PATENT DOCUMENT

Abstract:
The present invention comprises a method for determining an anti-hypertension therapy for an individual based upon the presence or absence of specific alleles affecting baseline blood pressure and sensititivity to different therapeutic formulations.

Full Description:
GOVERNMENT SUPPORT 
       [0001]    This invention was made with Government support under HL077378 (PI Michael Mendelsohn, MD) and HL069770 (Framingham Heart Study) awarded by the National Institutes of Health. The Government has certain rights in the invention. 
     
    
     FIELD OF THE INVENTION 
       [0002]    This invention relates generally to the fields of genetics and cardiovascular disease. 
       BACKGROUND OF THE INVENTION 
       [0003]    Elevated blood pressure remains the most common cardiovascular disease, contributing significant morbidity and mortality worldwide. The genetic and environmental factors responsible for cardiovascular disease are not well defined. 
       SUMMARY OF THE INVENTION 
       [0004]    The present invention comprises a method of selecting an anti-hypertensive therapy for an individual comprising the steps of identifying an individual with a hypertension condition, testing for the presence or absence of a non-synonymous substitution within the nucleic acid or amino acid sequence of the BK channel protein; and selecting a therapeutic treatment in accordance with the results of genetic testing. Substitutions that result in amino acid replacements are nonsynonymous while substitutions that do not case an amino acid replacement (such as a change in the nucleotide sequence from GGG to GGC in which both codons encode glycine) are referred to as synonymous substitutions. In one preferred embodiment, a non-synonymous substitution results from a change in the nucleotide sequence that subsequently causes a change in the amino acid sequence. 
         [0005]    Genetic testing reveals differences in the nucleic acid or amino acid sequences that encode for a BK channel protein. The BK channel protein comprises a transcript variant of KCNMA1, KCNMB1, KCNMB2, or KCNMB3. Alternatively, or in addition, the BK channel protein comprises a protein isoform of KCNMA1, KCNMB1, KCNMB2, or KCNMB3. In a preferred embodiment, the BK channel protein comprises a transcript variant or protein isoform of KCNMB1, which is a blood vessel wall specific isoform associated with cardiovascular function. In a preferred embodiment, the BK channel protein comprises a transcript variant or protein isoform of KCNMA1, which is associated with blood pressure regulation. For example, the mutation leads to a substitution of a glutamic acid (E) residue for an amino acid residue other than glutamic acid at position 65 of the amino acid sequence encoding KCNMB1. The genetic test results in the identification of a substitution of a lysine (K) for a glutamic acid (E) residue at amino acid position 65 (E65K) in the KCNMB1 protein. Consequently, individuals who carry the E65K substitution are provided at least a beta blocker as an anti-hypertensive therapy. For example, a change in the nucleotide sequence of KCNMB1 at positions 593-595 (gag) to either “aag” to “aaa” would result in the substitution of a lysine (K) residue. In a preferred embodiment the E65K mutation results from a single polynucleotide polymorphism, or the mutation of a single nucleotide of codon 65. Thus, a mutation of the sequence “gag” to “aag” resulting in the substitution of a lysine for a glutamic acid residue, occurs in a preferred embodiment. 
         [0006]    The anti-hypertensive therapy of the present invention is a diuretic, an angiotensin-coverting enzyme (ACE) inhibitors, an angiotensin-2 receptor antagonist, a beta blocker, a calcium channel blocker, an alpha blocker, or an antiandrenergic. Moreover, the present invention comprises a combination of one or more anti-hypertensive therapies. In an alternate embodiment, the anti-hypertensive therapy is not verapamil. 
         [0007]    The present invention encompasses hypertension that is either primary or secondary. 
         [0008]    Publications, U.S. patents and applications, Genbank/NCBI accession numbers, and all other references cited herein, are hereby incorporated by reference. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0009]      FIG. 1  is a table showing clinical characteristics of Heart SCORE and FHS subjects. 
           [0010]      FIG. 2  is a table showing multivariate associations between E65K polymorphism and BP measurements. 
           [0011]      FIG. 3  is a table showing odds of systolic and diastolic hypertension for E65K K-allele carriers. 
           [0012]      FIG. 4  is multivariate associations between E65K polymorphism and blood pressure measurements by anti-hypertensive class. 
           [0013]      FIG. 5  is a bar graph showing adjusted-mean systolic, diastolic and pulse pressures by E65K genotype in caucasians using antihypertensive medications. Compared with E-carriers (shaded bar), K-carriers (white bar) exhibit lower adjusted systolic and diastolic pressures. No significant difference was noted in subjects not receiving therapy. Adjusted mean pressures (mmHg) for each group are shown above bar. 
           [0014]      FIG. 6  is a bar graph showing adjusted-mean systolic and diastolic pressure by E65K genotype in subjects receiving beta-blockade. Results shown for entire cohort, and limited to beta-blockade use alone. Compared with E-carriers, in the presence of beta-blockade, K-carriers (white bar) exhibit lower diastolic pressure, with a trend toward significantly systolic pressure. Adjusted mean pressures (mmHg) for each group are shown above bar. 
       
