Microarray is captured with a scanner. 
         [0129]    In the Primer extension strategy, two oligonucleotides are designed for detection of the wild type and mutant sequences respectively. The extension reaction is subsequently carried out with one fluorescently labelled nucleotide and the remaining nucleotides unlabelled. In either case the starting material can be either an RNA sample or a DNA product amplified by PCR. 
         [0130]    In the Tag arrays strategy, an extension reaction is carried out in solution with specific primers, which carry a determined 5′ sequence or “tag”. The use of Microarrays with oligonucleotides complementary to these sequences or “tags” allows the capture of the resultant products of the extension. Examples of this include the high density Microarray “Flex-flex” (Affymetrix). 
         [0131]    For cost-effective genetic diagnosis, in some embodiments, the need for amplification and purification reactions presents disadvantages for the on-chip or on-bead extension/amplification methods compared to the differential hybridization based methods. However the techniques may still be used to detect and diagnose conditions according to the invention. 
         [0132]    Typically, Microarray or bead analysis is carried out using differential hybridization techniques. However, differential hybridization does not produce as high specificity or sensitivity as methods associated with amplification on glass slides. For this reason the development of mathematical algorithms, which increase specificity and sensitivity of the hybridization methodology, are needed (Cutler D J, Zwick M E, Carrasquillo M N, Yohn C T, Tobi K P, Kashuk C, Mathews D J, Shah N, Eichler E E, Warrington J A, Chakravarti A. Genome Research; 11 :1913-1925 (2001). Methods of genotyping using microarrays and beads are known in the art. 
         [0133]    Some non-limiting examples of genotyping and data analysis can be found in co-pending patent application U.S. Ser. No. 11/813,646 (WO 2006/075254), which is hereby incorporated by reference. In some embodiments the genotypes are determined as follows: The signal from the probes which detect the different genetic variations is determined with a scanner. The scanner software executes a function to subtract the local background noise from the absolute signal intensity value obtained for each probe. Next, the replicates for each of the 4 probes that are used to characterize each genetic variation are grouped. The average intensity value for each of 4 probes is calculated using the average collated from the replicates in order to identify abnormal values (outliers) that can be excluded from further consideration. Once the average intensity value for each of the probes is known then two ratios are calculated (ratio 1 and ratio 2): 
         [0000]    
       
         
           
             
               Ratio 
                
               
                   
               
                
               1 
             
             = 
             
               
                 Average 
                  
                 
                     
                 
                  
                 intensity 
                  
                 
                     
                 
                  
                 for 
                  
                 
                     
                 
                  
                 probe 
                  
                 
                     
                 
                  
                 1 
               
               
                 
                   Average 
                    
                   
                       
                   
                    
                   intensity 
                    
                   
                       
                   
                    
                   for 
                    
                   
                       
                   
                    
                   probe 
                    
                   
                       
                   
                    
                   1 
                 
                 + 
                 
                   Average 
                    
                   
                       
                   
                    
                   intensity 
                    
                   
                       
                   
                    
                   for 
                    
                   
                       
                   
                    
                   probe 
                    
                   
                       
                   
                    
                   2 
                 
               
             
           
         
       
       
         
           
             
               Ratio 
                
               
                   
               
                
               2 
             
             = 
             
               
                 Average 
                  
                 
                     
                 
                  
                 intensity 
                  
                 
                     
                 
                  
                 for 
                  
                 
                     
                 
                  
                 probe 
                  
                 
                     
                 
                  
                 3 
               
               
                 
                   Average 
                    
                   
                       
                   
                    
                   intensity 
                    
                   
                       
                   
                    
                   for 
                    
                   
                       
                   
                    
                   probe 
                    
                   
                       
                   
                    
                   3 
                 
                 + 
                 
                   Average 
                    
                   
                       
                   
                    
                   intensity 
                    
                   
                       
                   
                    
                   for 
                    
                   
                       
                   
                    
                   probe 
                    
                   
                       
                   
                    
                   4 
                 
               
             
           
         
       
     
         [0000]    wherein probe 1 detects (is capable of specifically hybridising to) genetic variation A (e.g. a normal allele), probe 2 detects (is capable of specifically hybridising to) genetic variation B (e.g. a mutant allele), probe 3 detects (is capable of specifically hybridising to) genetic variation A (e.g. a normal allele) and probe 4 detects (is capable of specifically hybridising to) genetic variation B (e.g. a mutant allele). 
         [0134]    These ratios are substituted in three Fisher linear functions which characterize each one of the three possible genotypes: 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 AA 
                 Function 1 
               
               
                   
                 AB 
                 Function 2 
               
               
                   
                 BB 
                 Function 3 
               
               
                   
                   
               
             
          
         
       
     
         [0135]    The function which presents the highest absolute value determines the genotype of the patient. 
         [0136]    The Fisher linear functions are obtained by analyzing 3 subjects for each of the three possible genotypes of the genetic variation (AA, AB, BB). With the results, ratios 1 and 2 are calculated for the SNPs analyzed and for the 3 subjects. These ratios are classification variables for the three groups to create the linear functions, with which the discriminatory capacity of the two pairs of designed probes is evaluated. If the discriminatory capacity is not 100%, the probes are redesigned. New subjects characterized for each of the three genotypes make up new ratios 1 and 2 to perfect the linear functions and in short, to improve the discriminatory capacity of the algorithm based on these three functions. 
         [0137]    When using a fluorescent laser, to obtain reliable results it is preferable that ratios 1 and 2 are within the range of the ratios used to build the groups. 
         [0138]    Again when a fluorescent scanner is used in the experiment, for a complete hybridization to be considered reliable preferably the ratio of probe fluorescence intensity to background noise of all the beads DNA array probes is above 15. Likewise, the average of all the ratios is preferably above 0.6 and the negative control is preferably less than or equal to 3 times the background noise. 
         [0139]    In summary, four probes are presented in the hybridization analysis for detection of each mutation. Two of the probes detect one genetic variation (A) and the other two the other genetic variation (B). The examined base is located in the central position of the probes. 
         [0140]    A subject homozygous for the genetic variation A will not show genetic variation B. Consequently, the probes which detect genetic variation B will show a hybridization signal significantly less than that shown by variation A and vice versa. In this case the ratios 1 and 2 will show 1 and the subjects will be assigned as homozygous AA by the software analysis. 
         [0141]    On the other hand, a heterozygous subject for the determined genetic variation shows both the genetic variations. Therefore, the probes which detect them show an equivalent hybridization signal. The ratios 1 and 2 will show 0.5 and the subject will be assigned as heterozygous AB the software analysis as described. 
         [0142]    In one aspect of the invention, DNA polymorphisms are selected based on their association with the etiology of MS, such as those shown in Table 1 below: 
         [0000]    
       
         
               
               
               
             
           
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                 Gene 
                 RefSNP accession I.D. 
               
               
                   
                   
               
             
             
               
                   
                 ACCN1 
                 rs28936 
               
               
                   
                 ACE 
                 rs4343 
               
               
                   
                 ADAMTS14 
                 rs4747075 
               
               
                   
                 ADAMTS14 
                 rs7081273 
               
               
                   
                 ADAMTS14 
                 rs4746060 
               
               
                   
                 ALK 
                 rs7577363 
               
               
                   
                 ANKRD15 
                 rs10975200 
               
               
                   
                 Apo I/Fas 
                 rs1800682 
               
               
                   
                 Apo I/Fas 
                 rs3781202 
               
               
                   
                 Apo I/Fas 
                 rs2234978 
               
               
                   
                 BDNF 
                 rs6265 
               
               
                   
                 BTNL2 
                 rs2076530 
               
               
                   
                 C10orf27 
                 rs2254174 
               
               
                   
                 C10orf27 
                 rs12221473 
               
               
                   
                 C10orf27 
                 rs12221474 
               
               
                   
                 C10orf27 
                 rs2791196 
               
               
                   
                 CACNG4 
                 rs4790896 
               
               
                   
                 CBLB 
                 rs12487066 
               
               
                   
                 CCL11 
                 rs17735961 
               
               
                   
                 CCL14 
                 rs854682 
               
               
                   
                 CCL17 
                 rs223828 
               
               
                   
                 CCL2 
                 rs1024610 
               
               
                   
                 CCL22 
                 rs4359426 
               
               
                   
                 CCL23 
                 rs1003645 
               
               
                   
                 CCL23 
                 rs854655 
               
               
                   
                 CCL5 
                 rs2107538 
               
               
                   
                 CCL5 
                 rs2280788 
               
               
                   
                 CCR5 
                 rs333 
               
               
                   
                 CD14 
                 rs2569190 
               
               
                   
                 CD226 
                 rs763361 
               
               
                   
                 CD24 
                 rs8734 
               
               
                   
                 CD58 
                 rs12044852 
               
               
                   
                 CNTF 
                 rs1800169 
               
               
                   
                 CRYAB 
                 rs14133 
               
               
                   
                 CRYAB 
                 rs762550 
               
               
                   
                 CRYAB 
                 rs2234702 
               
               
                   
                 CTLA4 
                 rs231775 
               
               
                   
                 CTLA4 
                 rs5742909 
               
               
                   
                 CTSS 
                 rs1136774 
               
               
                   
                 CTSS 
                 rs3754212 
               
               
                   
                 CXLCL10 
                 rs3921 
               
               
                   
                 CXLCL10 
                 rs8878 
               
               
                   
                 DBC1 
                 rs10984447 
               
               
                   
                 DRB1 
                 rs3135388 
               
               
                   
                 EBF 
                 rs1368297 
               
               
                   
                 EVI5 
                 rs10735781 
               
               
                   
                 EVI5 
                 rs6680578 
               
               
                   
                 FAM69A 
                 rs11164838 
               
               
                   
                 FAM69A 
                 rs7536563 
               
               
                   
                 GABBRA1 
                 rs1805057 
               
               
                   
                 GLO1 
                 rs2736654 
               
               
                   
                 GR 
                 rs6189 
               
               
                   
                 GR 
                 rs6190 
               
               
                   
                 HELZ 
                 rs2363846 
               
               
                   
                 HFE 
                 rs1800562 
               
               
                   
                 HLA 
                 rs2395166 
               
               
                   
                 HLA 
                 rs2213584 
               
               
                   
                 HLA 
                 rs2227139 
               
               
                   
                 HLA 
                 rs3135388 
               
               
                   
                 HLA 
                 rs9268458 
               
               
                   
                 HLA 
                 rs6457594 
               
               
                   
                 HLA-DRA 
                 rs2395182 
               
               
                   
                 HLA-DRA 
                 rs2239802 
               
               
                   
                 ICOS 
                 rs4404254 
               
               
                   
                 ICOS 
                 rs10932036 
               
               
                   
                 ICOS 
                 rs4675379 
               
               
                   
                 IFI30 
                 rs11554159 
               
               
                   
                 IFNAR 
                 rs1012334 
               
               
                   
                 IFNAR1 
                 rs2257167 
               
               
                   
                 IFNG 
                 rs1861494 
               
               
                   
                 IFNG 
                 rs2069727 
               
               
                   
                 IFNG 
                 rs2430561 
               
               
                   
                 IFNG 
                 rs3181034 
               
               
                   
                 IFNG 
                 rs7954499 
               
               
                   
                 IFNGR2 
                 rs9808753 
               
               
                   
                 IKBL 
                 rs3130062 
               
               
                   
                 IL10 
                 rs1800871 
               
               
                   
                 IL10 
                 rs1800872 
               
               
                   
                 IL10 
                 rs1800896 
               
               
                   
                 IL1A 
                 rs1800587 
               
               
                   
                 IL1B 
                 rs1799916 
               
               
                   
                 IL1B 
                 rs1143627 
               
               
                   
                 IL1B 
                 rs1143634 
               
               
                   
                 IL1RN 
                 2073 Intron2 C/T (rs423904) 
               
               
                   
                 IL1RN 
                 rs419598 
               
               
                   
                 IL2 
                 rs2069763 
               
               
                   
                 IL2 
                 rs2069762 
               
               
                   
                 IL23R 
                 rs7517847 
               
               
                   
                 IL23R 
                 rs11209026 
               
               
                   
                 IL2RA 
                 rs12722489 
               
               
                   
                 IL2RA 
                 rs2104282 
               
               
                   
                 IL4R 
                 rs1801275 
               
               
                   
                 IL5RA 
                 rs2290608 
               
               
                   
                 IL7R 
                 rs11567685 
               
               
                   
                 IL7R 
                 rs7718919 
               
               
                   
                 IL7R 
                 rs11567686 
               
               
                   
                 IL7R 
                 rs6897932 
               
               
                   
                 IL7R 
                 rs3194051 
               
               
                   
                 IL7R 
                 rs987106 
               
               
                   
                 IL7R 
                 rs987107 
               
               
                   
                 IL7R 
                 rs11567685 
               
               
                   
                 IL7R 
                 rs7718919 
               
               
                   
                 IL7R 
                 rs11567686 
               
               
                   
                 IL8 
                 rs4073 
               
               
                   
                 IRF1 
                 rs2070721 
               
               
                   
                 IRF5 
                 rs3807306 
               
               
                   
                 IRF5 
                 rs4728142 
               
               
                   
                 IRF5 
                 5 bp insertion-deletion polymorphism located 
               
               
                   
                   
                 in the promoter and first intron of the IRF5 
               
               
                   
                   
                 gene 
               
               
                   
                 IRF-5 
                 rs10954213 
               
               
                   
                 IRF-5 
                 rs2004640 
               
               
                   
                 IRF-5 
                 rs2280714 
               
               
                   
                 IRF-5 
                 rs3757385 
               
               
                   
                 ITGA4 
                 rs1449263 
               
               
                   
                 KCNH7 
                 rs2068330 
               
               
                   
                 KIAA0350 
                 rs6498169 
               
               
                   
                 KLC1 
                 rs8702 
               
               
                   
                 KLRB1 
                 rs4763655 
               
               
                   
                 LAG3 
                 rs1922452 
               
               
                   
                 LAG3 
                 rs870849 
               
               
                   
                 LAG3 
                 rs951818 
               
               
                   
                 LAG3 
                 rs19922452 
               
               
                   
                 LMP7 
                 rs2071543 
               
               
                   
                 MBP 
                 rs470929 
               
               
                   
                 MC1R 
                 rs1805009 
               
               
                   
                 MC1R 
                 rs1805006 
               
               
                   
                 MEFV 
                 rs28940577 
               
               
                   
                 MGC33887 
                 rs987931 
               
               
                   
                 MHC2TA 
                 rs4774 
               
               
                   
                 MHC2TA 
                 rs3087456 
               
               
                   
                 MOG 
                 rs2857766 
               
               
                   
                 MOG 
                 rs3130250 
               
               
                   
                 MOG 
                 rs3130253 
               
               
                   
                 MxA 
                 rs2071430 
               
               
                   
                 NDUFA7 
                 rs2288414 
               
               
                   
                 NDUFA7 
                 rs561 
               
               
                   
                 NDUFS5 
                 rs2889683 
               
               
                   
                 NDUFS5 
                 rs6981 
               
               
                   
                 NDUFS7 
                 rs2074897 
               
               
                   
                 NOS2A 
                 rs1137933 
               
               
                   
                 NOS2A 
                 rs2779248 
               
               
                   
                 NOTCH4 
                 rs367398 
               
               
                   
                 NR4A2 
                 rs1405735 
               
               
                   
                 OAS1 
                 rs10774071 
               
               
                   
                 OAS1 
                 rs3741981 (rs1131454 in version. 37.1) 
               
               
                   
                 PD-1 
                 rs11568821 
               
               
                   
                 PDE4B 
                 rs1321172 
               
               
                   
                 PITPNC1 
                 rs1318 
               
               
                   
                 PITPNC1 
                 rs2365403 
               
               
                   
                 PNMT 
                 rs876493 
               
               
                   
                 PON 
                 rs854560 
               
               
                   
                 PPARG 
                 rs1801282 
               
               
                   
                 PRKCA 
                 rs7220007 
               
               
                   
                 PRKCA 
                 rs887797 
               
               
                   
                 PRKCA 
                 rs2078153 
               
               
                   
                 PRKCA 
                 rs3890137 
               
               
                   
                 PTPN22 
                 rs2476601 
               
               
                   
                 PTPRC 
                 rs17612648 
               
               
                   
                 PTPRC 
                 rs4915154 
               
               
                   
                 PVRL2 
                 rs394221 
               
               
                   
                 RPL5 
                 rs6604026 
               
               
                   
                 SELE 
                 rs1805193 
               
               
                   
                 SELE 
                 rs5361 
               
               
                   
                 SPARCL1 
                 rs1049544 
               
               
                   
                 Spp1 
                 rs1126616 
               
               
                   
                 Spp1 
                 rs1126772 
               
               
                   
                 Spp1 
                 rs2853744 
               
               
                   
                 Spp1 
                 rs9138 
               
               
                   
                 Spp1 
                 rs4754 
               
               
                   
                 STAT1 
                 rs1547550 
               
               
                   
                 STAT1 
                 rs2066802 
               
               
                   
                 TAC1 
                 rs2072100 
               
               
                   
                 TAC1 
                 rs7793277 
               
               
                   
                 TGFB1 
                 rs1800469 
               
               
                   
                 TGFB1 
                 rs1800470 
               
               
                   
                 TGFB1 
                 rs1800471 
               
               
                   
                 TGFB1 
                 rs1982073 
               
               
                   
                 TNF-alpha 
                 rs1800629 
               
               
                   
                 TRAIL 
                 rs1131568 
               
               
                   
                 TRIF (TICAM1) 
                 rs1046673 
               
               
                   
                 TRIF (TICAM1) 
                 rs2292151 
               
               
                   
                 UCP2 
                 rs659366 
               
               
                   
                 VDR 
                 rs10735810 
               
               
                   
                 VDR 
                 rs1544410 
               
               
                   
                 VDR 
                 rs731236 
               
               
                   
                   
               
             
          
         
       
     
         [0143]    Each individual in the study population is tested to determine an outcome for each of the discriminating variables for the particular phenotype. This provides a number of outcomes for each individual. Testing, e.g. genotyping, may be carried out by any of the methods described herein, e.g. by microarray analysis as described herein. Testing is typically ex vivo, carried out on a suitable sample obtained from an individual. 
         [0144]    Multiple genotype-phenotype associations may then be analysed using stepwise multivariate logistic regression analysis, using as the dependent variable the clinically determined MS phenotype and as independent variables the outcomes of the informative variables. The goodness of fit of the models obtained may be evaluated using Hosmer-Lemeshow statistics and their accuracy assessed by calculating the area under the curve (AUC) of the Receiver Operating Characteristic curve (ROC) with 95% confidence intervals (see, e.g. (Janssens A C J W et al., 2006)). 
         [0145]    Mean probability function values for each of the alternative phenotypes in the population can be compared using a t test. In general the probability functions are able to distinguish between the different phenotypes in the study population in a statistically significant way, for example, at p≦0.05 in a t-test. Thus the probability functions produce a statistically significant separation between individuals of different phenotype in the population. 
         [0146]    In some embodiments, the presence of two or more genetic markers in a sample from an MS patient is compared to the presence of two or more genetic markers in a control sample. In some embodiments a control sample is a sample from an individual who does not have MS. In other embodiments a control sample is a sample from an individual who has MS. In certain embodiments, a control sample is a sample from an individual who has MS of a specified classification or degree of severity. It will be understood that the interpretation of a comparison between a test sample and a control sample will depend on the nature of both samples. One possible measurement of the level of expression of genetic markers in a sample is the absolute number of genetic markers identified in a sample. Another measurement of the level of expression of genetic markers in a sample is a measurement of the specific combination of genetic markers in a sample. 
         [0147]    In some embodiments, a control value may be a predetermined value, which can take a variety of forms. It can be a single cut-off value, such as a median or mean. It can be established based upon comparative groups, such as in groups not having MS, or groups have specified classifications or levels of severity of MS. For example, in some embodiments, a control sample that is taken from an individual who does not have MS, may be considered to exhibit control or normal patterns of expression of genetic markers for MS. In some embodiments where severity of MS is being assessed, a control sample that is taken from an individual that has a specified classification or level of severity of MS, such as a mild form of MS, may be considered to exhibit a normal or control pattern of expression of markers for MS. In some embodiments a control sample will be from an individual who is of the same ethnic background, gender, age, MS classification and/or MS disease duration as the individual who is being screened and/or diagnosed. 
         [0148]    Based at least in part on results of correlations and methods discussed herein, predetermined values can be arranged. For example, test samples and subjects from which the samples were extracted can be divided into groups such as low-severity, medium-severity, and high-severity groups based on the presence of two or more genetic markers that are correlated to MS severity. In some embodiments the classification of a sample and subject into a group can be used to aid or assist in screening, diagnosis, prognosis or development of a treatment strategy for a given subject. 
         [0149]    Described herein are correlations between the presence of specific genetic markers and the severity of symptoms of MS in a patient. Such correlations and methods for detecting such correlations have widespread applications for MS patients. In some embodiments methods described herein are used to screen patients who have or are at risk of having MS. In some embodiments, evaluation of the presence of two or more SNPs in a patient will be used to assist in the diagnosis or to indicate or evaluate the severity of MS in the patient. In some embodiments, genetic information obtained from methods described herein will be combined with other clinical data to assess the severity of MS in a given patient. 
         [0150]    In some embodiments, the identification of two or more SNPs in a DNA sample from an MS patient will be used to initiate or change a treatment regimen for the patient. For example, in some embodiments, detection of two or more SNPs that are associated with increased severity of MS may cause a physician to change the treatment strategy of an MS patient in order to target a more severe form of the disease, or advise a patient that they may benefit from a change in treatment strategy. In some embodiments, detection of two or more SNPs that are associated with increased severity of MS may cause a physician to monitor an MS patient more closely or rigorously. In some embodiments, detection of two or more SNPs that are associated with increased severity of MS may cause a physician to recommend or advise that a patient undergo genetic counselling. 
         [0151]    In some aspects of the invention measurement of clinical variables comprises part of the severity prediction model along with the genetic variables in Table 1, above. Some non-limiting examples are age at onset, gender of patient studied, and type of onset of the disease (e.g. progressive or relapsing) (see Table 2). Age at onset refers to the age in years at which the patient was diagnosed with MS. In the present models this measure has been treated as a continuous variable, which is included in the logistic regression function of the models. Thus an outcome for this variable is age of patient when diagnosed for MS. 
         [0152]    Gender refers to the gender of the patient diagnosed with MS. In the present models this measure has been treated as a categorical variable, with levels “male” and “female”, which is included in the logistic regression function of the models. Thus an outcome for this variable is gender of patient diagnosed with MS. If the gender is male, this is coded as (1), and if the gender is female, this is coded as (0). 
         [0153]    Type of onset refers to the type of onset of disease, progressive or relapsing, for the studied patient diagnosed with MS. In the present models this measure has been treated as a categorical variable, which is included in the logistic regression function of the models. Thus an outcome for this variable is age of patient when diagnosed for MS. If the type of onset is progressive, this is coded as (1), and if the type of onset is relapsing, this is coded as (0). 
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Clinical Variables 
               