    
    
     DETAILED DESCRIPTION 
       [0015]    Genetic polymorphisms that influence smooth muscle cell contraction and relaxation affect the response to anti-hypertensive therapy. The β subunit of the large conductance calcium-activated potassium channel contains a non-synonymous polymorphism (E65K, minor allele frequency ˜10%) that is associated with reduced diastolic pressure. Studies were carried out to determine whether E65K is associated with blood pressure in the Heart SCORE (n=1,075) and Framingham Heart Study (n=1,519) cohorts without cardiovascular disease. In Heart SCORE Caucasians (n=687), but not African-Americans (n=388), analysis of covariance revealed an association between E65K and lower systolic (E=wild type, K=substitution) (adjusted-mean mmHg (±SD) for E: 133.7 (±7.3), K 130.6 (±8.4), p=0.02) and diastolic pressures (E 79.7 (±2.6), K 77.6 (±3.1), p=0.02). In logistic regression, Caucasian K-carriers were at lower risk for elevated systolic (OR=0.55, 95% CI: 0.33-0.91) and diastolic (OR=0.47, 95% CI: 0.28-0.79) blood pressure. The protective effect of E65K was primarily evident only among subjects receiving anti-hypertensive therapy. In the Framingham Heart Study, the E65K polymorphism was not associated with blood pressure or hypertension, although a trend similar was noted. In pooled Caucasian Heart SCORE and Framingham Heart Study subjects we found that in subjects receiving beta-blockade, K-carriers had lower systolic and diastolic pressure (p=0.09, 0.03, respectively). In summary, Caucasians wild-type carriers are less responsive to beta-blockade treatment than subjects harboring the E65K allele. This discovery is consistent with carriers of the E65K allele being more responsive to beta-blocker treatment for hypertension compared with subjects that do not carry the allele. This finding indicates that E65K genetic testing is useful to determine whether beta-blocker therapy would be a preferred agent for treatment of hypertension. 
         [0016]    Carriers of a polymorphism in the KCNMB1 gene are characterized by a greater sensitivity to beta blocker treatment in the setting of hypertension. The KCNMB1 carrier status is used to identify patients that respond favorably to beta blocker treatment. Thus, identification of this polymorphism is useful for genetic testing and the practice of personalized medicine in which patients are targeted for treatment with beta blockers as distinguished from other treatment options. 
       Blood Pressure 
       [0017]    Blood pressure, or vascular pressure, is the force exerted by circulating blood on the walls of blood vessels. The term “blood pressure” predominantly refers to arterial pressure, however, blood pressure measurements reflect the combined pressure of blood circulating through arteries, arterioles, capillaries, and veins. Arterial pressure is most commonly reported in millimetres of mercury (mmHg) and measured using a sphygmomanometer, in which changes in the height of a column of mercury reflect the circulating pressure. 
         [0018]    Blood pressure varies with the progression through the cardiac cycle and with circadian rhythms. The term “cardiac cycle” refers the series of events that occur from the beginning of one heartbeat to the beginning of the next heartbeat. The term “heart rate” refers to the frequency of the cardiac cycle. Every heartbeat comprises three major stages: atrial systole, ventricular systole and complete cardiac diastole. The term “diastole” refers to the relaxation of the cardiac muscle. 
         [0019]    The term “systolic” arterial pressure refers to the peak pressure and occurs near the beginning of the cardiac cycle. Conversely, the term “diastolic” arterial pressure referes to the lowest pressure and occurs during the resting phase of the cardiac cycle. The term “mean” arterial pressure is the average of the systolic and diastolic values. The term “pulse pressure” refers to the difference between the highest and lowest pressures observed during the cardiac cycle. Healthy adults, at rest, typically have a systolic score of 120 mmHg and a diastolic score of 80 mmHg. These pressures are often reported as a ratio of systolic over diastolic pressures, e.g. 120/80 mmHg. The resting pulse pressure in healthy adults is about 40 mmHg. 