             
          
           
               
                   
                 Variable 
                 Variable Type 
               
               
                   
                   
               
               
                   
                 Age at onset (Age_at_onset) 
                 Continuous variable 
               
               
                   
                 Gender 
                 Categorical variable 
               
               
                   
                 Onset type (Onsettype_cod) 
                 Categorical variable 
               
               
                   
                   
               
             
          
         
       
     
         [0154]    In embodiments comprising methods of evaluation of MS severity in a patient, the method typically comprises determining or obtaining for the subject, an outcome for each of the variables listed in Table 2. In some embodiments, use of the results of the measurements of these variables, along with the variables in Table 1, allows prognosis of MS severity phenotype in a Dutch population with an LR+ of 8.4. Details for the calculation of a probability function using these variables are given in Table 3. 
         [0155]    Preferably the number and combination of variables such as SNPs used to construct a model for predicting a phenotype according to the invention, is such that the model allows prediction to be made with an LR+ value of at least 1.5, such as at least 2, 3, 4, 5, 6, 7, 8, 9, or 10. Calculation of LR+ values is described herein. 
         [0156]    Once an outcome is determined for each of the variables for prediction of a given phenotype, these outcomes are used in or inserted in a suitable probability function (for prediction of that phenotype), as described herein and a probability function value is calculated. Outcomes may be codified for use in the probability function and calculation of the probability function value. The probability function value is then compared with probability function values obtained for a population of individuals of known (clinically determined) phenotype. The risk of the subject having or developing the particular phenotype is thereby determined. 
         [0157]    The sensitivity, specificity, and positive likelihood ratio (LR+=sensitivity/(1-specificity)) may be computed by means of ROC curves. Preferably the model has an LR+ value of at least 1.5, for example, at least 2, 3, 4, 5, 6, 7, 8, 9 or 10. 
         [0158]    Also within the scope of the invention are kits and instructions for their use. In some embodiments kits associated with the invention are kits for identifying two or more SNPs within a patient sample. In some embodiments a kit may contain primers for amplifying a specific genetic locus. In some embodiments, a kit may contain a probe for hybridizing to a specific SNP. A kit of the invention can include a description of use of the contents of the kit for participation in any biological or chemical mechanism disclosed herein. A kit can include instructions for use of the kit components alone or in combination with other methods or compositions for assisting in screening or diagnosing a sample and/or determining a treatment strategy for MS. 
         [0159]    The kits described herein may also contain one or more containers, which may contain a composition and other ingredients as previously described. The kits also may contain instructions for mixing, diluting, and/or administering or applying the compositions of the invention in some cases. The kits also can include other containers with one or more solvents, surfactants, preservative and/or diluents (e.g., normal saline (0.9% NaCl), or 5% dextrose) as well as containers for mixing, diluting or administering the components in a sample or to a subject in need of such treatment. 
         [0160]    The compositions of the kit may be provided as any suitable form, for example, as liquid solutions or as dried powders. When the composition (e.g., a primer) provided is a dry powder, the composition may be reconstituted by the addition of a suitable solvent, which may also be provided. In embodiments where liquid forms of the composition are used, the liquid form may be concentrated or ready to use. The solvent will depend on the composition and the mode of use or administration. Suitable solvents for drug compositions are well known, for example as previously described, and are available in the literature. The solvent will depend on the composition and the mode of use or administration. 
         [0161]    As used herein, the term “subject” refers to a human or non-human mammal or animal. Non-human mammals include livestock animals, companion animals, laboratory animals, and non-human primates. Non-human subjects also specifically include, without limitation, chickens, horses, cows, pigs, goats, dogs, cats, guinea pigs, hamsters, mink, and rabbits. In some embodiments of the invention, a subject is a patient. As used herein, a “patient” refers to a subject who is under the care of a physician or other health care worker, including someone who has consulted with, received advice from or received a prescription or other recommendation from a physician or other health care worker. A patient is typically a subject having or at risk of having MS. 
         [0162]    The term “treatment” or “treating” is intended to relate to prophylaxis, amelioration, prevention and/or cure of a condition (e.g., MS). Treatment after a condition (e.g., MS) has started aims to reduce, ameliorate or altogether eliminate the condition, and/or its associated symptoms, or prevent it from becoming worse. Treatment of subjects before a condition (e.g., MS) aims to reduce the risk of developing the condition and/or lessen its severity if the condition does develop. As used herein, the term “prevent” refers to the prophylactic treatment of a subject who is at risk of developing a condition (e.g., MS) resulting in a decrease in the probability that the subject will develop the disorder, and to the inhibition of further development of an already established disorder. 
         [0163]    Treatment for MS varies with the stage of the disease and the clinical presentation of the patient. In general it is advantageous to begin treatment early in the course of the disease. Goals for treatment may include slowing the progression of the disease, reducing the number of the attacks, and improving recovery from attacks. Corticosteroids such as Methylprednisolone (Solu-Medrol®, Medrol, Depo-Medrol), and Prednisone (Deltasone®, Liquid Pred, Orasone, Prednicen-M) are used to treat exacerbations of MS. In some embodiments Methylpredisone is given intravenously for 2-7 days, followed by a course of Prednisone. Corticosteroids may be used only for very severe attacks, as the effects vary and there are numerous reported side effects. 
         [0164]    In some embodiments an MS patient is treated with therapies that can modify the course of the disease. Certain immune modulatory therapies are thought to slow the progression of MS by tempering the immune system&#39;s attack on the central nervous system. Some non-limiting examples include Interferon beta-1a, Interferon beta-1b, and Glatiramer acetate. Some examples of Interferon beta-1a include Avonex® and Rebif®. Avonex® is typically administered by intramuscular injection once weekly, whereas Rebif® is typically administered subcutaneously 3 times per week, at a dose of 22 or 44 mcg. Interferon beta-1b, e.g. Betaseron, is in some embodiments given by subcutaneous injection ever other day. Patients treated with interferon may experience fewer relapses or faster recovery from attacks, and an overall slowing of the progression of the disease. Glatiramer acetate, e.g. Copaxone®, is a synthetic amino acid that modifies actions of the immune system that may affect the progression of MS. It has been shown to reduce the frequency of exacerbations and the level of disability. In some embodiments this medication is given subcutaneously daily. 
         [0165]    Other immune modulatory therapies include Natalizumab (Tysabri®), a monoclonal antibody against VLA-4, Mitoxantrone (Novantrone®), a chemotherapy drug. Natalizumab is administered via monthly intravenous injections and has been shown to reduce the frequency of clinical relapses and delay the progression of physical disability. Mitoxantrone is used for reducing neurologic disability and/or the frequency of clinical relapses. In some embodiments vitamin D is used as a treatment. 
         [0166]    Other treatments for relief from complications of the disease are aimed at specific to symptoms, such as muscle spasticity, weakness, eye problems, fatigue, emotional outbursts, pain, bladder dysfunction, constipation, sexual dysfunction, and tremors. 
       EXAMPLES 
       [0167]    In multiple sclerosis (MS), the total volume of spinal and brain lesions and their spatial distribution are highly variable. Elucidating this variability may contribute to understanding clinical heterogeneity in MS. 
       Materials and Methods 
     Study Participants: 
       [0168]    Patients were selected retrospectively from natural history studies conducted at the 
         [0169]    MS Center at the VU University Medical Center in Amsterdam. Patients were selected for the availability of DNA material, as well as spinal cord and brain MRI, which fulfilled certain standardization requirements and were performed less than two years apart. The study was carried out with the approval of the Medical Ethical Committee of the VUmc and informed consent was obtained from all participants. Patients, all diagnosed with MS ascertained by Poser or McDonald criteria (Poser et al., Ann. Neurol 1983;3:227-231; Polman C H et al., Ann. Neurol. 2005;6:840-846). For the patients included in the analysis, clinical data were collected including age, gender, type of disease onset, age at onset, disease course and duration of disease. Disability status was determined for all subjects by using Kurtzke&#39;s Expanded Disability Status Scale (EDSS) and when available Multiple Sclerosis Functional Composite scale (MSFC). 
       Selection of SNPs: 
       [0170]    Polymorphisms were selected based on published involvement in MS pathogenesis, prognosis and response to treatment. The polymorphisms were confirmed and associated to an identifier by using dbsnp database (www.ncbi.nlm.nih.gov/SNP). Nucleotide sequences for the design of allele-specific probes and PCR primers where retrieved in the SNPper database (http://snpper.chip.org/bio). Sequence specific probes and primers were designed by using the software Primer3 freely available at http://frodo.wi.mit.edu/. Some non-limiting examples of probes and primers useful in the instant invention can be found in Tables 7-9. 
         [0171]    If a polymorphism was not present in the database, position and sequences were established by performing a blast search (http://www.ncbi.nlm.nih.gov.catalog.llu.edu/BLAST/) using the data available in the literature. 
       Genotyping 
       [0172]    Genomic DNA was isolated from anti-coagulated blood with DNAzo1 reagent (Molecular Research Center, Inc., Cincinnati, Ohio). 
         [0173]    Genotyping was carried out using a newly developed low-density DNA microarray based on allele-specific probes. The design, fabrication, validation and analysis of the arrays were performed following the procedure described by Tejedor et al. (2005),  Clin. Chem.,  Vol. 51(7), pp. 1137-1144, with minor modifications. 
       Brain MRI 
       [0174]    Scans were acquired either on 1.0 Tesla or 1.5 Tesla (Siemens) scanners with standard head coils, using standard 2D conventional or fast spin-echo PD- and T2-weighted images (TR: 2200-3000 ms, TE: 20-30 &amp; 80-100 ms) with a slice thicknesses of 3-5 mm, a maximum gap between slices of 0.5 mm, and an in-plane resolution of 1×1 mm 2 . Lesions were identified by an expert reader and then outlined on the corresponding PD image using home-developed semi-automated seed-growing software based on a local thresholding technique. Lesion areas were multiplied with the interslice distance to obtain total T2 brain lesion volume for each patient. 
       Spinal Cord MRI: 
       [0175]    Spinal cord scanning included a cardiac-triggered sagittal PD and T2-weighted dual-echo spin echo sequence with a slice-thickness of 3mm covering the whole spinal cord (TR: 2500-3000 ms, TE: 20-30 &amp; 80-100 ms) with an in plane resolution of 1×1 mm. From this sequence the number of focal abnormalities and the presence of diffuse abnormalities were scored by one experienced reader (CL). Diffuse abnormalities were defined as areas with poorly delineated areas of increased signal intensity compared to signal intensity of spinal CSF on intermediate-weighted images. 
       Statistical Methods for MRI Data: 
       [0176]    First the association between the brain parameter (T2 lesion load) and spinal cord parameters (number of focal lesions, presence of diffuse abnormalities) were tested per SNP and per clinical variable. The non-parametric Kruskal-Wallis test and ChiSquare test were used appropriately, applying the False Discovery Rate (FDR) according to Benjamini and Hochberg (Benjamini, Y, 1995, J. R. Stat. Soc. B Met 289) to correct for multiple testing. The corrected number represents the expected proportion false discoveries for a given p-value cut-off. The cut-off point after FDR correction of p&lt;0.05 was used. Pearson&#39;s correlation coefficient was used to test the correlations between two scaled variables. All analyses were performed using SPSS (version 15; SPSS Inc., Chicago, Ill., USA). 
       Statistical Methods for Regression and Association Analysis: 
       [0177]    First the association between MS severity score, the brain parameter (T2 lesion load) and spinal cord parameters (number of focal lesions, presence of diffuse abnormalities) were tested per SNP and per clinical variable and statistically significant associations between particular genotypes and particular phenotypes are identified. Methods for determining statistical significance are known in the art. Models were created by means of multivariate logistic and/or linear regression, for categorical or continuous dependent variables respectively, with clinically determined disease phenotypes as dependent variables and the SNPs and clinical variables as independent variables or regressors. To evaluate the impact of the regressors included in the prognosis of the analysed phenotypes, the sensitivity, specificity and positive likelihood ratio (LR+=sensitivity/(1-specificity)) were computed by means of Receiver Operating Characteristic curves. In the case of multiple linear regression, the impact of the regressors the corrected R square was computed. All analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 15 and HelixTree (Golden Helix, Inc., Bozeman, Mont.). 
       Example 1 
     Identification of Polymorphisms Associated with Increased MSSS Score 
       [0178]    The invention presents a model for predicting the probability of having a stronger disability, as measured by the MSSS scale, thus allowing differential treatment management for a given patient. This model was obtained from the analysis of 605 MS patients. The invention evaluates differences between patients that have an MSSS score of less than 2.5 versus patients that have an MSSS score of 2.5 or greater. 
         [0179]    Table 3 (shown below) shows the six SNPs (rs876493, rs1137933, rs1318, rs2069763, rs2107538 and 2073 Intron2 C/T (rs423904)) with the associated genotypes and the three clinical variables (age at onset, gender and onset type) and the associated levels, together with their significance (Sig.), the coefficients in the model (B) and their odds ratios (OR) with lower and upper bound confidence intervals (I.C 95.0% for OR) used to compute the model for the prediction of the MSSS&lt;2.5 versus≧2.5 phenotype. This model provides the probability to develop a severe form of MS. 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Regression Analysis 
               
             
          
           
               
                   
                 I.C. 95% for OR 
               
             
          
           
               
                   
                 Genotype/ 
                   
                   
                   
                 Lower 
                   
               
               
                 Variable name 
                 Variable level 
                 Sig. 
                 B 
                 OR 
                 bound 
                 Upper bound 
               
               
                   
               
             
          
           
               
                 IL1RN 2073 Intron2 
                 CC vs CT/TT 
                 0.064 
                 −0.469 
                 0.625 
                 0.381 
                 1.028 
               
               
                 C/T (rs423904) 
               
               
                 PNMT rs876493 
                 AA/AG vs GG 
                 0.025 
                 −0.65 
                 0.522 
                 0.295 
                 0.923 
               
               
                 Age_at_onset 
                   
                 0.004 
                 0.048 
                 1.049 
                 1.016 
                 1.083 
               
               
                 gender 
                 0 = female vs 
                 0.017 
                 0.684 
                 1.982 
                 1.127 
                 3.485 
               
               
                   
                 1 = male 
               
               
                 Onsettype_cod 
                 0 = relapsing 
                 0.021 
                 1.466 
                 4.331 
                 1.244 
                 15.082 
               
               
                   
                 vs 1 = progressive 
               
               
                 NOS2A rs1137933 
                 GG vs AG/AA 
                 0.005 
                 −0.715 
                 0.489 
                 0.298 
                 0.803 
               
               
                 PITPNC1 rs1318 
                 AA vs AG/GG 
                 0.002 
                 −0.775 
                 0.461 
                 0.28 
                 0.759 
               
               
                 IL2 rs2069763 
                 GG vs GT/TT 
                 0.001 
                 −0.922 
                 0.398 
                 0.23 
                 0.688 
               
               
                 CCL5 rs2107538 
                 CC vs CT/TT 
                 0.023 
                 0.649 
                 1.914 
                 1.092 
                 3.355 
               
               
                   
               
             
          
         
       
     
         [0180]      FIG. 1  shows a ROC (receiver operating characteristic) curve obtained for the model MSSS&lt;2.5 versus≧2.5 that allows the estimation of its discriminatory power. The 
         [0181]    ROC curve was calculated in order to maximize the specificity, thus reducing at the same time the “false” positive rate. A specificity of 95.3% with a sensibility of 39.7% is the cut-off for this model regarding the phenotype MSSS&lt;2.5 versus≧2.5. This model shows a positive likelihood ratio (LR+) value of 8.4. 
         [0182]    Additional MS patients have been recruited increasing the MS cohort to 700 MS patients. In a first stage of analysis, feature selection was employed to identify the most important and predictive features in the model to be analyzed. This approach of variable filtering is based on the marginal association between each variable (SNP or clinical variable) and phenotype, as variables are typically filtered on the basis of a p-value cut-off from a univariate analysis. For the selection of variables, HelixTree® software (Golden Helix, Inc., Bozeman, Mont., USA) was used to calculate allelic association between different groups. In Table 3A, SNPs associated with MSSS score at a significance level of p&lt;0.1 set as the decision threshold are shown. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3A 
               
             
             
               
                   
               
               
                 Table showing the 37 SNPs associated with MSSS score at the selected 
               
               
                 significance level 
               
             
          
           
               
                   
                 Rs-number SNP 
                 Gene 
                 Sig. p-value 
               
               
                   
                   
               
             
          
           
               
                   
                 rs3756450 
                 LOC728594 
                 0.00436 
               
               
                   
                 rs12047808 
                 C1orf125 
                 0.00883 
               
               
                   
                 rs10259085 
                 C1GALT1 
                 0.00949 
               
               
                   
                 rs1042173 
                 SLC6A4 
                 0.01142 
               
               
                   
                 rs1318 
                 PITPNC1 
                 0.01426 
               
               
                   
                 rs6077690 
                 SNAP25 
                 0.02478 
               
               
                   
                 rs1611115 
                 DBH 
                 0.02577 
               
               
                   
                 rs2107538 
                 CCL5 
                 0.03258 
               
               
                   
                 rs4473631 
                 MORF4 
                 0.03348 
               
               
                   
                 rs2032893 
                 SLC1A3 
                 0.03470 
               
               
                   
                 rs2066713 
                 SLC6A4 
                 0.03744 
               
               
                   
                 rs260461 
                 ZNF544 
                 0.03924 
               
               
                   
                 rs3787283 
                 SNAP25 
                 0.03976 
               
               
                   
                 rs1137933 
                 NOS2A 
                 0.04094 
               
               
                   
                 rs6917747 
                 IGF2R 
                 0.04710 
               
               
                   
                 rs2049306 
                 CSMD1 
                 0.04909 
               
               
                   
                 rs12861247 
                 STS 
                 0.05177 
               
               
                   
                 rs4404254 
                 ICOS 
                 0.05585 
               
               
                   
                 rs4680534 
                 IL12A 
                 0.05729 
               
               
                   
                 rs17641078 
                 DMRT2 
                 0.05833 
               
               
                   
                 rs2187668 
                 HLA-DQA1 
                 0.06045 
               
               
                   
                 rs7528684 
                 FCRL3 
                 0.06099 
               
               
                   
                 rs876493 
                 PNMT 
                 0.06135 
               
               
                   
                 rs7577925 
                 FLJ34870 
                 0.06232 
               
               
                   
                 rs1805009 
                 MC1R 
                 0.06375 
               
               
                   
                 rs423904 
                 IL1RN 
                 0.06449 
               
               
                   
                 rs3741981 
                 OAS1 
                 0.06993 
               
               
                   
                 (rs1131454 in 
               
               
                   
                 version. 37.1) 
               
               
                   
                 rs2069763 
                 IL2 
                 0.07750 
               
               
                   
                 rs12202350 
                 IGF2R 
                 0.07981 
               
               
                   
                 rs28386840 
                 SLC6A2 
                 0.08145 
               
               
                   
                 rs2028455 
                 LOC647094 
                 0.08244 
               
               
                   
                 rs10492503 
                 GPC5 
                 0.08486 
               
               
                   
                 rs8049651 
                 GRIN2A 
                 0.08826 
               
               
                   
                 rs13353224 
                 DSEL 
                 0.08906 
               
               
                   
                 rs1555322 
                 MMP24 
                 0.09161 
               
               
                   
                 rs10243024 
                 MET 
                 0.09398 
               
               
                   
                 rs6570426 
                 LOC729293 
                 0.09635 
               
               
                   
                   
               
             
          
         
       
     
         [0183]    A Multivariate prognostic model was then constructed for dichotomous MSSS with the cut-off point of 2.5 using logistic regression model, using SPSS version 15.0 (SPSS Inc. Headquarters, Chicago, Ill., USA) and R packages Design (Harrell, 2001) and Stats (R Development Core Team, 2008). The model was developed including information for the clinical variables available. 
         [0184]    85% of the cohort was selected at random as exploratory cohort (n=595) and the 15% of the cohort as replication cohort (n=105). The model obtained with the exploratory cohort (Table 3B) included the same variables as the one obtained from the analysis of 605 io MS patients (Table 3). The model showed in Table 3B was validated in the replication cohort (AUC exploratory cohort=0.743 (0.691-0.796) ( FIG. 5 ) versus AUC replication cohort=0.787 (0.667-0906) ( FIG. 6 ), differences between both ROC curves not statistically significant). 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 3B 
               
             
             
               
                   
               
               
                 Regression Analysis 
               
             
          
           
               
                   
                 I.C. 95% for OR 
               
             
          
           
               
                 Variable name 
                 Genotype/Variable level 
                 Sig. 
                 B 
                 OR 
                 Lower bound 
                 Upper bound 
               
               
                   
               
             
          
           
               
                 IL1RN 2073 Intron2 C/T (rs423904) 
                 CC vs CT/TT 
                 0.056 
                 −0.482 
                 0.618 
                 0.377 
                 1.012 
               
               
                 PNMT rs876493 
                 AA/AG vs GG 
                 0.071 
                 −0.531 
                 0.588 
                 0.331 
                 1.046 
               
               
                 Age_at_onset 
                   
                 0.069 
                 0.028 
                 1.029 
                 0.998 
                 1.061 
               
               
                 gender 
                 0 = female vs 1 = male 
                 0.01 
                 0.743 
                 2.102 
                 1.194 
                 3.703 
               
               
                 Onsettype_cod 
                 0 = relapsing vs 1 = progressive 
                 0.006 
                 1.71 
                 5.529 
                 1.616 
                 18.917 
               
               
                 NOS2A rs1137933 
                 GG vs AG/AA 
                 0.018 
                 −0.593 
                 0.553 
                 0.339 
                 0.901 
               
               
                 PITPNC1 rs1318 
                 AA vs AG/GG 
                 0.026 
                 −0.561 
                 0.571 
                 0.349 
                 0.934 
               
               
                 IL2 rs2069763 
                 GG vs GT/TT 
                 0.009 
                 −0.709 
                 0.492 
                 0.288 
                 0.839 
               
               
                 CCL5 rs2107538 
                 CC vs CT/TT 
                 0.031 
                 0.606 
                 1.832 
                 1.058 
                 3.173 
               
               
                   
               
             
          
         
       
     
         [0185]    The model obtained from the analysis of the 700 MS patients is showed in Table 3C. The model includes the same variables that the obtained from the analysis of 605 MS patients (Table 3) and from the analysis of the exploratory cohort or 595 MS patients (Table 3B). 
         [0000]                                                                                          TABLE 3C                   Regression Analysis                I.C. 95% for OR            Variable name   Genotype/Variable level   Sig.   B   OR   Lower bound   Upper bound                    IL1RN 2073 Intron2 C/T (rs423904)   CC vs CT/TT   .084   −.404   .668   .422   1.056       PNMT rs876493   AA/AG vs GG   .053   −.533   .587   .342   1.006       Age_at_onset       .015   .036   1.036   1.007   1.066       gender   0 = female vs 1 = male   .017   .634   1.884   1.119   3.173       Onsettype_cod   0 = relapsing vs 1 = progressive   .005   1.758   5.801   1.714   19.638       NOS2A rs1137933   GG vs AG/AA   .005   −.649   .522   .331   .824       PITPNC1 rs1318   AA vs AG/GG   .025   −.527   .590   .373   .935       IL2 rs2069763   GG vs GT/TT   .001   −.818   .441   .267   .730       CCL5 rs2107538   CC vs CT/TT   .015   .643   1.902   1.132   3.196                    
The ROC curve area obtained for the model MSSS≧2.5 vs MSSS&lt;2.5 analysing the 700 MS patients is 0.749 (95% CI 0.700-0.797) ( FIG. 7 ). A specificity of 95% with a sensitivity of 32% is the cut-off for this model. The model shows a positive likelihood ratio (LR+) value of 6.2.
 
       Example 2 
     Identification of SNPs Associated with T2 Brain Lesions 
       [0186]    In order to determine whether certain SNPs are associated with increasing size and distribution of T2 brain lesions, analysis was performed on a group of 208 MS patients with MRI data collected. The MRI data show spatial distribution of T2 brain lesions.  FIG. 2  shows lesion frequency across the patient sample. 
         [0187]      FIG. 3  shows maps of clusterwise (t=2) associations of lesion presence with genotype, on a background of the common brain image. The cluster colour bar indicates clusterwise p-value, with the range indicated by the colour bar; only clusters with p&lt;0.05 are shown. These data have been correlated to genotype data. The results show significant associations for four SNPs to brain lesions. A: rs2213584 (HLA-DRA gene); B: rs2227139 (HLA-DRA gene); C: rs2076530 (BTNL2 gene); D: rs876493 (PNMT gene). 
       Example 2A 
     Identification of SNPs Associated with T2 Brain Lesions 
       [0188]    Further investigation was carried out essentially as described in Example 2. Additionally, lesions were manually outlined on Magnetic Resonance Imaging scans and binary lesion masks were produced and registered to a common space. Using Randomise software, the lesion masks were related to genotype using a voxelwise nonparametric General Linear Model approach, followed by clusterwise analysis. The results show significant associations for eight SNPs to brain lesions: rs9808753 (IFNGR2 gene), rs2074897 (NDUFS7 gene), rs762550 (CRYAB gene), rs2076530 (BTNL2 gene), rs2234978 (FAS gene), rs3781202 (FAS gene), rs2107538 (CCL5 gene), rs659366 (UCP2 gene). 
       Example 3 
     Identification of SNPs Associated with MS Severity Phenotypes 
     Patient Characteristics: 
       [0189]    One hundred and fifty patients were included in the analysis. The patient group reflects a representative MS population, with approximately 35% men and 20% primary progressive MS patients (see Table 4). The majority of patients (132/150) demonstrated abnormalities on the spinal cord MRI scan, while all patients had abnormalities on the brain MRI scan. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 Patient characteristics 
               
             
          
           
               
                   
                 All 
                 RR 
                 SP 
                 PP 
               
               
                   
                   
               
             
          
           
               
                 Total n 
                 150 
                 88 
                 32 
                 30 
               
             
          
           
               
                 Gender (n; % M) 
                 55 
                 (36.7%) 
                 26 
                 (29.5%) 
                 17 
                 (53.1%) 
                 12 
                 (40%) 
               
             
          
           
               
                 Age at MRI (mean) 
                 41.4 
                 36.1 
                 46.5 
                 51.2 
               
             
          
           
               
                 Disease duration mean (range) 
                 7.1 
                 (0.0-33.0) 
                 4.36 
                 (0.0-32.0) 
                 12.8 
                 (2.0-33.0) 
                 9.2 
                 (0.0-28.0) 
               
             
          
           
               
                 EDSS (median) 
                 3.5 
                 2.0 
                 5.5 
                 4.0 
               
               
                 T2 lesionload (ml) (mean) 
                 7.7 
                 4.9 
                 16.2 
                 7.0 
               
               
                 Number of focal lesions in the spinal 
                 3.4 
                 3.3 
                 4.5 
                 2.8 
               
               
                 cord (mean) 
               
               
                 Percentage of patients with diffuse 
                 13.3 
                 10.2 
                 18.8 
                 16.7 
               
               
                 abnormalities (%) 
               
               
                   
               
             
          
         
       
     
       Genotyping: 
       [0190]    In total 80 SNPs in 44 genes were selected on the MSchip. Twelve SNPs were excluded from further analysis: five were monomorphic and seven SNPs had a minor allele frequency below five percent (see Table). Hardy Weinberg equilibrium was calculated for all SNPs. Values are noted in table 5. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Results analysis of the correlation SNPs and MRI parameters. 
               
             
          
           
               
                 Clinical/MRI 
                   
                   
                   
                   
               
               
                 parameter 
                   
                   
                 Uncorrected p- 
                 FDR- 
               
               
                 correlated 
                 Rs-number 
                   
                 value Kruskal 
                 corrected 
               
               
                 with SNPs: 
                 SNP 
                 Gene 
                 Wallis test: 
                 p-value 
               
               
                   
               
             
          
           
               
                 Number of 
                 rs3135388 
                 MHC II 
                 0.00082 
                 0.03 
               
               
                 focal 
                 rs2395182* 
                 MHC II 
                 0.00107 
                 0.03 
               
               
                 lesion in the 
                 rs2239802* 
                 MHC II 
                 0.00122 
                 0.03 
               
               
                 spinal cord 
                 rs2227139** 
                 MHC II 
                 0.00169 
                 0.03 
               
               
                   
                 rs2213584** 
                 MHC II 
                 0.00330 
                 0.05 
               
               
                   
                 rs3087456 
                 MHC II 
                 0.00900 
                 0.10 
               
               
                   
                   
                 TransActivator 
               
               
                 T2 lesion 
                 rs2107538 
                 CCL5 
                 0.001 
                 0.07 
               
               
                 load in the 
               
               
                 brain 
               
               
                   
               
               
                 * and ** LD values still need to be calculated. 
               
             
          
         
       
     
       Correlation Between Clinical Parameters and MRI Features: 
       [0191]    The EDSS showed a mild correlation with the number of focal lesions in the spinal cord (p=0.043, r=0.165, Pearson correlation), with the number of segments involved (p=0.006, r=0.224, Pearson correlation) and a moderate correlation with T2 lesion load in the brain (p&lt;0.001, r=0.395). A weak correlation was present between the number of focal spinal cord lesions and T2 lesion load in the brain (p=0.063, r=0.152). 
         [0192]    Disease duration was found to be related to number of segments of the spinal cord involved (p=0.017, r=0.195). 
         [0193]    The T2 lesion load in the brain was closely related to the PASAT score (p=0.000, r=−0.581) and 9 Hole Peg Test of the dominant hand (p=0.001, r=0.306). 
       Correlation Between Lesion Load in the Brain and Genotypes: 
       [0194]    In the univariate analysis on T2 lesion load in the brain and the MS-chip, the only ‘trend’ correlation was rs2107538 (CCL5) (see Table 5). 
       Correlation Between Spinal Cord Abnormalities and Genotypes: 
       [0195]    Several HLA SNPs were found to be related to the number of focal spinal cord abnormalities (see Table 5). The most significant is SNP rs3135388. Carriership of the A-allele (surrogate marker for HLA-DRB1*1501) was associated with a significantly higher number of lesions in the spinal cord ( FIG. 4 ). 
         [0196]    When corrected for multiple testing, five SNPs within the MHC region (rs3135388, rs2395182, rs2239802, rs2227139 and rs2213584), remained significant and one SNP within the MHC-2TA gene (Major Histocompatibility Complex Class II Transactivator) showed a trend towards a correlation. The five HLA SNPs are in high linkage disequilibrium. 
         [0197]    A linear model has been developed using multiple linear regression to predict the number of focal lesions in the spinal cord. This method uses three of these SNPs rs3135388, rs3087456, and rs2227139. A model including the combination of these three SNPs improves the use of one single SNP (rs3135388) for prediction of number of focal lesions in the spinal cord. Corrected Rsquared for model using only one SNP=0.064. Corrected Rsquared for model using combination of three SNPs=0.112. The combination of these three SNPs or any SNP in linkage disequilibrium with any of these three SNPs improves prediction of number of focal lesions in the spinal cord over the use of one single SNP. 
         [0198]    No interactions between the SNPs and the clinical variables were present. No association was observed between the presence of diffuse abnormalities and the evaluated SNPs. 
       Example 4 
     Identification of Additional SNPs Associated with MRI Parameters: Number of Focal Lesion in the Spinal Cord, T2 Lesion Load in the Brain and Presence of Diffuse Abnormalities 
       [0199]    In order to determine whether certain additional SNPs are associated with MRI parameters, a similar analysis to Example 3 was performed using different SNPs on one hundred and fifty patients. Results of the correlation of additional SNPs and MRI parameters are shown in table 5A. 
         [0200]    In our study cohort of 150 MS patients with MRI data, MRI data are significantly correlated with MS severity given by MSSS (p=0.023). It can thus be assumed that identification of SNPs associated with MRI parameters allows inferring MS severity. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 5A 
               
             
             
               
                   
               
               
                 Results of analysis of the correlation of additional SNPs and MRI 
               
               
                 parameters. 
               
             
          
           
               
                   
                 Clinical/ 
                   
                   
                   
               
               
                   
                 MRI 
                   
                   
                 Uncorrected 
               
               
                   
                 parameter 
                   
                   
                 p-value 
               
               
                   
                 correlated 
                 Rs-number 
                   
                 Kruskal 
               
               
                   
                 with SNPs: 
                 SNP 
                 Gene 
                 Wallis test: 
               
               
                   
                   
               
             
          
           
               
                   
                 Number of 
                 rs10492972 
                 KIF1B 
                 0.0063 
               
               
                   
                 focal lesion in 
                 rs12202350 
                 IGF2R 
                 0.005 
               
               
                   
                 the 
                 rs8049651 
                 GRIN2A 
                 0.0023 
               
               
                   
                 spinal cord 
                 rs8702 
                 KLC1 
                 5.00E−04 
               
               
                   
                 T2 lesion load 
                 rs987107 
                 IL7R 
                 0.0091 
               
               
                   
                 in the brain 
                 rs12861247 
                 STS 
                 0.005 
               
               
                   
                   
                 rs2074897 
                 NDUFS7 
                 0.006 
               
               
                   
                   
                 rs7995215 
                 GPC6 
                 0.006 
               
               
                   
                 Presence of 
                 rs1350666 
                 EREG 
                 0.008 
               
               
                   
                 diffuse 
                 rs3808585 
                 ADRA1A 
                 0.003 
               
               
                   
                 abnormalities 
                 rs4128767 
                 IL16 
                 0.006 
               
               
                   
                   
                 rs6457594 
                 MHC II 
                 0.005 
               
               
                   
                   
                 rs7208257 
                 ARRB2 
                 0.006 
               
               
                   
                   
                 rs7956189 
                 NTF3 
                 0.008 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 SNPs included in the analyses; HWE = Hardy-Weinberg Equilibrium in 
               
               
                 our sample; MAF = minor allele frequency in our sample 
               
             
          
           
               
                   
                   
                   
                 Poly- 
                   
                   
               
               
                 Gene 
                 rs-nr 
                 Chromosome 
                 morphism 
                 HWE* 
                 MAF 
               
               
                   
               
             
          
           
               
                 ADAMTS14 
                 rs4747075 
                 10q22 
                 A/G 
                 7.74* 
                 0.30 
               
               
                 ADAMTS14 
                 rs7081273 
                 10q22 
                 C/G 
                 1.2 
                 0.34 
               
               
                 ADAMTS14 
                 rs4746060 
                 10q22 
                 C/T 
                 1.05 
                 0.08 
               
               
                 Apo I/Fas 
                 rs1800682 
                 10q23 
                 C/T 
                 0.02 
                 0.47 
               
               
                 Apo I/Fas 
                 rs3781202 
                 10q23 
                 C/T 
                 7.41* 
                 0.40 
               
               
                 Apo I/Fas 
                 rs2234978 
                 10q23 
                 C/T 
                 0.43 
                 0.31 
               
               
                 BTNL2 
                 rs2076530 
                 6p21.3 
                 A/G 
                 29.78* 
                 0.26 
               
               
                 CACNG4 
                 rs4790896 
                 17q24 
                 A/G 
                 0.36 
                 0.41 
               
               
                 CCR5 
                 rs333 
                 3p21 
                 −/+ 
                 0.02 
                 0.11 
               
               
                 CD24 
                 rs8734 
                 6q21 
                 C 
                 NA 
                 0.00** 
               
               
                 CNTF 
                 rs1800169 
                 11q12 
                 A/G 
                 0.80 
                 0.12 
               
               
                 CRYAB 
                 rs14133 
                 11q21-q23 
                 C/G 
                 0.08 
                 0.27 
               
               
                 CRYAB 
                 rs762550 
                 11q21-q23 
                 A/G 
                 0.14 
                 0.42 
               
               
                 CRYAB 
                 rs2234702 
                 11q21-q23 
                 C 
                 NA 
                 0.00** 
               
               
                 CTLA4 
                 rs231775 
                 2q33 
                 A/G 
                 1.03 
                 0.37 
               
               
                 CTLA4 
                 rs5742909 
                 2q33 
                 C/T 
                 0.45 
                 0.09 
               
               
                 EBF 
                 rs1368297 
                 5q34 
                 A/T 
                 0.06 
                 0.38 
               
               
                 GABBRA1 
                 rs1805057 
                 6p22 
                 C 
                 NA 
                 0.00** 
               
               
                 HELZ 
                 rs2363846 
                 17q24 
                 C/T 
                 2.23 
                 0.48 
               
               
                 HLA 
                 rs2395166 
                 6p21.3 
                 C/T 
                 3.46 
                 0.47 
               
               
                 HLA 
                 rs2213584 
                 6p21.3 
                 A/G 
                 3.61 
                 0.40 
               
               
                 HLA 
                 rs2227139 
                 6p21.3 
                 C/T 
                 2.89 
                 0.40 
               
               
                 HLA 
                 rs3135388 
                 6p21.3 
                 A/G 
                 0.97 
                 0.33 
               
               
                 HLA 
                 rs9268458 
                 6p21.3 
                 A/C 
                 1.29 
                 0.20 
               
               
                 HLA 
                 rs6457594 
                 6p21.3 
                 A/G 
                 35.65* 
                 0.40 
               
               
                 HLA-DRA 
                 rs2395182 
                 6p21.3 
                 G/T 
                 1.04 
                 0.38 
               
               
                 HLA-DRA 
                 rs2239802 
                 6p21.3 
                 C/G 
                 1.34 
                 0.38 
               
               
                 IFNAR1 
                 rs2257167 
                 21q22 
                 C/G 
                 0.00 
                 0.08 
               
               
                 IFNGR2 
                 rs9808753 
                 21q22 
                 A/G 
                 0.00 
                 0.14 
               
               
                 IKBL 
                 rs3130062 
                 6p21.3. 
                 C/T 
                 1.14 
                 0.18 
               
               
                 IL-10 
                 rs1800896 
                 1q32 
                 A/G 
                 0.56 
                 0.46 
               
               
                 IL1B 
                 rs1799916 
                 2q14 
                 A 
                 NA 
                 0.00** 
               
               
                 IL1B 
                 rs1143627 
                 2q14 
                 A/G 
                 5.32* 
                 0.34 
               
               
                 IL-1B 
                 rs1143634 
                 2q14 
                 C/T 
                 0.01 
                 0.23 
               
               
                 IL-1RN 
                 rs419598 
                 2q12-q14 
                 C/T 
                 0.53 
                 0.31 
               
               
                 IL-1RN 
                 2073 
                 2q12-q14 
                 C/T 
                 0.72 
                 0.30 
               
               
                   
                 Intron2 C/T 
               
               
                   
                 (rs423904) 
               
               
                 IL-2 
                 rs2069763 
                 4q26 
                 G/T 
                 0.75 
                 0.36 
               
               
                 IL-2 
                 rs2069762 
                 4q26 
                 G/T 
                 0.31 
                 0.27 
               
               
                 IL-4R 
                 rs1801275 
                 16p12 
                 A/G 
                 0.37 
                 0.20 
               
               
                 IL7R 
                 rs11567685 
                 5p13 
                 C/T 
                 0.68 
                 0.25 
               
               
                 IL7R 
                 rs7718919 
                 5p13 
                 G/T 
                 0.22 
                 0.13 
               
               
                 IL7R 
                 rs11567686 
                 5p13 
                 A/G 
                 1.44 
                 0.34 
               
               
                 MC1R 
                 rs1805009 
                 16q24 
                 C/G 
                 0.02 
                 0.01** 
               
               
                 MC1R 
                 rs1805006 
                 16q24 
                 A/C 
                 0.00 
                 0.00** 
               
               
                 MEFV 
                 rs28940577 
                 16p13.3 
                 A 
                 NA 
                 0.00** 
               
               
                 MGC33887 
                 rs987931 
                 17q24 
                 G/T 
                 0.39 
                 0.32 
               
               
                 MHC2TA 
                 rs3087456 
                 16p13 
                 A/G 
                 0.13 
                 0.26 
               
               
                 MOG 
                 rs3130250 
                 6p22 
                 A/G 
                 0.01 
                 0.19 
               
               
                 MOG 
                 rs3130253 
                 6p22 
                 A/G 
                 0.80 
                 0.12 
               
               
                 NDUFA7 
                 rs2288414 
                 19p13.2 
                 C/G 
                 7.90* 
                 0.03** 
               
               
                 NDUFA7 
                 rs561 
                 19p13.2 
                 A/G 
                 0.04 
                 0.21 
               
               
                 NDUFS5 
                 rs2889683 
                 1p34.2 
                 C/T 
                 2.63 
                 0.31 
               
               
                 NDUFS5 
                 rs6981 
                 1p34.2 
                 A/G 
                 105.96* 
                 0.04** 
               
               
                 NDUFS7 
                 rs2074897 
                 19p13.3 
                 A/G 
                 6.21* 
                 0.47 
               
               
                 NOS2A 
                 rs1137933 
                 17q11.2 
                 A/G 
                 0.49 
                 0.25 
               