         [0020]    Individuals differ greatly in baseline, or resting, blood pressure. If the baseline blood pressure of an individual is chronically elevated above average, e.g. the individual has a blood pressure ratio of 140/90 mmHg (systolic/diastolic) or greater, he/she is diagnosed with hypertension. In the present invention, hypertension is defined by the blood pressure ratio of at least 140/90 mmHg (systolic/diastolic). 
         [0021]    Hypertension is categorized as either primary or secondary depending on the cause. Primary hypertension is diagnosed when no specific medical cause is immediately evident. Secondary hypertension is diagnosed when hypertension occurs as a secondary effect caused by another medical condition. Individuals show variable suseptibility to primary and secondary hypertension as well as variable responses to anti-hypertensive drug therapy. 
         [0022]    Variation in responses of individuals to anti-hypertensive drug therapy can result from a number of factors including, but not limited to, age, gender, race, diet, weight, hormone levels/balance, insulin resistance, smoking habits, fitness level, sleep/wake cycles, primary illness, medication, and stress. Body mass index (BMI, calculated by dividing the weight in kilograms by the height in meters squared), Diabetes (defined as fasting blood glucose greater than 126 mg/dL) and smoking (based on subject reporting of cigarette use) are contemplated iinfluenctial hypertensive factors. 
         [0023]    Hypertension can be a secondary consequence of a primary illness. Exemplary primary conditions that cause secondary hypertension include, but are not limited to, renal disorders, renovascular hypertension, chronic renal failure, kidney disease, renal artery stenosis, renal segmental hypoplasia, endocrine disorders, pheochromocytoma, hyperaldosteronism (Conn&#39;s syndrome), Crushing&#39;s disease, hyperparathyroidism, acromegaly, hyperthyroidism, hypothyroidism, obstructive sleep apnea, unbalanced diet, scleroderma, neurofibromatosis, pregnancy, cancer, drugs, alcohol, nasal decongenstants, non-steroidal anti-inflammatory drugs (NSAIDs), monoamine oxidase inhibitors (MAOIs), adrenoceptor stimulants, hormonal contraception, steroid use, malformed aorta, slow pulse, aortic valve disease, coarcation of the aorta, anemia, and fever. 
         [0024]    A major factor influencing individual susptibility to hypertension and response to treatment is genetic variation. Individuals carry mutations in genes that directly affect cellular events within blood vessel walls and, consequently, blood pressure. 
       BK Channel 
       [0025]    The BK channel regulates vascular smooth muscle polarity and, by extension, cellular contraction and relaxation. Studies on the BK channel have shown that genetic effects within the blood vessel wall can have a direct effect on blood pressure. For example, mice lacking the BK channel β1-regulatory subunit show reduced calcium-dependent channel opening, blood vessel constriction, and increased blood pressure. 
         [0026]    The BK channel (also called a Maxi-K or slo1 channel) is a large conductance calcium-activated potassium channel. This channel mediates the efflux of potassium from the cell cytoplasm into the extracellular space when activated by changes in membrane potential and/or increases in intracellular calcium ions. Activation of the BK channel results in hyperpolarization of the cell and a decrease in cell excitability. The BK channel comprises a pore-forming alpha subunit (the ion channel) and a regulatory beta subunit. 
         [0027]    The present invention encompasses testing for changes in the human nucleotide or amino acid sequences of the alpha and beta subunits of one or more BK channel(s). 
         [0028]    Human KCNMB1 is encoded by the following mRNA sequence (NCBI Accession No. NM — 004137 and SEQ ID NO: 1; for all nucleotide sequences, the start codon, ATG, is capitalized and bolded)(For this sequence the codon encoding for amino acid position 65 is bolded: 
         [0000]    
       
         
               
               
             
           
               
                    1 cagagagaag aagaaatatt tccaaatata ccaggctgat ctttcgtagt ttctcagtct 
                   
               
               
                   
               
               
                   61 tgctgtctgt tgttgtttga aatctgtttc ccacgagact ctgggaagat ggaggtgcag 
               
               
                   