               
                 NOS2A 
                 rs2779248 
                 17q11.2 
                 C/T 
                 0.00 
                 0.39 
               
               
                 NOTCH4 
                 rs367398 
                 6p21.3 
                 A/G 
                 0 
                 0.16 
               
               
                 PD-1 
                 rs11568821 
                 2q37 
                 G/A 
                 6.24* 
                 0.11 
               
               
                 PITPNC1 
                 rs1318 
                 17q24 
                 A/G 
                 0.01 
                 0.21 
               
               
                 PITPNC1 
                 rs2365403 
                 17q24 
                 C/G 
                 0.55 
                 0.18 
               
               
                 PNMT 
                 rs876493 
                 17q11-q23 
                 A/G 
                 0.70 
                 0.39 
               
               
                 PRKCA 
                 rs7220007 
                 17q24 
                 A/G 
                 0.10 
                 0.49 
               
               
                 PRKCA 
                 rs887797 
                 17q24 
                 C/T 
                 0.50 
                 0.30 
               
               
                 PRKCA 
                 rs2078153 
                 17q24 
                 C/G 
                 0.91 
                 0.23 
               
               
                 PRKCA 
                 rs3890137 
                 17q24 
                 A/G 
                 0.44 
                 0.37 
               
               
                 PTPN22 
                 rs2476601 
                 1p13 
                 A/G 
                 2.29 
                 0.11 
               
               
                 PTPRC 
                 rs17612648 
                 1q31 
                 C/G 
                 0.11 
                 0.03** 
               
               
                 PTPRC 
                 rs4915154 
                 1q31 
                 A/G 
                 0.00 
                 0.00** 
               
               
                 CCL5 
                 rs2280788 
                 17q11.2-q12 
                 C/G 
                 0.06 
                 0.02** 
               
               
                 CCL5 
                 rs2107538 
                 17q11.2-q12 
                 C/T 
                 0.00 
                 0.18 
               
               
                 Spp1 
                 rs1126616 
                 4q21 
                 C/T 
                 0.01 
                 0.23 
               
               
                 Spp1 
                 rs1126772 
                 4q21 
                 A/G 
                 0.23 
                 0.18 
               
               
                 Spp1 
                 rs2853744 
                 4q21 
                 G/T 
                 0.48 
                 0.05 
               
               
                 Spp1 
                 rs9138 
                 4q21 
                 A/C 
                 0.03 
                 0.24 
               
               
                 Spp1 
                 rs4754 
                 4q21 
                 C/T 
                 0.07 
                 0.24 
               
               
                 TNF-alpha 
                 rs1800629 
                 6p21.3 
                 A/G 
                 2.02 
                 0.17 
               
               
                 TRAIL 
                 rs1131568 
                 3q26 
                 C/T 
                 1.53 
                 0.32 
               
               
                 UCP2 
                 rs659366 
                 11q13 
                 C/T 
                 0.15 
                 0.37 
               
               
                 VDR 
                 rs1544410 
                 12q13 
                 A/G 
                 1.27 
                 0.48 
               
               
                 VDR 
                 rs731236 
                 12q13 
                 A/G 
                 0.39 
                 0.48 
               
               
                   
               
               
                 *ChiSquare value. A value &gt;3.84 indicates deviation from Hardy-Weinberg Equilibrium (p &lt; 0.05). 
               
               
                 **Excluded due to minor allele frequency &lt;0.05) 
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 6A 
               
             
             
               
                   
               
               
                 Additional SNPs included in the analyses 
               
             
          
           
               
                   
                 Gene 
                 rs-nr 
               
               
                   
                   
               
               
                   
                 KIF1B 
                 rs10492972 
               
               
                   
                 IGF2R 
                 rs12202350 
               
               
                   
                 GRIN2A 
                 rs8049651 
               
               
                   
                 KLC1 
                 rs8702 
               
               
                   
                 IL7R 
                 rs987107 
               
               
                   
                 STS 
                 rs12861247 
               
               
                   
                 GPC6 
                 rs7995215 
               
               
                   
                 EREG 
                 rs1350666 
               
               
                   
                 ADRA1A 
                 rs3808585 
               
               
                   
                 IL16 
                 rs4128767 
               
               
                   
                 ARRB2 
                 rs7208257 
               
               
                   
                 NTF3 
                 rs7956189 
               
               
                   
                 IL12A 
                 rs4680534 
               
               
                   
                 SLC6A4 
                 rs1042173 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 Examples of Probes Used in SNP Analysis 
               
             
          
           
               
                 Gene 
                   
                   
                   
                 Oligonucleotide sequence 
                   
               
               
                 Symbol 
                 Gene Name 
                 rs ID 
                 SNP 
                 (5′ &gt; 3′) 
               
               
                   
               
               
                 EBF1 
                 Early B-cell Factor 1 
                 rs1368297 
                 intron 7 (271,440) 
                 TAAAGTTAGTC A GTTCTATGCTT 
                   
               
               
                   
                   
                   
                 A/T 
                 TAAAGTTAGTC T GTTCTATGCTT 
               
               
                   
                   
                   
                   
                 AAGCATAGAAC T GACTAACTTTA 
               
               
                   
                   
                   
                   
                 AAGCATAGAAC A GACTAACTTTA 
               
               
                   
               
               
                 RANTES/ 
                 chemokine (C-C motif) 
                 rs2280788 
                 −28C/G 
                 GGGATGCCCCT C AACTGGCCCTA 
               
               
                 CCL5 
                 ligand 5 
                   
                   
                 GGGATGCCCCT G AACTGGCCCTA 
               
               
                   
                   
                   
                   
                 TAGGGCCAGTT G AGGGGCATCCC 
               
               
                   
                   
                   
                   
                 TAGGGCCAGTT C AGGGGCATCCC 
               
               
                   
               
               
                 RANTES/ 
                 chemokine (C-C motif) 
                 rs2107538 
                 −403G/A 
                 AGGGAAAGGAG G TAAGATCTGTA 
               
               
                 CCL5 
                 ligand 5 
                   
                   
                 AGGGAAAGGAG A TAAGATCTGTA 
               
               
                   
                   
                   
                   
                 TACAGATCTTA C CTCCTTTCCCT 
               
               
                   
                   
                   
                   
                 TACAGATCTTA T CTCCTTTCCCT 
               
               
                   
               
               
                 TGFB1 
                 transforming growth factor, 
                 rs17851976 
                 L10P G869A 
                 GTAGCAGCAGC G GCAGCAGCCGC 
               
               
                   
                 beta 1 
                   
                   
                 GTAGCAGCAGC A GCAGCAGCCGC 
               
               
                   
                   
                   
                   
                 GCGGCTGCTGC C GCTGCTGCTAC 
               
               
                   
                   
                   
                   
                 GCGGCTGCTGC T GCTGCTGCTAC 
               
               
                   
               
               
                 UPC2 
                 uncoupling protein 2 
                 rs659366 
                 −866G/A 
                 GGGGTAACTGA C GCGTGAACAGC 
               
               
                   
                   
                   
                   
                 GGGGTAACTGA T GCGTGAACAGC 
               
               
                   
                   
                   
                   
                 GCTGTTCACGC G TCAGTTACCCC 
               
               
                   
                   
                   
                   
                 GCTGTTCACGC A TCAGTTACCCC 
               
               
                   
               
               
                 IKBL 
                 inhibitory kappaB-like 
                 rs3130062 
                 C224R; 738T/C 
                 CAGAGGGATCC C GTCGACCCCCA 
               
               
                   
                   
                   
                   
                 CAGAGGGATCC T GTCGACCCCCA 
               
               
                   
                   
                   
                   
                 TGGGGGTCGAC G GGATCCCTCTG 
               
               
                   
                   
                   
                   
                 TGGGGGTCGAC A GGATCCCTCTG 
               
               
                   
               
               
                 Apo I/Fas 
                 tumor necrosis factor receptor 
                 rs1800682 
                 −671A/G 
                 GTCCATTCCAG A AACGTCTGTGA 
               
               
                 (CD 95) 
                 superfamily 
                   
                   
                 GTCCATTCCAG G AACGTCTGTGA 
               
               
                   
                   
                   
                   
                 TCACAGACGTT T CTGGAATGGAC 
               
               
                   
                   
                   
                   
                 TCACAGACGTT C CTGGAATGGAC 
               
               
                   
               
               
                 Apo I/Fas 
                 tumor necrosis factor receptor 
                 rs3781202 
                 A/T (735)G/C 
                 ATAAAATTTTC C TAGCAAATAAA 
               
               
                 (CD 95) 
                 superfamily 
                   
                 intron 4 
                 ATAAAATTTTC T TAGCAAATAAA 
               
               
                   
                   
                   
                   
                 TTTATTTGCTA G GAAAATTTTAT 
               
               
                   
                   
                   
                   
                 TTTATTTGCTA A GAAAATTTTAT 
               
               
                   
               
               
                 IL2 
                 interleukin 2 
                 rs2069763 
                 114G/T 
                 GAGCATTTACT G CTGGATTTACA 
               
               
                   
                   
                   
                   
                 GAGCATTTACT T CTGGATTTACA 
               
               
                   
                   
                   
                   
                 TGTAAATCCAG C AGTAAATGCTC 
               
               
                   
                   
                   
                   
                 TGTAAATCCAG A AGTAAATGCTC 
               
               
                   
               
               
                 IL2 
                 interleukin 2 
                 rs2069762 
                 −385A/C 
                 TTTTCTTTGTC A TAAAACTACAC 
               
               
                   
                   
                   
                   
                 TTTTCTTTGTC C TAAAACTACAC 
               
               
                   
                   
                   
                   
                 TTCAGTGTAGTTTTA T 
               
               
                   
                   
                   
                   
                 GACAAAGAAAATTTT 
               
               
                   
                   
                   
                   
                 TTCAGTGTAGTTTTA G 
               
               
                   
                   
                   
                   
                 GACAAAGAAAATTTT 
               
               
                   
               
               
                 IL10 
                 interleukin 10 
                 rs1800896 
                 −1082G/A 
                 GCTTCTTTGGGAAGGGGAAGTAGGG 
               
               
                   
                   
                   
                   
                 GCTTCTTTGGGAGGGGGAAGTAGGG 
               
               
                   
                   
                   
                   
                 CCCTACTTCCCCTTCCCAAAGAAGC 
               
               
                   
                   
                   
                   
                 CCCTACTTCCCCCTCCCAAAGAAGC 
               
               
                   
               
               
                 IL4R 
                 interleukin 4 receptor 
                 rs1801275 
                 Q551R 
                 CAGTGGCTATC G GGAGTTTGTAC 
               
               
                   
                   
                   
                   
                 CAGTGGCTATC A GGAGTTTGTAC 
               
               
                   
                   
                   
                   
                 TACAAACTCC C GATAGCCACT 
               
               
                   
                   
                   
                   
                 TACAAACTCC T GATAGCCACT 
               
               
                   
               
               
                 PTPRC 
                 protein tyrosine 
                 rs17612648 
                 C77G 
                 GCATTCTCACC C GCAAGCACCTT 
               
               
                   
                 phosphatase, receptor 
                   
                   
                 GCATTCTCACC G GCAAGCACCTT 
               
               
                   
                 type, C 
                   
                   
                 AAGGTGCTTGC G GGTGAGAATGC 
               
               
                   
                   
                   
                   
                 AAGGTGCTTGC C GGTGAGAATGC 
               
               
                   
               
               
                 PTPRC 
                 protein tyrosine phosphatase, 
                 rs4915154 
                 A138G 
                 TCACAGCGAAC G CCTCAGGTCTG 
               
               
                   
                 receptor type, C 
                   
                   
                 TCACAGCGAAC A CCTCAGGTCTG 
               
               
                   
                   
                   
                   
                 CAGACCTGAGG C GTTCGCTGTGA 
               
               
                   
                   
                   
                   
                 CAGACCTGAGG T GTTCGCTGTGA 
               
               
                   
               
               
                 PD- 
                 programmed cell death 1 
                 rs11568821 
                 G7146A 
                 AGCCCACCTGC G GTCTCCGGGGG 
               
               
                 1/PDCD1 
                   
                   
                   
                 AGCCCACCTGC A GTCTCCGGGGG 
               
               
                   
                   
                   
                   
                 CCCCCGGAGAC C GCAGGTGGGCT 
               
               
                   
                   
                   
                   
                 CCCCCGGAGAC T GCAGGTGGGCT 
               
               
                   
               
               
                 CRYAB 
                 crystallin, alpha B 
                 rs14133 
                 −C249G 
                 TGAAACAAGAC C ATGACAAGTCA 
               
               
                   
                   
                   
                   
                 TGAAACAAGAC G ATGACAAGTCA 
               
               
                   
                   
                   
                   
                 TGACTTGTCAT G GTCTTGTTTCA 
               
               
                   
                   
                   
                   
                 TGACTTGTCAT C GTCTTGTTTCA 
               
               
                   
               
               
                 CRYAB 
                 crystallin, alpha B 
                 rs762550 
                 −A652G 
                 GAGCCACATAGAACGAAAGATGC 
               
               
                   
                   
                   
                   
                 GAGCCACATAGGACGAAAGATGC 
               
               
                   
                   
                   
                   
                 GCATCTTTCGTTCTATGTGGCTC 
               
               
                   
                   
                   
                   
                 CATCTTTCGT C CTATGTGGCT 
               
               
                   
               
               
                 CRYAB 
                 crystallin, alpha B 
                 rs2234702 
                 −C650G 
                 GCCACATAGAA C GAAAGATGCAA 
               
               
                   
                   
                   
                   
                 GCCACATAGAA G GAAAGATGCAA 
               
               
                   
                   
                   
                   
                 TTGCATCTTTC G TTCTATGTGGC 
               
               
                   
                   
                   
                   
                 TTGCATCTTTC C TTCTATGTGGC 
               
               
                   
               
               
                 NDUFS5 
                 NADH dehydrogenase 
                 rs2889683 
                 −5649T/C 
                 ACAACAGCAGA A ATAATAATCAA 
               
               
                   
                 (ubiquinone) Fe—S 
                   
                   
                 ACAACAGCAGA G ATAATAATCAA 
               
               
                   
                 protein 5 
                   
                   
                 TTGATTATTAT T TCTGCTGTTGT 
               
               
                   
                   
                   
                   
                 TTGATTATTAT C TCTGCTGTTGT 
               
               
                   
               
               
                 NDUFS5 
                 NADH dehydrogenase 
                 rs6981 
                 3′ UTR 5789 
                 CAGCTGCTGAT A TCTGGAGGCTG 
               
               
                   
                 (ubiquinone) Fe—S 
                   
                 A/G 
                 CAGCTGCTGAT G TCTGGAGGCTG 
               
               
                   
                 protein 5 
                   
                   
                 CAGCCTCCAGA T ATCAGCAGCTG 
               
               
                   
                   
                   
                   
                 CAGCCTCCAGA C ATCAGCAGCTG 
               
               
                   
               
               
                 NDUFS7 
                 NADH dehydrogenase 
                 rs2074897 
                 intron 6 (6 + 71) 
                 GCCCTGATGGC A CTTATCAAAAG 
               
               
                   
                 (ubiquinone) Fe—S 
                   
                 A/G 
                 GCCCTGATGGC G CTTATCAAAAG 
               
               
                   
                 protein 7 
                   
                   
                 CTTTTGATAAG T GCCATCAGGGC 
               
               
                   
                   
                   
                   
                 CTTTTGATAAG C GCCATCAGGGC 
               
               
                   
               
               
                 NDUFA7 
                 NADH dehydrogenase 
                 rs2288414 
                 intron 2 (2 + 89) 
                 ATGTCAGCCCT C CGTTTCAGGGG 
               
               
                   
                 (ubiquinone) 1 alpha 
                   
                 C/G 
                 ATGTCAGCCCT G CGTTTCAGGGG 
               
               
                   
                   
                   
                   
                 CCCCTGAAACG G AGGGCTGACAT 
               
               
                   
                   
                   
                   
                 CCCCTGAAACG C AGGGCTGACAT 
               
               
                   
               
               
                 NDUFA7 
                 NADH dehydrogenase 
                 rs561 
                 9825 A/G 
                 CCACCTCTTTAT A GGAGGAGCTGGA 
               
               
                   
                 (ubiquinone) 1 alpha 
                   
                   
                 CCACCTCTTTAT G GGAGGAGCTGGA 
               
               
                   
                   
                   
                   
                 CCAGCTCCTCC T ATAAAGAGGTG 
               
               
                   
                   
                   
                   
                 CCAGCTCCTCC C ATAAAGAGGTG 
               
               
                   
               
               
                 ADAMTS14 
                 ADAM metallopeptidase with 
                 rs4747075 
                 intron 2 16860 A/G 
                 CCCAGATGATG A CATTCGCCTTC 
               
               
                   
                 thrombospondin type 1 
                   
                   
                 CCCAGATGATG G CATTCGCCTTC 
               
               
                   
                   
                   
                   
                 GAAGGCGAATG T CATCATCTGGG 
               
               
                   
                   
                   
                   
                 GAAGGCGAATG C CATCATCTGGG 
               
               
                   
               
               
                 ADAMTS14 
                 ADAM metallopeptidase with 
                 rs7081273 
                 intron 2 24479 C/G 
                 CATTTGGCAAA C GTAGGCTGGTC 
               
               
                   
                 thrombospondin type 1 
                   
                   
                 CATTTGGCAAA G GTAGGCTGGTC 
               
               
                   
                   
                   
                   
                 GACCAGCCTAC G TTTGCCAAATG 
               
               
                   
                   
                   
                   
                 GACCAGCCTAC C TTTGCCAAATG 
               
               
                   
               
               
                 ADAMTS14 
                 ADAM metallopeptidase with 
                 rs4746060 
                 intron 4 44225 C/T 
                 GCACATCTATA C TGGGTCATCTT 
               
               
                   
                 thrombospondin type 1 
                   
                   
                 GCACATCTATA T TGGGTCATCTT 
               
               
                   
                   
                   
                   
                 AAGATGACCCA G TATAGATGTGC 
               
               
                   
                   
                   
                   
                 AAGATGACCCA A TATAGATGTGC 
               
               
                   
               
               
                 NFKBIA 
                 nuclear factor of kappa 
                 rs11569591 
                 −708ins8 
                 GCGTGGGGGGG T GGGGGCGAAGC 
               
               
                   
                 light polypeptide gene enhancer 
                   
                   
                 GGGTGGGGGGG A GGGGGCGAAGC 
               
               
                   
                 in B-cells inhibitor, alpha 
                   
                   
                 GCTTCGCCCCC A CCCCCCCACGC 
               
               
                   
                   
                   
                   
                 GCTTCGCCCCC T CCCCCCCACCC 
               
               
                   
               
               
                 NFKBIA 
                 nuclear factor of kappa 
                 rs11569591 
                 −708ins8 
                 CGTGGGGGGG T GGGGGCGAAG 
               
               
                   
                 light polypeptide gene enhancer 
                   
                   
                 GGTGGGGGGG A GGGGGCGAAG 
               
               
                   
                 in B-cells inhibitor, alpha 
                   
                   
                 CTTCGCCCCC A CCCCCCCACG 
               
               
                   
                   
                   
                   
                 CTTCGCCCCC T CCCCCCCACC 
               
               
                   
               
               
                 NFKBIA 
                 nuclear factor of kappa 
                 rs11569591 
                 −708ins8 
                 TGCGTGGGGGGG T GGGGGCGAAGCT 
               
               
                   
                 light polypeptide gene enhancer 
                   
                   
                 GGGGTGGGGGGG A GGGGGCGAAGCT 
               
               
                   
                 in B-cells inhibitor, alpha 
                   
                   
                 AGCTTCGCCCCC A CCCCCCCACGCA 
               
               
                   
                   
                   
                   
                 AGCTTCGCCCCC T CCCCCCCACCCC 
               
               
                   
               
               
                 SPP1 
                 secreted phosphoprotein 1 
                 rs28357094 
                 −66[G/T] 
                 GACACAATCTC G CCGCCTCCCTG 
               
               
                   
                   
                   
                   
                 GACACAATCTC T CCGCCTCCCTG 
               
               
                   
                   
                   
                   
                 CAGGGAGGCGG C GAGATTGTGTC 
               
               
                   
                   
                   
                   
                 CAGGGAGGCGG A GAGATTGTGTC 
               
               
                   
               
               
                 HLA- 
                 major histocompatibility 
                 rs367398 
                 −25 A/G (NOTCH4) 
                 CTCCAAGCCCC A GTCCCTGTCCC 
               
               
                 DR*1501 
                 complex, class II, DR 
                   
                   
                 CTCCAAGCCCC G GTCCCTGTCCC 
               
               
                   
                   
                   
                   
                 GGGACAGGGAC T GGGGCTTGGAG 
               
               
                   
                   
                   
                   
                 GGGACAGGGAC C GGGGCTTGGAG 
               
               
                   
               
               
                 HLA- 
                 major histocompatibility 
                 rs1800629 
                 −308G &gt; A 
                 TGAGGGGCATG A GGACGGGGTTC 
               
               
                 DR*1501 
                 complex, class II, DR 
                   
                 (TNF-alpha) 
                 TGAGGGGCATG G GGACGGGGTTC 
               
               
                   
                   
                   
                   
                 _AACCCCGTCC T CATGCCCCTC —   
               
               
                   
                   
                   
                   
                 _AACCCCGTCC C CATGCCCCTC —   
               
               
                   
               
               
                 IL7R 
                 interleukin 7 receptor 
                 rs11567685 
                 −504T/C 
                 GCATTTGCCTGCAGTCCTAGCTA 
               
               
                   
                   
                   
                   
                 GCATTTGCCTGTAGTCCTAGCTA 
               
               
                   
                   
                   
                   
                 TAGCTAGGACTGCAGGCAAATGC 
               
               
                   
                   
                   
                   
                 TAGCTAGGACTACAGGCAAATGC 
               
               
                   
               
               
                 IL7R 
                 interleukin 7 receptor 
                 rs7718919 
                 −1085G/T 
                 CACAAATGGGT G AGGCTGTATTC 
               
               
                   
                   
                   
                   
                 CACAAATGGGT T AGGCTGTATTC 
               
               
                   
                   
                   
                   
                 GAATACAGCCT C ACCCATTTGTG 
               
               
                   
                   
                   
                   
                 GAATACAGCCT A ACCCATTTGTG 
               
               
                   
               
               
                 IL7R 
                 interleukin 7 receptor 
                 rs11567686 
                 −449A/G 
                 CCTGGGAGGTG A AAATTGCAGTG 
               
               
                   
                   
                   
                   
                 CCTGGGAGGTG G AAATTGCAGTG 
               
               
                   
                   
                   
                   
                 CACTGCAATTT T CACCTCCCAGG 
               
               
                   
                   
                   
                   
                 CACTGCAATTT C CACCTCCCAGG 
               
               
                   
               
               
                 IFNAR1 
                 interferon (alpha, beta 
                 rs2257167 
                 V168L (G18417C) 
                 ACATATAGCTTA C TTATCTGGAAAA 
               
               
                   
                 and omega) receptor 1 
                   
                   
                 ACATATAGCTTA G TTATCTGGAAAA 
               
               
                   
                   
                   
                   
                 TTTTCCAGATAA G TAAGCTATATGT 
               
               
                   
                   
                   
                   
                 TTTTCCAGATAA C TAAGCTATATGT 
               
               
                   
               
               
                 IFNAR2 
                 interferon (alpha, beta 
                 rs7279064 
                 F10V (11876T &gt; G) 
                 ATGCCTTCATC G TCAGATCACTT 
               
               
                   
                 and omega) receptor 2 
                   
                   
                 ATGCCTTCATC T TCAGATCACTT 
               
               
                   
                   
                   
                   
                 AAGTGATCTGA C GATGAAGGCAT 
               
               
                   
                   
                   
                   
                 AAGTGATCTGA A GATGAAGGCAT 
               
               
                   
               
               
                 IL1B 
                 interleukin 1, beta 
                 rs1799916 
                 −511 A/C 
                 AAGAGAATCCC A GAGCAGCCTGT 
               
               
                   
                 proprotein 
                   
                   
                 AAGAGAATCCC C GAGCAGCCTGT 
               
               
                   
                   
                   
                   
                 ACAGGCTGCTC T GGGATTCTCTT 
               
               
                   
                   
                   
                   
                 ACAGGCTGCTC G GGGATTCTCTT 
               
               
                   
               
               
                 IFNGR2 
                 interferon gamma receptor 
                 rs9808753 
                 Q64R 
                 TGTTGTCTACC A AGTGCAGTTTA 
               
               
                   
                 2 (interferon gamma 
                   
                   
                 TGTTGTCTACC G AGTGCAGTTTA 
               
               
                   
                 transducer 1) 
                   
                   
                 TAAACTGCACT T GGTAGACAACA 
               
               
                   
                   
                   
                   
                 TAAACTGCACT C GGTAGACAACA 
               
               
                   
               
               
                 Apo I/Fas 
                 tumor necrosis factor 
                 rs2234978 
                 E7(74) C &gt; T 
                 GAATCTCCAAC C TTAAATCCTGT 
               
               
                 (CD 95) 
                 receptor superfamily 
                   
                   
                 GAATCTCCAAC T TTAAATCCTGT 
               
               
                   
                   
                   
                   
                 ACAGGATTTAA G GTTGGAGATTC 
               
               
                   
                   
                   
                   
                 ACAGGATTTAA A GTTGGAGATTC 
               
               
                   
               
               
                 CD24 
                 CD24 antigen precursor 
                 rs8734 
                 V57A (226T &gt; C) 
                 CACCACCAAGG T GGCTGGTGGTG 
               
               
                   
                   
                   
                   
                 CACCACCAAGG C GGCTGGTGGTG 
               
               
                   
                   
                   
                   
                 CACCACCAGCC A CCTTGGTGGTG 
               
               
                   
                   
                   
                   
                 CACCACCAGCC G CCTTGGTGGTG 
               
               
                   
               
               
                 MEFV 
                 Mediterranean fever protein 
                 rs28940577 
                 M694V 
                 GGGTGGTGATA A TGATGAAGGAA 
               
               
                   
                   
                   
                   
                 GGGTGGTGATA G TGATGAAGGAA 
               
               
                   
                   
                   
                   
                 TTCCTTCATCA T TATCACCACCC 
               
               
                   
                   
                   
                   
                 TTCCTTCATCA C TATCACCACCC 
               
               
                   
               
               
                 CTLA4 
                 cytotoxic T-lymphocyte- 
                 rs231775 
                 +49A/G 
                 TGAACCTGGCT A CCAGGACCTGG 
               
               
                   
                 associated antigen 4 
                   
                   
                 TGAACCTGGCT G CCAGGACCTGG 
               
               
                   
                   
                   
                   
                 CCAGGTCCTGG T AGCCAGGTTCA 
               
               
                   
                   
                   
                   
                 CCAGGTCCTGG C AGCCAGGTTCA 
               
               
                   
               
               
                 CNTF 
                 ciliary neurotrophic factor 
                 rs1800169 
                 intron 1 (2-7) A/G 
                 CCTGTATCCTC A GCCAGGTGAAG 
               
               
                   
                   
                   
                   
                 CCTGTATCCTC G GCCAGGTGAAG 
               
               
                   
                   
                   
                   
                 CTTCACCTGGC T GAGGATACAGG 
               
               
                   
                   
                   
                   
                 CTTCACCTGGC C GAGGATACAGG 
               
               
                   
               
               
                 MHC2TA 
                 class II, major 
                 rs3087456 
                 −168A/G 
                 TTCAGAGGTGT A GGGAGGGCTTA 
               
               
                   
                 histocompatibility complex, 
                   
                   
                 TTCAGAGGTGT G GGGAGGGCTTA 
               
               
                   
                 transactivator 
                   
                   
                 TAAGCCCTCCC T ACACCTCTGAA 
               
               
                   
                   
                   
                   
                 TAAGCCCTCCC C ACACCTCTGAA 
               
               
                   
               
               
                 VDR 
                 vitamin D receptor 
                 rs1544410 
                 33062 A/G Intron 
                 GACAGGCCTGC A CATTCCCAATA 
               
               
                   
                   
                   
                   
                 GACAGGCCTGC G CATTCCCAATA 
               
               
                   
                   
                   
                   
                 ATTGGGAATG T GCAGGCCTGT 
               
               
                   
                   
                   
                   
                 TTGGGAATG C GCAGGCCTG 
               
               
                   
               
               
                 PRKCA 
                 protein kinase C, alpha 
                 rs7220007 
                 intron 3 264550 A/G 
                 CCCCTGCTGGC A GATTGTTGCTA 
               
               
                   
                   
                   
                   
                 CCCCTGCTGGC G GATTGTTGCTA 
               
               
                   
                   
                   
                   
                 TAGCAACAATC T GCCAGCAGGGG 
               
               
                   
                   
                   
                   
                 TAGCAACAATC C GCCAGCAGGGG 
               
               
                   
               
               
                 PRKCA 
                 protein kinase C, alpha 
                 rs887797 
                 intron 3 280475 C/T 
                 GTCTTTTTAATA G CTGTAGACATCT 
               
               
                   
                   
                   
                   
                 GTCTTTTTAATA A CTGTAGACATCT 
               
               
                   
                   
                   
                   
                 GTCTTTTTAATA G CTGTAGACATCT 
               
               
                   
                   
                   
                   
                 GTCTTTTTAATA A CTGTAGACATCT 
               
               
                   
               
               
                 PRKCA 
                 protein kinase C, alpha 
                 rs2078153 
                 intron 3 252845 C/G 
                 AGTTACAGGGA C AAGAAGCCTTT 
               
               
                   
                   
                   
                   
                 AGTTACAGGGA G AAGAAGCCTTT 
               
               
                   
                   
                   
                   
                 AAAGGCTTCTT G TCCCTGTAACT 
               
               
                   
                   
                   
                   
                 AAAGGCTTCTT C TCCCTGTAACT 
               
               
                   
               
               
                 CTLA4 
                 cytotoxic T-lymphocyte- 
                 rs5742909 
                 −318C/T 
                 ATCCAGATCCT C AAAGTGAACAT 
               
               
                   
                 associated protein 4 
                   
                   
                 ATCCAGATCCT T AAAGTGAACAT 
               
               
                   
                   
                   
                   
                 ATGTTCACTTT G AGGATCTGGAT 
               
               
                   
                   
                   
                   
                 ATGTTCACTTT A AGGATCTGGAT 
               
               
                   
               
               
                 MGC33887 
                 coiled-coil domain containing 
                 rs987931 
                 intron 21 413506 
                 GCAGCAGTTT G CCCTGTGAGT 
               
               
                   
                 46 
                   
                 G/T 
                 GCAGCAGTTT T CCCTGTGAGT 
               
               
                   
                   
                   
                   
                 ACTCACAGGG C AAACTGCTGC 
               
               
                   
                   
                   
                   
                 ACTCACAGGG A AAACTGCTGC 
               
               
                   
               
               
                 CACNG4 
                 calcium channel, voltage- 
                 rs4790896 
                 intron 1 15546 C/T 
                 GACTCCGATGA A GTTTGAGCAGA 
               
               
                   
                 dependent, gamma 
                   
                   
                 GACTCCGATGA G GTTTGAGCAGA 
               
               
                   
                 subunit 4 
                   
                   
                 TCTGCTCAAAC T TCATCGGAGTC 
               
               
                   
                   
                   
                   
                 TCTGCTCAAAC C TCATCGGAGTC 
               
               
                   
               
               
                 HELZ 
                 helicase with zinc finger 
                 rs2363846 
                 intron 18 68091 C/T 
                 TCAATAATAAA C ATCATCTGACC 
               
               
                   
                   
                   
                   
                 TCAATAATAAA T ATCATCTGACC 
               
               
                   
                   
                   
                   
                 GGTCAGATGAT G TTTATTATTGA 
               
               
                   
                   
                   
                   
                 GGTCAGATGAT A TTTATTATTGA 
               
               
                   
               
               
                 PITPNC1 
                 phosphatidylinositol 
                 rs1318 
                 C/T 
                 TGGGTGGTGTA A ATATTCCTTTA 
               
               
                   
                 transfer protein, 
                   
                   
                 TGGGTGGTGTA G ATATTCCTTTA 
               
               
                   
                 cytoplasmic 1 
                   
                   
                 GCTAAAGGAATAT T TACACCACCCACC 
               
               
                   
                   
                   
                   
                 GCTAAAGGAATAT C TACACCACCCACC 
               
               
                   
               
               
                 PITPNC1 
                 phosphatidylinositol 
                 rs2365403 
                 C/G 
                 ACTGACTTTCT C TGCCTAATGTA 
               
               
                   
                 transfer protein, 
                   
                   
                 ACTGACTTTCT G TGCCTAATGTA 
               
               
                   
                 cytoplasmic 1 
                   
                   
                 TACATTAGGCA G AGAAAGTCAGT 
               
               
                   
                   
                   
                   
                 TACATTAGGCA C AGAAAGTCAGT 
               
               
                   
               
               
                 MC1R 
                 melanocortin 1 receptor 
                 rs1805009 
                 294 D/H 
                 ATGCCATCATC C ACCCCCTCATC 
               
               
                   
                   
                   
                   
                 ATGCCATCATC G ACCCCCTCATC 
               
               
                   
                   
                   
                   
                 GATGAGGGGGT G GATGATGGCAT 
               
               
                   
                   
                   
                   
                 GATGAGGGGGT C GATGATGGCAT 
               
               
                   
               
               
                 MC1R 
                 melanocortin 1 receptor 
                 rs1805006 
                 84 Asp/Glu 
                 GCCTTGTCGGA A CTGCTGGTGAG 
               
               
                   
                   
                   
                   
                 GCCTTGTCGGA C CTGCTGGTGAG 
               
               
                   
                   
                   
                   
                 CTCACCAGCAG T TCCGACAAGGC 
               
               
                   
                   
                   
                   
                 CTCACCAGCAG G TCCGACAAGGC 
               
               
                   
               
               
                 PRKCA 
                 protein kinase C, alpha 
                 rs1010544 
                 intron 8 388476 C/T 
                 TAAAAAGGTGC A TGTATCTGTGT 
               
               
                   
                   
                   
                   
                 TAAAAAGGTGC G TGTATCTGTGT 
               
               
                   
                   
                   
                   
                 ACACAGATACA T GCACCTTTTTA 
               
               
                   
                   
                   
                   
                 ACACAGATACA C GCACCTTTTTA 
               
               
                   
               
               
                 PRKCA 
                 protein kinase C, alpha 
                 rs3890137 
                 intron 8 427857 A/G 
                 GGCTGGCTTT A CCACAGACTG 
               
               
                   
                   
                   
                   
                 TGGCTGGCTTT G CCACAGACTGT 
               
               
                   
                   
                   
                   
                 CAGTCTGTGG T AAAGCCAGCC 
               
               
                   
                   
                   
                   
                 ACAGTCTGTGG C AAAGCCAGCCA 
               
               
                   
               
               
                 BTNL2 
                 butyrophilin-like 2 
                 rs2076530 
                 11084C/T 
                 TGAAGGTGGTA A GTAAGAATTCT 
               
               
                 (DRb1*15) 
                   
                   
                   
                 TGAAGGTGGTA G GTAAGAATTCT 
               
               
                   
                   
                   
                   
                 AGAATTCTTAC T TACCACCTTCA 
               
               
                   
                   
                   
                   
                 AGAATTCTTAC C TACCACCTTCA 
               
               
                   
               
               
                 PNMT 
                 phenylethanolamine 
                 rs876493 
                 −184G/A 
                 CACTCACCTCC A GTGTGTCTGCA 
               
               
                   
                 N-methyltransferase 
                   
                   
                 CACTCACCTCC G GTGTGTCTGCA 
               
               
                   
                   
                   
                   
                 CACTCACCTCC A GTGTGTCTGCA 
               
               
                   
                   
                   
                   
                 CACTCACCTCC G GTGTGTCTGCA 
               
               
                   
               
               
                 PNMT 
                 phenylethanolamine 
                 rs3764351 
                 −390G/A 
                 ATGGCTGCGGG A GGCTGGAGAAG 
               
               
                   
                 N-methyltransferase 
                   
                   
                 ATGGCTGCGGG G GGCTGGAGAAG 
               
               
                   
                   
                   
                   
                 CTTCTCCAGCC T CCCGCAGCCAT 
               
               
                   
                   
                   
                   
                 CTTCTCCAGCC C CCCGCAGCCAT 
               
               
                   
               
               
                 TRAIL/ 
                 tumor necrosis factor 
                 rs9880164 
                 1595C/T 
                 GCTAATTTTTG C ACTTTCAGTAG 
               
               
                 TNFSF10 
                 (ligand) superfamily, 
                 (rs1131568 
                   
                 GCTAATTTTTG T ACTTTCAGTAG 
               
               
                   
                 member 10 
                 in v. 37.1) 
                   
                 CTACTGAAAGT G CAAAAATTAGC 
               
               
                   
                   
                   
                   
                 CTACTGAAAGT A CAAAAATTAGC 
               
               
                   
               
               
                 PTPN22 
                 protein tyrosine phosphatase, 
                 rs2476601 
                 1858C/T: (620 W/R) 
                 TTCAGGTGTCC A TACAGGAAGTG 
               
               
                   
                 non-receptor type 22 
                   
                   
                 TTCAGGTGTCC G TACAGGAAGTG 
               
               
                   
                   
                   
                   
                 CACTTCCTGTA T GGACACCTGAA 
               
               
                   
                   
                   
                   
                 CACTTCCTGTA C GGACACCTGAA 
               
               
                   
               
               
                 MOG 
                 myelin oligodendrocyte 
                 rs3130250 
                 15G/A [S5S] 
                 GCAAGCTTATC A AGACCCTCTCT 
               
               
                   
                 glycoprotein 
                   
                   
                 GCAAGCTTATC G AGACCCTCTCT 
               
               
                   
                   
                   
                   
                 AGAGAGGGTCT T GATAAGCTTGC 
               
               
                   
                   
                   
                   
                 AGAGAGGGTCT C GATAAGCTTGC 
               
               
                   
               
               
                 MOG 
                 myelin oligodendrocyte 
                 rs3130253 
                 520G/A [V145I] 
                 CTGTTGGCCTC A TCTTCCTCTGC 
               
               
                   
                 glycoprotein 
                   
                   
                 CTGTTGGCCTC G TCTTCCTCTGC 
               
               
                   
                   
                   
                   
                 GCAGAGGAAGA T GAGGCCAACAG 
               
               
                   
                   
                   
                   
                 GCAGAGGAAGA C GAGGCCAACAG 
               
               
                   
               
               
                 SPP1 
                 secreted phosphoprotein 1 
                 rs9138 
                 1286 A/C 
                 ATTTATGTAGA A GCAAACAAAAT 
               
               
                   
                   
                   
                   
                 ATTTATGTAGA C GCAAACAAAAT 
               
               
                   
                   
                   
                   
                 ATTTTGTTTGC T TCTACATAAAT 
               
               
                   
                   
                   
                   
                 ATTTTGTTTGC G TCTACATAAAT 
               
               
                   
               
               
                 SPP1 
                 secreted phosphoprotein 1 
                 rs4754 
                 282T/C 
                 GAAGATGATGA C GACCATGTGGA 
               
               
                   
                   
                   
                   
                 GAAGATGATGA T GACCATGTGGA 
               
               
                   
                   
                   
                   
                 TCCACATGGTC G TCATCATCTTC 
               
               
                   
                   
                   
                   
                 TCCACATGGTC A TCATCATCTTC 
               
               
                   
               
               
                 SPP1 
                 secreted phosphoprotein 1 
                 rs1126616 
                 750C/T 
                 AAGCGGAAAGC C AATGATGAGAG 
               
               
                   
                   
                   
                   
                 AAGCGGAAAGC T AATGATGAGAG 
               
               
                   
                   
                   
                   
                 CTCATCATT G GCTTTCCGC 
               
               
                   
                   
                   
                   
                 CTCATCATT A GCTTTCCGC 
               
               
                   
               
               
                 SPP1 
                 secreted phosphoprotein 1 
                 rs1126772 
                 1083A/G 
                 TGGAAATAACT A ATGTGTTTGAT 
               
               
                   
                   
                   
                   
                 TGGAAATAACT G ATGTGTTTGAT 
               
               
                   
                   
                   
                   
                 ATCAAACACAT T AGTTATTTCCA 
               
               
                   
                   
                   
                   
                 ATCAAACACAT C AGTTATTTCCA 
               
               
                   
               
               
                 HLA-DRA 
                 major histocompatibility 
                 rs2395182 
                 G/T 
                 AGATGCCTATT G TATTACCGAGA 
               
               
                   
                 complex, class II, 
                   
                   
                 AGATGCCTATT T TATTACCGAGA 
               
               
                   
                 DR alpha 
                   
                   
                 TCTCGGTAATA C AATAGGCATCT 
               
               
                   
                   
                   
                   
                 TCTCGGTAATA A AATAGGCATCT 
               
               
                   
               
               
                 HLA 
                 major histocompatibility 
                 rs2395166 
                 C/T 
                 ATAAGGTGAAA C AGAAACAGATC 
               
               
                   
                 complex 
                   
                   
                 ATAAGGTGAAA T AGAAACAGATC 
               
               
                   
                   
                   
                   
                 GATCTGTTTCT G TTTCACCTTAT 
               
               
                   
                   
                   
                   
                 GATCTGTTTCT A TTTCACCTTAT 
               
               
                   
               
               
                 HLA 
                 major histocompatibility 
                 rs2213584 
                 A/G 
                 TGAGCAAAGAG A TTGGACACTGA 
               
               
                   
                 complex 
                   
                   
                 TGAGCAAAGAG G TTGGACACTGA 
               
               
                   
                   
                   
                   
                 TCAGTGTCCAA T CTCTTTGCTCA 
               
               
                   
                   
                   
                   
                 TCAGTGTCCAA C CTCTTTGCTCA 
               
               
                   
               
               
                 HLA 
                 major histocompatibility 
                 rs2227139 
                 C/T 
                 CAACAGTTCAT C GTGTTTCAAAT 
               
               
                   
                 complex 
                   
                   
                 CAACAGTTCAT T GTGTTTCAAAT 
               
               
                   
                   
                   
                   
                 ATATTTGAAACTC G ATGAACTGTTGCT 
               
               
                   
                   
                   
                   
                 ATATTTGAAACTC A ATGAACTGTTGCT 
               
               
                   
               
               