               
               
                  121 ggcttgggta acagctgcct tcctcagggc tgggtacctg ctctccgagt ctgtgtctcc 
               
               
                   
               
               
                  181 aggctgtgtg ctcagacttg accatgtttg ggcatggagg cttgccccag atggggacca 
               
               
                   
               
               
                  241 aaagctgctt ccctggagac gggcggggag gccaaacttc ctgctgaagc tctgtggcct 
               
               
                   
               
               
                  301 cttttggggt gggggcgggg gtccaggcag aaagaaactg tctgctgctc aagacccaca 
               
               
                   
               
               
                  361 ggacgccggg aagactaaat gatcactgcc cccagtgaat  ATG gtgaaga agctggtgat 
               
               
                   
               
               
                  421 ggcccagaag cggggagaga cacgagccct ttgcctgggt gtaaccatgg tggtgtgtgc 
               
               
                   
               
               
                  481 cgtcatcacc tactacatcc tggtcacgac tgtgctgccc ctctaccaga aaagcgtgtg 
               
               
                   
               
               
                  541 gacccaggaa tccaagtgcc acctgattga gaccaacatc agggaccagg aggagctgaa 
               
               
                   
               
               
                  601 gggcaagaag gtgccccagt acccatgcct gtgggtcaac gtgtcagctg ccggcaggtg 
               
               
                   
               
               
                  661 ggctgtgctg taccacacgg aggacactcg ggaccagaac cagcagtgct cctacatccc 
               
               
                   
               
               
                  721 aggcagcgtg gacaattacc agacggcccg ggccgacgtg gagaaggtca gagccaaatt 
               
               
                   
               
               
                  781 ccaagagcag caggtcttct actgcttctc cgcacctcgg gggaacgaaa ccagcgtcct 
               
               
                   
               
               
                  841 attccagcgc ctctacgggc cccaggccct cctcttctcc ctcttctggc ccaccttcct 
               
               
                   
               
               
                  901 gctgaccggt ggcctcctca ttatcgccat ggtgaagagc aaccagtacc tgtccatcct 
               
               
                   
               
               
                  961 ggcggcccag aagtagagcc atccatccat gccataccac ttgtcagggc acaggggact 
               
               
                   
               
               
                 1021 ggctgggccc ccagggctgc tccccacttg cagcacaatg ccttctccac ctgccctccc 
               
               
                   
               
               
                 1081 actcttccag tccaatccac gctgtcttct gttgcaggac taacctttga gaaatccttt 
               
               
                   
               
               
                 1141 tgtgaagtca ttgcctgctc aagaatgtac agtggctccc caatgccttg gaggccataa 
               
               
                   
               
               
                 1201 ggccagccag ttctagctct ctattacctg tccccactca actgactcat acctgtttcc 
               
               
                   
               
               
                 1261 ggctgcatca ctatgtgccc cacagagaac gatgatcgtc acctctgtgc ctgagttctc 
               
               
                   
               
               
                 1321 cctgttgtct caaagcggta cccatcctcc cccagaagct gtccccagcg agcctccctt 
               
               
                   
               
               
                 1381 ctttgtttga attctctaat aagagcaaca gcagctccca tttctagaac acatttacag 
               
               
                   
               
               
                 1441 tattactatt ttctaggata taaagtgcca tatatatttt taattccaat attaataaat 
               
               
                   
               
               
                 1501 gtatgccaaa caacaata 
               
             
          
         
       
     
         [0029]    Human KCNMB1 is encoded by the following polypeptide sequence (NCBI Accession No. NP — 004128.1 and SEQ ID NO: 2)(For this sequence position 65 is bolded): 
         [0000]    
       
         
               
             
           
               
                 MVKKLVMAQKRGETRALCLGVTMVVCAVITYYILVTTVLPLYQKSVWTQ 
               
               
                   
               
               
                 ESKCHLIETNIRDQE E LKGKKVPQYPCLWVNVSAAGRWAVLYHTEDTRD 
               
               
                   
               
               
                 QNQQCSYIPGSVDNYQTARADVEKVRAKFQEQQVFYCFSAPRGNETSVL 
               
               
                   
               
               
                 FQRLYGPQALLFSLFWPTFLLTGGLLIIAMVKSNQYLSILAAQK 
               
             
          