                 IL1RN 
                 interleukin 1 receptor 
                 rs419598 
                 2018 T/C 
                 CCAACTAGTTGCTGGATACTTGCAA 
               
               
                   
                 antagonist 
                   
                   
                 CCAACTAGTTGCCGGATACTTGCAA 
               
               
                   
                   
                   
                   
                 TTGCAAGTATCCAGCAACTAGTTGG 
               
               
                   
                   
                   
                   
                 TTGCAAGTATCCGGCAACTAGTTGG 
               
               
                   
               
               
                 IL1RN 
                 interleukin 1 receptor 
                 2073 intron2 
                 2073 C/T Intron2 
                 TGCCAGGAAAG C CAATGTATGTG 
               
               
                   
                 antagonist 
                 C/T 
                   
                 TTGCCAGGAAAG T CAATGTATGTGG 
               
               
                   
                   
                 (rs423904) 
                   
                 CCACATACATTG G CTTTCCTGGCAA 
               
               
                   
                   
                   
                   
                 CCACATACATTG A CTTTCCTGGCAA 
               
               
                   
               
               
                 NOS2A 
                 nitric oxide synthase 2A 
                 rs1137933 
                 exon 10 C/T, D346D 
                 TAGCGCTGGAC A TCACAGAAGTC 
               
               
                   
                 isoform 1 
                   
                   
                 TAGCGCTGGAC G TCACAGAAGTC 
               
               
                   
                   
                   
                   
                 GACTTCTGTGA T GTCCAGCGCTA 
               
               
                   
                   
                   
                   
                 GACTTCTGTGA C GTCCAGCGCTA 
               
               
                   
               
               
                 GABBRA1 
                 gamma-aminobutyric acid 
                 rs1805057 
                 G1465A (489 G/S) 
                 ACCAGAACGGC C GCCTCCTCCAG 
               
               
                   
                 (GABA) B receptor 1 
                   
                   
                 ACCAGAACGGC T GCCTCCTCCAG 
               
               
                   
                   
                   
                   
                 CTGGAGGAGGC G GCCGTTCTGGT 
               
               
                   
                   
                   
                   
                 CTGGAGGAGGC A GCCGTTCTGGT 
               
               
                   
               
               
                 VDR 
                 vitamin D receptor 
                 rs731236 
                 Taq 1 
                 TGGATGGCCTC A ATCAGCGCGGC 
               
               
                   
                   
                   
                   
                 TGGATGGCCTC G ATCAGCGCGGC 
               
               
                   
                   
                   
                   
                 GCCGCGCTGAT T GAGGCCATCCA 
               
               
                   
                   
                   
                   
                 GCCGCGCTGAT C GAGGCCATCCA 
               
               
                   
               
               
                 NOS2A 
                 nitric oxide synthase 2A 
                 rs2779248 
                 −277 A/G 
                 GGCTGCTAAGA C AGAGGCACCAC 
               
               
                   
                 isoform 1 
                   
                   
                 GGCTGCTAAGA T AGAGGCACCAC 
               
               
                   
                   
                   
                   
                 GTGGTGCCTCT G TCTTAGCAGCC 
               
               
                   
                   
                   
                   
                 GTGGTGCCTCT A TCTTAGCAGCC 
               
               
                   
               
               
                 IL1B 
                 interleukin 1, beta 
                 rs1143627 
                 −31 Tata 
                 CTTTTGAAAGC T ATAAAAACAGC 
               
               
                   
                   
                   
                   
                 CTTTTGAAAGC C ATAAAAACAGC 
               
               
                   
                   
                   
                   
                 CTTTTGAAAGC T ATAAAAACAGC 
               
               
                   
                   
                   
                   
                 CTTTTGAAAGC C ATAAAAACAGC 
               
               
                   
               
               
                 HLA-DRA 
                 major histocompatibility 
                 rs2239802 
                 intron 4 4118 C/G 
                 CCAGATGATAC C AATGTCTGATT 
               
               
                   
                 complex, class II, 
                   
                   
                 CCAGATGATAC G AATGTCTGATT 
               
               
                   
                 DR alpha 
                   
                   
                 AATCAGACATT G GTATCATCTGG 
               
               
                   
                   
                   
                   
                 AATCAGACATT C GTATCATCTGG 
               
               
                   
               
               
                 IL1B 
                 interleukin 1, beta 
                 rs1143634 
                 +3953-4 
                 CCTATCTTCTT C GACACATGGGA 
               
               
                   
                   
                   
                   
                 CCTATCTTCTT T GACACATGGGA 
               
               
                   
                   
                   
                   
                 TCCCATGTGTC G AAGAAGATAGG 
               
               
                   
                   
                   
                   
                 TCCCATGTGTC A AAGAAGATAGG 
               
               
                   
               
               
                 SPP1 
                 secreted phosphoprotein 1 
                 rs2853744 
                 −616G/T 
                 GCAGTCATCCT G CTCTCAGTCAG 
               
               
                   
                   
                   
                   
                 GCAGTCATCCT T CTCTCAGTCAG 
               
               
                   
                   
                   
                   
                 CTGACTGAGAG C AGGATGACTGC 
               
               
                   
                   
                   
                   
                 CTGACTGAGAG A AGGATGACTGC 
               
               
                   
               
               
                 CCR5 
                 chemokine (C-C motif) 
                 rs333 
                 CCR5*D32 
                 TTTTCCATACAGTCAGTATCAAT 
               
               
                   
                 receptor 5 
                   
                   
                 TTTTCCATACATTAAAGATAGTC 
               
               
                   
                   
                   
                   
                 ATTGATACTGACTGTATGGAAAA 
               
               
                   
                   
                   
                   
                 GACTATCTTTAATGTATGGAAAA 
               
               
                   
               
               
                 HLA-DRA 
                 major histocompatibility 
                 rs3135388 
                 3′ UTR 5323 C/T 
                 CCTAAAGTGGG A TTGGTTTGTTG 
               
               
                   
                 complex, class II, 
                   
                   
                 CCTAAAGTGGG G TTGGTTTGTTG 
               
               
                   
                 DR alpha 
                   
                   
                 CAACAAACCAA T CCCACTTTAGG 
               
               
                   
                   
                   
                   
                 CAACAAACCAA C CCCACTTTAGG 
               
               
                   
               
               
                 HLA 
                 major histocompatibility 
                 rs9268458 
                 A/C 
                 AAAGTGCTCGG A TGTTGGGATTA 
               
               
                   
                 complex 
                   
                   
                 AAAGTGCTCGG C TGTTGGGATTA 
               
               
                   
                   
                   
                   
                 TAATCCCAACA T CCGAGCACTTT 
               
               
                   
                   
                   
                   
                 TAATCCCAACA G CCGAGCACTTT 
               
               
                   
               
               
                 HLA 
                 major histocompatibility 
                 rs6457594 
                 A/G 
                 TCCACACATAC A GGTTTGTCACT 
               
               
                   
                 complex 
                   
                   
                 TCCACACATAC G GGTTTGTCACT 
               
               
                   
                   
                   
                   
                 AGTGACAAACC T GTATGTGTGGA 
               
               
                   
                   
                   
                   
                 AGTGACAAACC C GTATGTGTGGA 
               
               
                   
               
               
                 HLA 
                 major histocompatibility 
                 rs7451962 
                 A/G 
                 GGCAGGAATTC A GAATCCCTCAT 
               
               
                   
                 complex 
                   
                   
                 GGCAGGAATTC G GAATCCCTCAT 
               
               
                   
                   
                   
                   
                 ATGAGGGATTC T GAATTCCTGCC 
               
               
                   
                   
                   
                   
                 ATGAGGGATTC C GAATTCCTGCC 
               
               
                   
               
               
                 HLA 
                 major histocompatibility 
                 rs7451962 
                 A/G 
                 GGGCAGGAATTC A GAATCCCTCATC 
               
               
                   
                 complex 
                   
                   
                 GGGCAGGAATTC G GAATCCCTCATC 
               
               
                   
                   
                   
                   
                 GATGAGGGATTC T GAATTCCTGCCC 
               
               
                   
                   
                   
                   
                 GATGAGGGATTC C GAATTCCTGCCC 
               
               
                   
               
               
                 HLA 
                 major histocompatibility 
                 rs7451962 
                 A/G 
                 GCAGGAATTC A GAATCCCTCA 
               
               
                   
                 complex 
                   
                   
                 GCAGGAATTC G GAATCCCTCA 
               
               
                   
                   
                   
                   
                 TGAGGGATTC T GAATTCCTGC 
               
               
                   
                   
                   
                   
                 TGAGGGATTC C GAATTCCTGC 
               
               
                   
               
               
                 PNMT 
                 phenylethanolamine 
                 rs3764351 
                 −390G/A 
                 ATGGCTGCGGG A GGCTGGAGAAG 
               
               
                   
                 N-methyltransferase 
                   
                   
                 ATGGCTGCGGG G GGCTGGAGAAG 
               
               
                   
                   
                   
                   
                 TTCTCCAGCC T CCCGCAGCCA 
               
               
                   
                   
                   
                   
                 TTCTCCAGCC C CCCGCAGCCA 
               
               
                   
               
               
                 KIF1B 
                 kinesin family member 18 
                 rs10492972 
                 C/T 
                 CGCTACAATTCT C CTGGTCAGGTTT 
               
               
                   
                   
                   
                   
                 CGCTACAATTCT T CTGGTCAGGTTT 
               
               
                   
                   
                   
                   
                 AAACCTGACCAG G AGAATTGTAGCG 
               
               
                   
                   
                   
                   
                 AAACCTGACCAG A AGAATTGTAGCG 
               
               
                   
               
               
                 IGF2R 
                 Immunoglobulin G Fc 
                 rs12202350 
                 C/T 
                 GATAACTTCACA C AGATTGAAATGT 
               
               
                   
                 Receptor II 
                   
                   
                 GATAACTTCACA T AGATTGAAATGT 
               
               
                   
                   
                   
                   
                 ACATTTCAATCT G TGTGAAGTTATC 
               
               
                   
                   
                   
                   
                 ACATTTCAATCT A TGTGAAGTTATC 
               
               
                   
               
               
                 GRIN2A 
                 glutamate receptor, 
                 rs8049651 
                 C/T 
                 ACACGTCTCGGT C AGGGGGTCTATG 
               
               
                   
                 ionotropic, N-methyl 
                   
                   
                 ACACGTCTCGGT T AGGGGGTCTATG 
               
               
                   
                 D-aspartate 2A 
                   
                   
                 CATAGACCCCCT G ACCGAGACGTGT 
               
               
                   
                   
                   
                   
                 CATAGACCCCCT A ACCGAGACGTGT 
               
               
                   
               
               
                 KLC1 
                 kinesin light chain 1 
                 rs8702 
                 C/G 
                 ACATGCCTTGCT C TAAGGCTTAGTT 
               
               
                   
                   
                   
                   
                 ACATGCCTTGCT G TAAGGCTTAGTT 
               
               
                   
                   
                   
                   
                 AACTAAGCCTTA G AGCAAGGCATGT 
               
               
                   
                   
                   
                   
                 AACTAAGCCTTA C AGCAAGGCATGT 
               
               
                   
               
               
                 IL7R 
                 interleukin 7 receptor 
                 rs987107 
                 C/T 
                 TCTCTTTACTGA C AGCAACTCTGGC 
               
               
                   
                   
                   
                   
                 TCTCTTTACTGA T AGCAACTCTGGC 
               
               
                   
                   
                   
                   
                 GCCAGAGTTGCT G TCAGTAAAGAGA 
               
               
                   
                   
                   
                   
                 GCCAGAGTTGCT A TCAGTAAAGAGA 
               
               
                   
               
               
                 STS 
                 STS steroid sulfatase, 
                 rs12861247 
                 A/G 
                 CAGGGAGGAATG A ACCTGGATTCCT 
               
               
                   
                 isozyme S 
                   
                   
                 CAGGGAGGAATG G ACCTGGATTCCT 
               
               
                   
                   
                   
                   
                 AGGAATCCAGGT T CATTCCTCCCTG 
               
               
                   
                   
                   
                   
                 AGGAATCCAGGT C CATTCCTCCCTG 
               
               
                   
               
               
                 GPC6 
                 glypican 6 
                 rs7995215 
                 A/G 
                 TGCACACTTCAG A ATGTTTGGCACC 
               
               
                   
                   
                   
                   
                 TGCACACTTCAG G ATGTTTGGCACC 
               
               
                   
                   
                   
                   
                 GGTGCCAAACAT T CTGAAGTGTGCA 
               
               
                   
                   
                   
                   
                 GGTGCCAAACAT C CTGAAGTGTGCA 
               
               
                   
               
               
                 EREG 
                 epiregulin 
                 rs1350666 
                 C/T 
                 TGGCTATTGTTT C ATTGCATTCACT 
               
               
                   
                   
                   
                   
                 TGGCTATTGTTT T ATTGCATTCACT 
               
               
                   
                   
                   
                   
                 AGTGAATGCAAT G AAACAATAGCCA 
               
               
                   
                   
                   
                   
                 AGTGAATGCAAT A AAACAATAGCCA 
               
               
                   
               
               
                 ADRA1A 
                 adrenergic, alpha-1A-, 
                 rs3808585 
                 C/T 
                 GGGGTAGAGGGG C CGGTATAAAACC 
               
               
                   
                 receptor 
                   
                   
                 GGGGTAGAGGGG T CGGTATAAAACC 
               
               
                   
                   
                   
                   
                 GGTTTTATACCG G CCCCTCTACCCC 
               
               
                   
                   
                   
                   
                 GGTTTTATACCG A CCCCTCTACCCC 
               
               
                   
               
               
                 IL16 
                 interleukin 16 
                 rs4128767 
                 C/T 
                 GCTGTACCATAG C TTTTCTGAGAAA 
               
               
                   
                   
                   
                   
                 GCTGTACCATAG T TTTTCTGAGAAA 
               
               
                   
                   
                   
                   
                 TTTCTCAGAAAA G CTATGGTACAGC 
               
               
                   
                   
                   
                   
                 TTTCTCAGAAAA A CTATGGTACAGC 
               
               
                   
               
               
                 ARRB2 
                 arrestin, beta 2 
                 rs7208257 
                 C/T 
                 TGAAGTCTTCTC C TTCCTCCGCCAC 
               
               
                   
                   
                   
                   
                 TGAAGTCTTCTC T TTCCTCCGCCAC 
               
               
                   
                   
                   
                   
                 GTGGCGGAGGAA G GAGAAGACTTCA 
               
               
                   
                   
                   
                   
                 GTGGCGGAGGAA A GAGAAGACTTCA 
               
               
                   
               
               
                 NTF3 
                 neurotrophin-3 
                 rs7956189 
                 A/G 
                 TAAGTAAGTGGC A GAGTGAAGATTG 
               
               
                   
                   
                   
                   
                 TAAGTAAGTGGC G GAGTGAAGATTG 
               
               
                   
                   
                   
                   
                 CAATCTTCACTC T GCCACTTACTTA 
               
               
                   
                   
                   
                   
                 CAATCTTCACTC C GCCACTTACTTA 
               
               
                   
               
               
                 IL12A 
                 interleukin-12 subunit alpha 
                 rs4680534 
                 C/T 
                 ATCTATGTGTGT C TGTACATGAATA 
               
               
                   
                   
                   
                   
                 ATCTATGTGTGT T TGTACATGAATA 
               
               
                   
                   
                   
                   
                 TATTCATGTACA G ACACACATAGAT 
               
               
                   
                   
                   
                   
                 TATTCATGTACA A ACACACATAGAT 
               
               
                   
               
               
                 SLC6A4 
                 solute carrier family 6, 
                 rs1042173 
                 G/T 
                 GAGTAGCATATA G AATTTTATTGCT 
               
               
                   
                 member 4 
                   
                   
                 GAGTAGCATATA T AATTTTATTGCT 
               
               
                   
                   
                   
                   
                 AGCAATAAAATT C TATATGCTACTC 
               
               
                   
                   
                   
                   
                 AGCAATAAAATT A TATATGCTACTC 
               
               
                   
               
               
                 FLJ34870 
                 FLJ34870 
                 rs7577925 
                 A/G 
                 TCCTTGACTGTT A GACACCAAGGAG 
               
               
                   
                   
                   
                   
                 TCCTTGACTGTT G GACACCAAGGAG 
               
               
                   
                   
                   
                   
                 CTCCTTGGTGTC T AACAGTCAAGGA 
               
               
                   
                   
                   
                   
                 CTCCTTGGTGTC C AACAGTCAAGGA 
               
               
                   
               
               
                 FCRL3 
                 Fc receptor-like 3 
                 rs7528684 
                 nearGene-5′ A/G 
                 ATGTACAGATCA A GGACTTCCCGTA 
               
               
                   
                   
                   
                   
                 ATGTACAGATCA G GGACTTCCCGTA 
               
               
                   
                   
                   
                   
                 TACGGGAAGTCC T TGATCTGTACAT 
               
               
                   
                   
                   
                   
                 TACGGGAAGTCC C TGATCTGTACAT 
               
               
                   
               
               
                 IGF2R 
                 insulin-like growth factor 
                 rs6917747 
                 A/G 
                 CTGGGAGAGACT A GCTCACACAGCT 
               
               
                   
                 2 receptor 
                   
                   
                 CTGGGAGAGACT G GCTCACACAGCT 
               
               
                   
                   
                   
                   
                 AGCTGTGTGAGC T AGTCTCTCCCAG 
               
               
                   
                   
                   
                   
                 AGCTGTGTGAGC C AGTCTCTCCCAG 
               
               
                   
               
               
                 LOC729293 
                 LOC729293 
                 rs6570426 
                 A/T 
                 CCCTTCCAAATA A CCAATCATACAC 
               
               
                   
                   
                   
                   
                 CCCTTCCAAATA T CCAATCATACAC 
               
               
                   
                   
                   
                   
                 GTGTATGATTGG T TATTTGGAAGGG 
               
               
                   
                   
                   
                   
                 GTGTATGATTGG A TATTTGGAAGGG 
               
               
                   
               
               
                 SNAP25 
                 synaptosomal-associated 
                 rs6077690 
                 A/T 
                 CACTTTGGAAAA A ATTCTGACTACA 
               
               
                   
                 protein, 25 kDa 
                   
                   
                 CACTTTGGAAAA T ATTCTGACTACA 
               
               
                   
                   
                   
                   
                 TGTAGTCAGAAT T TTTTCCAAAGTG 
               
               
                   
                   
                   
                   
                 TGTAGTCAGAAT A TTTTCCAAAGTG 
               
               
                   
               
               
                 MORF4 
                 mortality factor 4 
                 rs4473631 
                 A/C 
                 CAGAGGACAATT A TCTTGGAAAGCA 
               
               
                   
                   
                   
                   
                 CAGAGGACAATT C TCTTGGAAAGCA 
               
               
                   
                   
                   
                   
                 TGCTTTCCAAGA T AATTGTCCTCTG 
               
               
                   
                   
                   
                   
                 TGCTTTCCAAGA G AATTGTCCTCTG 
               
               
                   
               
               
                 SNAP25 
                 synaptosomal-associated 
                 rs3787283 
                 C/T 
                 AATTCCAGAAAA C GAATGATTCCCA 
               
               
                   
                 protein, 25 kDa 
                   
                   
                 AATTCCAGAAAA T GAATGATTCCCA 
               
               
                   
                   
                   
                   
                 TGGGAATCATTC G TTTTCTGGAATT 
               
               
                   
                   
                   
                   
                 TGGGAATCATTC A TTTTCTGGAATT 
               
               
                   
               
               
                 LOC728594 
                 hypothetical protein 
                 rs3756450 
                 C/T 
                 CCACAATGATAA C AAAGCCGACTTG 
               
               
                   
                 LOC728594 
                   
                   
                 CCACAATGATAA T AAAGCCGACTTG 
               
               
                   
                   
                   
                   
                 CAAGTCGGCTTT G TTATCATTGTGG 
               
               
                   
                   
                   
                   
                 CAAGTCGGCTTT A TTATCATTGTGG 
               
               
                   
               
               
                 SLC6A2 
                 solute carrier family 6 
                 rs28386840 
                 A/T 
                 GGGCTGAGCACC A GTTTCCCCAGCA 
               
               
                   
                 member 2 
                   
                   
                 GGGCTGAGCACC T GTTTCCCCAGCA 
               
               
                   
                   
                   
                   
                 TGCTGGGGAAAC T GGTGCTCAGCCC 
               
               
                   
                   
                   
                   
                 TGCTGGGGAAAC A GGTGCTCAGCCC 
               
               
                   
               
               
                 ZNF544 
                 zinc finger protein 544 
                 rs260461 
                 A/G 
                 ATCAATGTCACT A GATCAAAATCAA 
               
               
                   
                   
                   
                   
                 ATCAATGTCACT G GATCAAAATCAA 
               
               
                   
                   
                   
                   
                 TTGATTTTGATC T AGTGACATTGAT 
               
               
                   
                   
                   
                   
                 TTGATTTTGATC C AGTGACATTGAT 
               
               
                   
               
               
                 MHC II/ 
                 major histocompatibility 
                 rs2187668 
                 A/G 
                 AGCTGAGAGTAA G TGAGGACCATGT 
               
               
                 HLA- 
                 complex, class II, 
                   
                   
                 AGCTGAGAGTAA A TGAGGACCATGT 
               
               
                 DQA1 
                 DQ alpha 1 
                   
                   
                 ACATGGTCCTCA C TTACTCTCAGCT 
               
               
                   
                   
                   
                   
                 ACATGGTCCTCA T TTACTCTCAGCT 
               
               
                   
               
               
                 SLC6A4 
                 solute carrier family 6, 
                 rs2066713 
                 C/T 
                 GCATTTCCCTTC C GTAGACCCTCTG 
               
               
                   
                 member 4 
                   
                   
                 GCATTTCCCTTC T GTAGACCCTCTG 
               
               
                   
                   
                   
                   
                 CAGAGGGTCTAC G GAAGGGAAATGC 
               
               
                   
                   
                   
                   
                 CAGAGGGTCTAC A GAAGGGAAATGC 
               
               
                   
               
               
                 CSMD1 
                 CUB and Sushi multiple 
                 rs2049306 
                 A/C 
                 GTTCTGAAAGCA A ACATTTAAATAT 
               
               
                   
                 domains 1 
                   
                   
                 GTTCTGAAAGCA C ACATTTAAATAT 
               
               
                   
                   
                   
                   
                 ATATTTAAATGT T TGCTTTCAGAAC 
               
               
                   
                   
                   
                   
                 ATATTTAAATGT G TGCTTTCAGAAC 
               
               
                   
               
               
                 SLC1A3 
                 solute carrier family 1 
                 rs2032893 
                 A/G 
                 ATAAATAAATAT A CAGAAGCATTGG 
               
               
                   
                 member 3 
                   
                   
                 ATAAATAAATAT G CAGAAGCATTGG 
               
               
                   
                   
                   
                   
                 CCAATGCTTCTG T ATATTTATTTAT 
               
               
                   
                   
                   
                   
                 CCAATGCTTCTG C ATATTTATTTAT 
               
               
                   
               
               
                 LOC647094 
                 LOC647094 
                 rs2028455 
                 A/G 
                 ACATGCCTGCCT A GAATGATTACTT 
               
               
                   
                   
                   
                   
                 ACATGCCTGCCT G GAATGATTACTT 
               
               
                   
                   
                   
                   
                 AAGTAATCATTC T AGGCAGGCATGT 
               
               
                   
                   
                   
                   
                 AAGTAATCATTC C AGGCAGGCATGT 
               
               
                   
               
               
                 DMRT2 
                 doublesex and mab-3 related 
                 rs17641078 
                 C/G 
                 AAGATCAGCAAA C AAAACACCAGGC 
               
               
                   
                 transcription factor 2 
                   
                   
                 AAGATCAGCAAA G AAAACACCAGGC 
               
               
                   
                   
                   
                   
                 GCCTGGTGTTTT G TTTGCTGATCTT 
               
               
                   
                   
                   
                   
                 GCCTGGTGTTTT C TTTGCTGATCTT 
               
               
                   
               
               
                 DBH 
                 dopamine beta-hydroxylase 
                 rs1611115 
                 C/T 
                 TCAGTCTACTTG C GGGAGAGGACAG 
               
               
                   
                 (dopamine beta- 
                   
                   
                 TCAGTCTACTTG T GGGAGAGGACAG 
               
               
                   
                 monooxygenase) 
                   
                   
                 CTGTCCTCTCCC G CAAGTAGACTGA 
               
               
                   
                   
                   
                   
                 CTGTCCTCTCCC A CAAGTAGACTGA 
               
               
                   
               
               
                 MMP24 
                 MMP24 matrix 
                 rs1555322 
                 A/G 
                 CACGCACTTCAC A TGTATCTTATTC 
               
               
                   
                 metallopeptidase 24 
                   
                   
                 CACGCACTTCAC G TGTATCTTATTC 
               
               
                   
                   
                   
                   
                 GAATAAGATACA T GTGAAGTGCGTG 
               
               
                   
                   
                   
                   
                 GAATAAGATACA C GTGAAGTGCGTG 
               
               
                   
               
               
                 DSEL 
                 DSEL 
                 rs13353224 
                 A/G 
                 ATCAGAGTTAAT A AACTTCCCTATT 
               
               
                   
                   
                   
                   
                 ATCAGAGTTAAT G AACTTCCCTATT 
               
               
                   
                   
                   
                   
                 AATAGGGAAGTT T ATTAACTCTGAT 
               
               
                   
                   
                   
                   
                 AATAGGGAAGTT C ATTAACTCTGAT 
               
               
                   
               
               
                 C1orf125 
                 chromosome 1 open reading 
                 rs12047808 
                 A/G 
                 AATGAGAGGGGT A ACACACATTATG 
               
               
                   
                 frame 125 
                   
                   
                 AATGAGAGGGGT G ACACACATTATG 
               
               
                   
                   
                   
                   
                 CATAATGTGTGT T ACCCCTCTCATT 
               
               
                   
                   
                   
                   
                 CATAATGTGTGT C ACCCCTCTCATT 
               
               
                   
               
               
                 GPC5 
                 glypican 5 
                 rs10492503 
                 A/T 
                 TGGATAACTGCT A CAATTATAGTTT 
               
               
                   
                   
                   
                   
                 TGGATAACTGCT T CAATTATAGTTT 
               
               
                   
                   
                   
                   
                 AAACTATAATTG T AGCAGTTATCCA 
               
               
                   
                   
                   
                   
                 AAACTATAATTG A AGCAGTTATCCA 
               
               
                   
               
               
                 C1GALT1 
                 core 1 synthase, 
                 rs10259085 
                 C/T 
                 TAAAAACAATTA C GTAACACCAAGA 
               
               
                   
                 glycoprotein-N- 
                   
                   
                 TAAAAACAATTA T GTAACACCAAGA 
               
               
                   
                 acetylgalactosamine 3-beta- 
                   
                   
                 TCTTGGTGTTAC G TAATTGTTTTTA 
               
               
                   
                 galactosyltransferase, 1 
                   
                   
                 TCTTGGTGTTAC A TAATTGTTTTTA 
               
               
                   
               
               
                 MET 
                 met proto-oncogene 
                 rs10243024 
                 A/G 
                 TATTTTTACTCC A AATACTGTTTCA 
               
               
                   
                 (hepatocyte growth 
                   
                   
                 TATTTTTACTCC G AATACTGTTTCA 
               
               
                   
                 factor receptor) 
                   
                   
                 TGAAACAGTATT T GGAGTAAAAATA 
               
               
                   
                   
                   
                   
                 TGAAACAGTATT C GGAGTAAAAATA 
               
               
                   
               
               
                 ICOS 
                 inducible T-cell co- 
                 rs4404254 
                 C/T 
                 TTACAAGTTTAG C TCTTTTTGTAGA 
               
               
                   
                 stimulator 
                   
                   
                 TTACAAGTTTAG T TCTTTTTGTAGA 
               
               
                   
                   
                   
                   
                 TCTACAAAAAGA G CTAAACTTGTAA 
               
               
                   
                   
                   
                   
                 TCTACAAAAAGA A CTAAACTTGTAA 
               
               
                   
               
               
                 OAS1 
                 2′,5′-oligoadenylate 
                 rs3741981/ 
                 A/G 
                 CAGTTGACTGGC A GCTATAAACCTA 
               
               
                   
                 synthetase 1 
                 rs1131454 
                   
                 CAGTTGACTGGC G GCTATAAACCTA 
               
               
                   
                   
                   
                   
                 TAGGTTTATAGC T GCCAGTCAACTG 
               
               
                   
                   
                   
                   
                 TAGGTTTATAGC C GCCAGTCAACTG 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 Examples of Forward Primers Used in SNP Analysis 
               
             
          
           
               
                 SNP # 
                 Gene Symbol 
                 rs ID 
                 Forward Primers (sequence 5′ &gt; 3′) 
               
               
                   
               
             
          
           
               
                 1 
                 EBF1 
                 rs1368297 
                 CCAAATCTTGGTTTTCAGTGC 
                   
               
               
                   
               
               
                 2 
                 RANTES/CCL5 
                 rs2280788 
                 TATGATACCGGCCAATGCTT 
               
               
                   
               
               
                 3 
                 RANTES/CCL5 
                 rs2107538 
                 CACCTCCTTTGGGGACTGTA 
               
               
                   
               
               
                 4 
                 TGFB1 
                 rs17851976 
                 TCGATAGTCTTGCAGGTGGA 
               
               
                   
               
               
                 6 
                 UPC2 
                 rs659366 
                 TTCGCCTTTAATTGGCTGAC 
               
               
                   
               
               
                 7 
                 IKBL 
                 rs3130062 
                 TGAGTCCTTCTCAGCCTGGT 
               
               
                   
               
               
                 8 
                 Apo I/Fas (CD 95) 
                 rs1800682 
                 CCTATGGCGCAACATCTGTA 
               
               
                   
               
               
                 9 
                 Apo I/Fas (CD 95) 
                 rs3781202 
                 CCAATGCCTACCTAGCCTGT 
               
               
                   
               
               
                 10 
                 IL2 
                 rs2069763 
                 GCATTGCACTAAGTCTTGCAC 
               
               
                   
               
               
                 11 
                 IL2 
                 rs2069762 
                 ACCCCCAAAGACTGACTGAA 
               
               
                   
               
               
                 12 
                 IL10 
                 rs1800896 
                 ATGGAGGCTGGATAGGAGGT 
               
               
                   
               
               
                 13 
                 IL4R 
                 rs1801275 
                 CAACCTGAGCCAGAAACCTG 
               
               
                   
               
               
                 14 
                 PTPRC 
                 rs17612648 
                 ATGCCCAGTGTTCCACTTTC 
               
               
                   
               
               
                 15 
                 PTPRC 
                 rs4915154 
                 GCAGATGTCCCAGGAGAGAG 
               
               
                   
               
               
                 16 
                 PD-1/PDCD1 
                 rs11568821 
                 TATAGCCAGGACCCCACCTC 
               
               
                   
               
               
                 17 
                 CRYAB 
                 rs14133 
                 TGCTTGGGATTCCTGACTCT 
               
               
                   
               
               
                 18 
                 CRYAB 
                 rs762550 
                 GCACCCAATTCCTAAAGCAC 
               
               
                   
               
               
                 19 
                 CRYAB 
                 rs2234702 
                 GCACCCAATTCCTAAAGCAC 
               
               
                   
               
               
                 20 
                 NDUFS5 
                 rs2889683 
                 TTGCTCAACTTTAGTTTTTCAGTCA 
               
               
                   
               
               
                 21 
                 NDUFS5 
                 rs6981 
                 GCAGCGGGATAAGCTGATAA 
               
               
                   
               
               
                 22 
                 NDUFS7 
                 rs2074897 
                 GGTCTCCAGGGACAGACGTA 
               
               
                   
               
               
                 24 
                 NDUFA7 
                 rs2288414 
                 CGCTGAGCACTGCAAATCTA 
               
               
                   
               
               
                 25 
                 NDUFA7 
                 rs561 
                 CCAAGGAGGCAAAGTAGTCG 
               
               
                   
               
               
                 26 
                 ADAMTS14 
                 rs4747075 
                 TCCATTGTGGGGATTTTTGT 
               
               
                   
               
               
                 27 
                 ADAMTS14 
                 rs7081273 
                 GCCTTGGAAGGAGAAAGGAG 
               
               
                   
               
               
                 28 
                 ADAMTS14 
                 rs4746060 
                 CTGGGGAGGTGCTATGGAT 
               
               
                   
               
               
                 29 
                 NFKBIA 
                 rs11569591 
                 AGGCTTTTCACTCCTCCAAA 
               
               
                   
               
               
                 29 
                 NFKBIA 
                 rs11569591 
                 AGGCTTTTCACTCCTCCAAA 
               
               
                   
               
               
                 29 
                 NFKBIA 
                 rs11569591 
                 AGGCTTTTCACTCCTCCAAA 
               
               
                   
               
               
                 30 
                 SPP1 
                 rs28357094 
                 TGTGTGTGTGCGTTTTTGTTT 
               
               
                   
               
               
                 31 
                 HLA-DR*1501 
                 rs367398 
                 TGAGACACATAGCAGCAGCA 
               
               
                   
               
               
                 32 
                 HLA-DR*1501 
                 rs1800629 
                 GCCCCTCCCAGTTCTAGTTC 
               
               
                   
               
               
                 34 
                 IL7R 
                 rs11567685 
                 GCAGGCAGATCACTTGAGGT 
               
               
                   
               
               
                 35 
                 IL7R 
                 rs7718919 
                 GCTCTGCCATTGTTGCATAA 
               
               
                   
               
               
                 36 
                 IL7R 
                 rs11567686 
                 CCGTCTCCACTGAAAACACA 
               
               
                   
               
               
                 37 
                 IFNAR1 
                 rs2257167 
                 GCTCAGATTGGTCCTCCAGA 
               
               
                   
               
               
                 38 
                 IFNAR2 
                 rs7279064 
                 TCTTGTCTTTGCTCCCATTTTT 
               
               
                   
               
               
                 39 
                 IL1B 
                 rs1799916 
                 GGCAGAGAGACAGAGAGACTCC 
               
               
                   
               
               
                 40 
                 IFNGR2 
                 rs9808753 
                 TGTACAACGCAGAGCAGGTC 
               
               
                   
               
               
                 41 
                 Apo I/Fas (CD 95) 
                 rs2234978 
                 TGCAGAAAGCACAGAAAGGA 
               
               
                   
               
               
                 42 
                 CD24 
                 rs8734 
                 ACCCACGCAGATTTATTCCA 
               
               
                   
               
               
                 43 
                 MEFV 
                 rs28940577 
                 TTGGAGACAAGACAGCATGG 
               
               
                   
               
               
                 44 
                 CTLA4 
                 rs231775 
                 GGATCCTGAAAGGTTTTGCTC 
               
               
                   
               
               
                 45 
                 CNTF 
                 rs1800169 
                 GACACTGGGGTGATGACAGA 
               
               
                   
               
               
                 46 
                 MHC2TA 
                 rs3087456 
                 AGGTTCCCCCAACAGACTTT 
               
               
                   
               
               
                 47 
                 VDR 
                 rs1544410 
                 CCTCACTGCCCTTAGCTCTG 
               
               
                   
               
               
                 48 
                 PRKCA 
                 rs7220007 
                 AGCTGAGTGTTGTGCAGTGG 
               
               
                   
               
               
                 49 
                 PRKCA 
                 rs887797 
                 AACCCCTGCATTTCAGAATTT 
               
               
                   
               
               
                 50 
                 PRKCA 
                 rs2078153 
                 AAACAACTCCACCCAGGTTC 
               
               
                   
               
               
                 51 
                 CTLA4 
                 rs5742909 
                 TGGTTAAGGATGCCCAGAAG 
               
               
                   
               
               
                 52 
                 MGC33887 
                 rs987931 
                 CTTCGATAAATAGTGCTGGGAAA 
               
               
                   
               
               
                 53 
                 CACNG4 
                 rs4790896 
                 CTTAATCGGAAAGCTGTGTCG 
               
               
                   
               
               
                 54 
                 HELZ 
                 rs2363846 
                 GGAAAACACCAACACTCTCCA 
               
               
                   
               
               
                 55 
                 PITPNC1 
                 rs1318 
                 TCAGTTGCAAAGCTACGATGA 
               
               
                   
               
               
                 56 
                 PITPNC1 
                 rs2365403 
                 ACGCCTTTGGAACAACAATC 
               
               
                   
               
               
                 57 
                 MC1R 
                 rs1805009 
                 AACCTCTTTCTCGCCCTCAT 
               
               
                   
               
               
                 58 
                 MC1R 
                 rs1805006 
                 TGCACTCACCCATGTACTGC 
               
               
                   
               
               
                 59 
                 PRKCA 
                 rs1010544 
                 ACCAGCTTGCAGTCTCTGCT 
               
               
                   
               
               
                 60 
                 PRKCA 
                 rs3890137 
                 AGCCAGGAGACCTGAGACTG 
               
               
                   
               
               
                 61 
                 BTNL2 (DRb1*15) 
                 rs2076530 
                 TACTCAGTGCCAGACCTTCG 
               
               
                   
               
               
                 62 
                 PNMT 
                 rs876493 
                 TAAAGATTGTGGGGGTGAGG 
               
               
                   
               
               
                 63 
                 PNMT 
                 rs3764351 
                 AAAGGGCCTAATTCCCCAGT 
               
               
                   
               
               
                 64 
                 TRAIL/TNFSF10 
                 rs9880164 
                 ACTACAGGCATGTGCCAACA 
               
               
                   
                   
                 (rs1131568 in v. 37.1) 
               
               
                   
               
               
                 65 
                 PTPN22 
                 rs2476601 
                 TGCCCATCCCACACTTTATT 
               
               
                   
               
               
                 66 
                 MOG 
                 rs3130250 
                 TCTGTCCCCAGGAACAGTAGA 
               
               
                   
               
               
                 67 
                 MOG 
                 rs3130253 
                 ATGCTGAGTGTTGGGGATTC 
               
               
                   
               
               
                 68 
                 SPP1 
                 rs9138 
                 GCTTCATGGAAACTCCCTGT 
               
               
                   
               
               
                 69 
                 SPP1 
                 rs4754 
                 AGACCCTTCCAAGTAAGTCCAA 
               
               
                   
               
               
                 70 
                 SPP1 
                 rs1126616 
                 AGAGTGCTGAAACCCACAGC 
               
               
                   
               
               
                 71 
                 SPP1 
                 rs1126772 
                 GAACATGAAATGCTTCTTTCTCAG 
               
               
                   
               
               
                 72 
                 HLA-DRA 
                 rs2395182 
                 GACTGGCCTTACCCATTCTG 
               
               
                   
               
               
                 73 
                 HLA 
                 rs2395166 
                 CGCTTTCCATAGAAACCTTGG 
               
               
                   
               
               
                 74 
                 HLA 
                 rs2213584 
                 CATTGCAGGATTTACATATCAACA 
               
               
                   
               
               
                 75 
                 HLA 
                 rs2227139 
                 CAGCCAAGATGAAACCCAAG 
               
               
                   
               
               
                 76 
                 IL1RN 
                 rs419598 
                 ACAAGTTCTGGGGGACACAG 
               
               
                   
               
               
                 77 
                 IL1RN 
                 2073 Intron2 C/T 
                 ACAAGTTCTGGGGGACACAG 
               
               
                   
                   
                 (rs423904) 
               
               
                   
               
               
                 78 
                 NOS2A 
                 rs1137933 
                 CAGAGTGATAGCGGCGAGT 
               
               
                   
               
               
                 79 
                 GABBRA1 
                 rs1805057 
                 TGGTCGGTAATGGTCTGGTT 
               
               
                   
               
               
                 80 
                 VDR 
                 rs731236 
                 AGGTCGGCTAGCTTCTGGAT 
               
               
                   
               
               
                 81 
                 NOS2A 
                 rs2779248 
                 CTCTGTGTGGTGCCTCTTCA 
               
               
                   
               
               
                 82 
                 IL1B 
                 rs1143627 
                 CAGTTTCTCCCTCGCTGTTT 
               
               
                   
               
               
                 83 
                 HLA-DRA 
                 rs2239802 
                 TGATCAAGGTGCCCGTCTAT 
               
               
                   
               
               
                 84 
                 IL1B 
                 rs1143634 
                 ATGCTCAGGTGTCCTCCAAG 
               
               
                   
               
               
                 85 
                 SPP1 
                 rs2853744 
                 ACACAGCGGAATTCAGAACC 
               
               
                   
               
               
                 87 
                 CCR5 
                 rs333 
                 CGTCTCTCCCAGGAATCATC 
               
               
                   
               
               
                 88 
                 HLA-DRA 
                 rs3135388 
                 CATTTGGGCTTGGTCTCATT 
               
               
                   
               
               
                 89 
                 HLA 
                 rs9268458 
                 AATGGGGCCTCACTATGTTG 
               
               
                   
               
               
                 90 
                 HLA 
                 rs6457594 
                 TGAATTCTGGGGGCTTACTG 
               
               
                   
               
               
                 91 
                 HLA 
                 rs7451962 
                 GCCAGCTCAGTGAGGTCAGTA 
               
               
                   
               
               
                 92 
                 HLA 
                 rs7451962 
                 GCCAGCTCAGTGAGGTCAGTA 
               
               
                   
               
               
                 93 
                 HLA 
                 rs7451962 
                 GCCAGCTCAGTGAGGTCAGTA 
               
               
                   
               
               
                 94 
                 PNMT 
                 rs3764351 
                 AAAGGGCCTAATTCCCCAGT 
               
               
                   
               
               
                 95 
                 KIF1B 
                 rs10492972 
                 TGACCTCACATTGGCTATTGG 
               
               
                   
               
               
                 96 
                 IGF2R 
                 rs12202350 
                 ATAGGCATAAGCCACCATGC 
               
               
                   
               
               
                 97 
                 GRIN2A 
                 rs8049651 
                 AGCATTCCTGCCACTCACTT 
               
               
                   
               
               
                 98 
                 KLC1 
                 rs8702 
                 AGAAAAGCAGAATGCCCAAA 
               
               
                   
               
               
                 99 
                 IL7R 
                 rs987107 
                 ACCTCTGGGAAAAAGCCCTA 
               
               
                   
               
               
                 100 
                 STS 
                 rs12861247 
                 TAAACAAGGAAGGGCACTGG 
               
               
                   
               
               
                 101 
                 GPC6 
                 rs7995215 
                 CAGCAGTGTCCATGAGAATCA 
               
               
                   
               
               
                 102 
                 EREG 
                 rs1350666 
                 TTGGGGGCTATTTAAGTTCA 
               
               
                   
               
               
                 103 
                 ADRA1A 
                 rs3808585 
                 CTCGGGCAAAGACTCTTGTT 
               
               
                   
               
               
                 104 
                 IL16 
                 rs4128767 
                 ATGATCACACCACTGCATCC 
               
               
                   
               
               
                 105 
                 ARRB2 
                 rs7208257 
                 CAGCGTCTCCAGCCTCTTAG 
               
               
                   
               
               
                 106 
                 NTF3 
                 rs7956189 
                 AATCCTTTGAGGGAGCCAGT 
               
               
                   
               
               
                 107 
                 IL12A 
                 rs4680534 
                 TCAGGTTTTCCTCCTACTTCAAA 
               
               
                   
               
               
                 108 
                 SLC6A4 
                 rs1042173 
                 AAACTGCGTAGGAGAGAACAGG 
               
               
                   
               
               
                 109 
                 FLJ34870 
                 rs7577925 
                 TGGGAGCAAAGTGAAAGTCA 
               
               
                   
               
               
                 110 
                 FCRL3 
                 rs7528684 
                 TCACACAGCCTTTGGTTCTG 
               
               
                   
               
               
                 111 
                 IGF2R 
                 rs6917747 
                 TTCCTGGTGGTGGTTTTCTC 
               
               
                   
               
               
                 112 
                 LOC729293 
                 rs6570426 
                 CATTTCTGGAACTGCCTTGG 
               
               
                   
               
               
                 113 
                 SNAP25 
                 rs6077690 
                 CCTCCTCCATTCCTTCACAA 
               
               
                   
               
               
                 114 
                 MORF4 
                 rs4473631 
                 TCATATGCCTGGCAGTTTACA 
               
               
                   
               
               
                 115 
                 SNAP25 
                 rs3787283 
                 AGGGCTGCTACCAGCATAAA 
               
               
                   
               
               
                 116 
                 LOC728594 
                 rs3756450 
                 TTGGAGACAGCAGTCAGTGG 
               
               
                   
               
               
                 117 
                 SLC6A2 
                 rs28386840 
                 GCGGCCTTCATGGATAAATA 
               
               
                   
               
               
                 118 
                 ZNF544 
                 rs260461 
                 GAGGCCACAAGTCCAAAATC 
               
               
                   
               
               
                 119 
                 MHC II/HLA-DQA1 
                 rs2187668 
                 CTTAGCCACATGCCCATTTT 
               
               
                   
               
               
                 120 
                 SLC6A4 
                 rs2066713 
                 CTTCTGAGATGGACCGCATT 
               
               
                   
               
               
                 121 
                 CSMD1 
                 rs2049306 
                 TTGCCACTAGTTCTGAAAGCA 
               
               
                   
               
               
                 122 
                 SLC1A3 
                 rs2032893 
                 ATCCCTATCAGGGGCAGACT 
               
               
                   
               
               
                 123 
                 LOC647094 
                 rs2028455 
                 GCATAATGCCACAGGACCTT 
               
               
                   
               
               
                 124 
                 DMRT2 
                 rs17641078 
                 GCCTCACACTCCTGAGATCC 
               
               
                   
               
               
                 125 
                 DBH 
                 rs1611115 
                 ACAGGAGGGAAAAGGAAGGA 
               
               
                   
               
               
                 126 
                 MMP24 
                 rs1555322 
                 CAACAGCTGCCATTCTGTGT 
               
               
                   
               
               
                 127 
                 DSEL 
                 rs13353224 
                 TGGGGGTGCTAAGACAGTTT 
               
               
                   
               
               
                 128 
                 C1orf125 
                 rs12047808 
                 GGCAAATCAAATCCAGCAGT 
               
               
                   
               
               
                 129 
                 GPC5 
                 rs10492503 
                 GCGGAAGATTGGATAACTGC 
               
               
                   
               
               
                 130 
                 C1GALT1 
                 rs10259085 
                 AGTCATAAGGCCGGAGTCCT 
               
               
                   
               
               
                 131 
                 MET 
                 rs10243024 
                 AGCGATTTCTGGAAGCATGT 
               
               
                   
               
               
                 132 
                 ICOS 
                 rs4404254 
                 CCCGGAATTGAAAGCAAAT 
               
               
                   
               
               
                 133 
                 OAS1 
                 rs3741981/rs1131454 
                 GGATCAGGAATGGACCTCAA 
               
               
                   
               
             
          
         
       
     
         [0000]                                                            TABLE 9                   Examples of Reverse Primers Used in SNP Analysis            SNP #   Gene Symbol   rs ID   Reverse Primers (sequence 5′ &gt; 3′)                    1   EBF1   rs1368297   CTGCCCAGTGCTTTTCATTT                   2   RANTES/CCL5   rs2280788   GAGGGCAGTAGCAATGAGGA               3   RANTES/CCL5   rs2107538   GGAGTGGCAGTTAGGACAGG               4   TGFB1   rs17851976   ACCACACCAGCCCTGTTC               6   UPC2   rs659366   AGTCCCTTCTGCTGGTGAAA               7   IKBL   rs3130062   CTCTCACGCAGCTCTTCCTC               8   Apo I/Fas (CD 95)   rs1800682   AGTTGGGGAGGTCTTGAAGG               9   Apo I/Fas (CD 95)   rs3781202   AAGGGCCTTGTCTTTTAGGC               10   IL2   rs2069763   TCCTGGTGAGTTTGGGATTC               11   IL2   rs2069762   TCTTGCTCTTGTCCACCACA               12   IL10   rs1800896   CTTCCCCAGGTAGAGCAACA               13   IL4R   rs1801275   CCACATTTCTCTGGGGACAC               14   PTPRC   rs17612648   CTTTTGTGTGCCAACCTGTG               15   PTPRC   rs4915154   AACTGAAGACACTACTAGAGCAGCA               16   PD-1/PDCD1   rs11568821   AGGCAGGCACACACATGG               17   CRYAB   rs14133   GACTTGTGATCCGGGATTTG               18   CRYAB   rs762550   GGTCAACATGTCAGCACCAG               19   CRYAB   rs2234702   GGTCAACATGTCAGCACCAG               20   NDUFS5   rs2889683   AGTGGCAGACCATCCACATC               21   NDUFS5   rs6981   CTTTGACAAGGAGGTTTGTCG               22   NDUFS7   rs2074897   AGGAATCGTTCTGGGGAGAG               24   NDUFA7   rs2288414   GCTCTGTCCTTTCTCCACCA               25   NDUFA7   rs561   AGAAAGTCCCTGTGGGTGTG               26   ADAMTS14   rs4747075   CTGGCTTCTCTGGGAGGAAT               27   ADAMTS14   rs7081273   GCTTGGCTCTCAGGAGACAG               28   ADAMTS14   rs4746060   GCTTCAAAGTGCTCAAATGGT               29   NFKBIA   rs11569591   AAGGACGCACTGTGGTTAGG               29   NFKBIA   rs11569591   AAGGACGCACTGTGGTTAGG               29   NFKBIA   rs11569591   AAGGACGCACTGTGGTTAGG               30   SPP1   rs28357094   CCAAGCCCTCCCAGAATTTA               31   HLA-DR*1501   rs367398   CAGGAAACAGCTCAGACGTG               32   HLA-DR*1501   rs1800629   AAAGTTGGGGACACACAAGC               34   IL7R   rs11567685   GCCCAGGCTGGAGTACAATA               35   IL7R   rs7718919   CACACCACAGTAGGCATTCAA               36   IL7R   rs11567686   GCCCAGGCTGGAGTACAATA               37   IFNAR1   rs2257167   TTCGCCTAATTTTTCTCTCACA               38   IFNAR2   rs7279064   GACTTCCTGCCAGTGCTCTC               39   IL1B   rs1799916   AAACAGCGAGGGAGAAACTG               40   IFNGR2   rs9808753   TGTTTCCCACGGGTTTGATA               41   Apo I/Fas (CD 95)   rs2234978   CTGGGCTATGGAGCAAGACT               42   CD24   rs8734   ACCACGAAGAGACTGGCTGT               43   MEFV   rs28940577   GCTTGGGAGGCTCCTTTATT               44   CTLA4   rs231775   CCTCCTCCATCTTCATGCTC               45   CNTF   rs1800169   GCCAACAAAACATGGAAGGT               46   MHC2TA   rs3087456   CAAGCTAAGCCAACATGCAA               47   VDR   rs1544410   CAGGAATGTTGAGCCCAGTT               48   PRKCA   rs7220007   GCATAGCCTCGGAGACAGAC               49   PRKCA   rs887797   TCCCGGGTATATGATCTCCA               50   PRKCA   rs2078153   TCACCTAAGGACAGTCTAAAATTGC               51   CTLA4   rs5742909   AGCCGTGGGTTTAGCTGTTA               52   MGC33887   rs987931   GCTTGGAAGTTGCCATTCAT               53   CACNG4   rs4790896   AGCTTGCCACAGGACAGTTT               54   HELZ   rs2363846   TTGAGTTGTTGCAGCAGAGATT               55   PITPNC1   rs1318   TGCCTTTTGATGACTGGGTTA               56   PITPNC1   rs2365403   AGCAGGGAAGCACTTGAAGA               57   MC1R   rs1805009   GGTCACACAGGAACCAGACC               58   MC1R   rs1805006   TGCAGGTGATCACGTCAATG               59   PRKCA   rs1010544   CCCCAAACCCTGACTTTCAT               60   PRKCA   rs3890137   TACTGATTGAGCCCCCTTGT               61   BTNL2 (DRb1*15)   rs2076530   TTAAAGTGGCAGGAGCAGGT               62   PNMT   rs876493   CCCATTCATCCATCTCCCTTA               63   PNMT   rs3764351   CCTCACCCCCACAATCTTTA               64   TRAIL/TNFSF10   rs9880164(rs1131568   CGAGATCAAGAGATCAAGACCA               in v. 37.1)               65   PTPN22   rs2476601   TGGATAGCAACTGCTCCAAG               66   MOG   rs3130250   GCTGGAAGACACTTGGAGGA               67   MOG   rs3130253   TCCAAGAAGCCAGCTCATTT               68   SPP1   rs9138   CACACCACAAAAAGATAATCACAA               69   SPP1   rs4754   CATCAGACTGGTGAGAATCATC               70   SPP1   rs1126616   ATTCACGGCTGACTTTGGAA               71   SPP1   rs1126772   TGAACATAGACATAACCCTGAAGC               72   HLA-DRA   rs2395182   TCCACTCAAAGACACATCTTCAA               73   HLA   rs2395166   TGTGTCAGGCAATGAGGCTA               74   HLA   rs2213584   GGCATCTGAGACTATGTCTAACAGAA               75   HLA   rs2227139   GGGTTGGGGAGAAAGATATGA               76   IL1RN   rs419598   ATTGCACCTAGGGTTTGTGC               77   IL1RN   2073 Intron2   ATTGCACCTAGGGTTTGTGC               C/T (rs423904)               78   NOS2A   rs1137933   CCCTTCAATGGCTGGTACAT               79   GABBRA1   rs1805057   TGGCCTATGATGCCATCTG               80   VDR   rs731236   CTGAGAGCTCCTGTGCCTTC               81   NOS2A   rs2779248   CAGCTTCCTGGACTCCTGTC               82   IL1B   rs1143627   TTTGCTACTCCTTGCCCTTC               83   HLA-DRA   rs2239802   TGTAAGGCACATGGAGGTGA               84   IL1B   rs1143634   GTGATCGTACAGGTGCATCG               85   SPP1   rs2853744   GCTTGTTACTTAGACAAATGGCACT               87   CCR5   rs333   TGTAGGGAGCCCAGAAGAGA               88   HLA-DRA   rs3135388   TCCATACCTTGGGGTTTCAG               89   HLA   rs9268458   TGCAGGGTTTTGATACATGG               90   HLA   rs6457594   ATTTCTCCTCCACCCTCTGC               91   HLA   rs7451962   GAACGGTCCTCTCACTTCTCA               92   HLA   rs7451962   GAACGGTCCTCTCACTTCTCA               93   HLA   rs7451962   GAACGGTCCTCTCACTTCTCA               94   PNMT   rs3764351   CCTCACCCCCACAATCTTTA               95   KIF1B   rs10492972   CACATTGGAATTTGGGAAGAA               96   IGF2R   rs12202350   AGGTGAGGGGCTGAAGAAGT               97   GRIN2A   rs8049651   GTCCTTCTCCGACTGTGAGC               98   KLC1   rs8702   CATGACGGTGACCTGTTGAC               99   IL7R   rs987107   CCCCACTTCCACCAAAATTA               100   STS   rs12861247   GGATTGGCTGAACATTTTGG               101   GPC6   rs7995215   AATGGGTGGGGGTGTTATTT               102   EREG   rs1350666   GACTGAGTGCAATGCCAAAA               103   ADRA1A   rs3808585   CGCTTTTTCCACCAGGTTT               104   IL16   rs4128767   CTGGGCTCTGCTTGTTTCTC               105   ARRB2   rs7208257   AGCTGTTCCTCCCGTACCTT               106   NTF3   rs7956189   AGACTAGTGCCGAGGGTTCA               107   IL12A   rs4680534   TCGTGCAAAATCAAGGTTCA               108   SLC6A4   rs1042173   CAAGCTTGCATGGACACACT               109   FLJ34870   rs7577925   ATCTTGGCATCTCCTTGGTG               110   FCRL3   rs7528684   TGAGAAGGGCTTTGGCTTTA               111   IGF2R   rs6917747   CCCTAAGAAAGGTGCCATGA               112   LOC729293   rs6570426   AAATGGTGCTGGGAAAACTG               113   SNAP25   rs6077690   GAATAGGGGGAAAGGGGTTT               114   MORF4   rs4473631   CTTGAAGGATGCTTTCCAAGA               115   SNAP25   rs3787283   AGTTTGGTTTCCCCACACTG               116   LOC728594   rs3756450   TTTGCCCTAAATGCCAAGTC               117   SLC6A2   rs28386840   AGGGAAGGAAACCAGGAGAA               118   ZNF544   rs260461   GGAGAAAGGCAGAGGGAGAT               119   MHC II/HLA-DQA1   rs2187668   TCTCCGGTGGTAGATCTTGG               120   SLC6A4   rs2066713   TCCTGACCTCACATGATCCA               121   CSMD1   rs2049306   TTCACTTCGACCAGGATATTCA               122   SLC1A3   rs2032893   TCGGGCATTCACAATGTTTA               123   LOC647094   rs2028455   AATCAGTGCTGCTGCTTGTG               124   DMRT2   rs17641078   TCAGGACCCGATTTGTCAGT               125   DBH   rs1611115   ACAGGACCTTTGCCATCATC               126   MMP24   rs1555322   GATCCTGAGGGTGGAACTGA               127   DSEL   rs13353224   CATGAGGCTGGGAGTTAGGA               128   C1orf125   rs12047808   GGCAGGCAATACACACACAC               129   GPC5   rs10492503   CATCCCATGGATTTGTAGCC               130   C1GALT1   rs10259085   GCAAGGCATCTATCCTGGAG               131   MET   rs10243024   GATGGGTCCCCATTTTTCTT               132   ICOS   rs4404254   GCTCTACCCCATGAGAATGC               133   OAS1   rs3741981/rs1131454   GGAGAACTCGCCCTCTTTCT                    
Table 10 shows SNPs and associated risk alleles for MS disease severity. Presence of one or more risk alleles as indicated in Table 10 at the specified SNPs is associated with a higher probability that the subject has a greater severity of MS disease phenotype, for example: a multiple sclerosis severity score (MSSS) of 2.5 or greater; an increase in size and/or distribution of T2 brain lesions; an increased number of focal lesions in the spinal cord; an increased T2 lesion load in the brain; and/or the presence of diffuse abnormalities in the spinal cord.
 
         [0000]    
       
         
               
               
               
               
             
           
               
                   
                 TABLE 10 
               
               
                   
                   
               
               
                   
                 Marker 
                 RS 
                 Risk allele 
               
               
                   
                   
               
             
             
               
                   
                 PGK_317 
                 rs2107538 
                 T 
               
               
                   
                 PGK_309 
                 rs1137933 
                 G 
               
               
                   
                 PGK_324 
                 rs1318 
                 A 
               
               
                   
                 PGK_066 
                 rs2069763 
                 G 
               
               
                   
                 PGK_027 
                 rs423904 
                 C 
               
               
                   
                 PGK_321 
                 rs876493 
                 A 
               
               
                   
                 PGK_169 
                 rs10243024 
                 G 
               
               
                   
                 PGK_156 
                 rs10259085 
                 G 
               
               
                   
                 PGK_310 
                 rs1042173 
                 A 
               
               
                   
                 PGK_268 
                 rs10492503 
                 T 
               
               
                   
                 KIF1B 
                 rs10492972 
                 G 
               
               
                   
                 PGK_014 
                 rs12047808 
                 G 
               
               
                   
                 PGK_154 
                 rs12202350 
                 A 
               
               
                   
                 PGK_377 
                 rs12861247 
                 G 
               
               
                   
                 PGK_332 
                 rs13353224 
                 A 
               
               
                   
                 PGK_059 
                 rs1350666 
                 G 
               
               
                   
                 PGK_358 
                 rs1555322 
                 A 
               
               
                   
                 PGK_202 
                 rs1611115 
                 A 
               
               
                   
                 PGK_186 
                 rs17641078 
                 G 
               
               
                   
                 PGK_302 
                 rs1805009 
                 G 
               
               
                   
                 PGK_328 
                 rs2028455 
                 G 
               
               
                   
                 PGK_097 
                 rs2032893 
                 A 
               
               
                   
                 PGK_176 
                 rs2049306 
                 A 
               
               
                   
                 PGK_312 
                 rs2066713 
                 A 
               
               
                   
                 NDUFS7 
                 rs2074897 
                 A 
               
               
                   
                 BTNL2 
                 rs2076530 
                 G 
               
               
                   
                 PGK_134 
                 rs2187668 
                 A 
               
               
                   
                 MHC II 
                 rs2213584 
                 A 
               
               
                   
                 MHC II 
                 rs2227139 
                 C 
               
               
                   
                 FAS 
                 rs2234978 
                 T 
               
               
                   
                 MHC II 
                 rs2239802 
                 G 
               
               
                   
                 MHC II 
                 rs2395182 
                 G 
               
               
                   
                 PGK_350 
                 rs260461 
                 A 
               
               
                   
                 PGK_289 
                 rs28386840 
                 A 
               
               
                   
                 MHC2TA 
                 rs3087456 
                 G 
               
               
                   
                 MHC II 
                 rs3135388 
                 A 
               
               
                   
                 PGK_256 
                 rs3741981 in NCBI db 
                 A 
               
               
                   
                   
                 SNP build 129; 
               
               
                   
                   
                   Homo sapiens  build 
               
               
                   
                   
                 36.3 
               
               
                   
                   
                 (rs1131454 in NCBI db 
               
               
                   
                   
                 SNP build 131; 
               
               
                   
                   
                   Homo sapiens  build 
               
               
                   
                   
                 37.1) 
               
               
                   
                 PGK_086 
                 rs3756450 
                 A 
               
               
                   
                 FAS 
                 rs3781202 
                 CT 
               
               
                   
                   
                   
                 heterozygosity 
               
               
                   
                 PGK_355 
                 rs3787283 
                 A 
               
               
                   
                 PGK_181 
                 rs3808585 
                 A 
               
               
                   
                 PGK_280 
                 rs4128767 
                 G 
               
               
                   
                 PGK_036 
                 rs4404254 
                 G 
               
               
                   
                 PGK_070 
                 rs4473631 
                 C 
               
               
                   
                 PGK_051 
                 rs4680534 
                 A 
               
               
                   
                 PGK_352 
                 rs6077690 
                 T 
               
               
                   
                 HLA_M9001 
                 rs6457594 
                 A 
               
               
                   
                 PGK_150 
                 rs6570426 
                 T 
               
               
                   
                 UCP2 
                 rs659366 
                 C 
               
               
                   
                 PGK_155 
                 rs6917747 
                 G 
               
               
                   
                 PGK_304 
                 rs7208257 
                 A 
               
               
                   
                 PGK_011 
                 rs7528684 
                 G 
               
               
                   
                 PGK_030 
                 rs7577925 
                 A 
               
               
                   
                 CRYAB 
                 rs762550 
                 A 
               
               
                   
                 PGK_234 
                 rs7956189 
                 G 
               
               
                   
                 GPC6 
                 rs7995215 
                 G 
               
               
                   
                 PGK_285 
                 rs8049651 
                 A 
               
               
                   
                 KLC1 
                 rs8702 
                 G 
               
               
                   
                 IFNGR2 
                 rs9808753 
                 G 
               
               
                   
                 IL7R 
                 rs987107 
                 A 
               
               
                   
                   
               
             
          
         
       
     
       Equivalents  
       [0201]    The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The present invention is not to be limited in scope by examples provided, since the examples are intended as a single illustration of one aspect of the invention and other functionally equivalent embodiments are within the scope of the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. The advantages and objects of the invention are not necessarily encompassed by each embodiment of the invention. 
         [0202]    All references, including patent documents, disclosed herein are incorporated by reference in their entirety, particularly for the disclosure referenced herein.