         
       
     
         [0030]    Human KCNMB2, transcript variant 1, is encoded by the following mRNA sequence (NCBI Accession No. NM — 181361 and SEQ ID NO: 3): 
         [0000]    
       
         
               
               
             
           
               
                    1 agtatgaagc agctttaacg gagctccaga taactaattt caagcatggc tgtctagcgt 
                   
               
               
                   
               
               
                   61 gcctgtcact cctattgtcc ttccaaactc tttcagacat tttgagcagg gagtattaaa 
               
               
                   
               
               
                  121 gctatgagtt agaaagggtt gtgacattaa tggtccacaa aggctttagg cacaagaggt 
               
               
                   
               
               
                  181 aatgatgatt accggtggct atttggagga ctgcaccgga tcgctgtcat taaaaattaa 
               
               
                   
               
               
                  241 gcgtggcttt tgaggaagat gtgacaacta ccggaggtct ttttgccatt cctccaggac 
               
               
                   
               
               
                  301 atccaccata aggaaaggag accctggacc aacattctct aagATGttta tatggaccag 
               
               
                   
               
               
                  361 tggccggacc tcttcatctt atagacatga tgaaaaaaga aatatttacc agaaaatcag 
               
               
                   
               
               
                  421 ggaccatgac ctcctggaca aaaggaaaac agtcacagca ctgaaggcag gagaggaccg 
               
               
                   
               
               
                  481 agctattctc ctgggactgg ctatgatggt gtgctccatc atgatgtatt ttctgctggg 
               
               
                   
               
               
                  541 aatcacactc ctgcgctcat acatgcagag cgtgtggacc gaagagtctc aatgcacctt 
               
               
                   
               
               
                  601 gctgaatgcg tccatcacgg aaacatttaa ttgctccttc agctgtggtc cagactgctg 
               
               
                   
               
               
                  661 gaaactttct cagtacccct gcctccaggt gtacgttaac ctgacttctt ccggggaaaa 
               
               
                   
               
               
                  721 gctcctcctc taccacacag aagagacaat aaaaatcaat cagaagtgct cctatatacc 
               
               
                   
               
               
                  781 taaatgtgga aaaaattttg aagaatccat gtccctggtg aatgttgtca tggaaaactt 
               
               
                   
               
               
                  841 caggaagtat caacacttct cctgctattc tgacccagaa ggaaaccaga agagtgttat 
               
               
                   
               
               
                  901 cctaacaaaa ctctacagtt ccaacgtgct gttccattca ctcttctggc caacctgtat 
               
               
                   
               
               
                  961 gatggctggg ggtgtggcaa ttgttgccat ggtgaaactt acacagtacc tctccctact 
               
               
                   
               
               
                 1021 atgtgagagg atccaacgga tcaatagata aatgcaaaaa tggataaaat aatttttgtt 
               
               
                   
               
               
                 1081 aaagctcaaa tactgttttc tttcattctt caccaaagaa ccttaagttt gtaacgtgca 
               
               
                   
               
               
                 1141 gtctgttatg agttccctaa tatattctta tatgtagagc aataatgcaa aagctgttct 
               
               
                   
               
               
                 1201 atatgcaaac atgatgtctt tattattcag gagaataaat aactgttttg tgttggttgg 
               
               
                   
               
               
                 1261 tggttttcat aatcttattt ctgtactgga actagtactt tcttctctca ttccgccaaa 
               
               
                   
               
               
                 1321 acagggctca gttattcatt tgccaagctt cgtggaggaa tgtaggtgac atcaatgtga 
               
               
                   
               
               
                 1381 taaagtctgt gttctgagtt gtcagatctc ttgaagacaa tatttttcat cacttattgt 
               
               
                   
               
               
                 1441 ttactaaagc tacagccaaa aatatttttt tttcttattc taaactgagc cctatagcaa 
               
               
                   
               
               
                 1501 gtgaagggac cagatttcct aattaaagga agttaggtac ttttcttgta ttttttacca 
               
               
                   
               
               
                 1561 tatcactgta aagaagaggg gaaacccagc cagctacttt ttttcatcac tttttattca 
               
               
                   
               
               
                 1621 taacttcaga tttgtaaaac taatttccaa aatataagct gttttcatta gccagttcta 
               
               
                   
               
               
                 1681 taatatcttc ctgtgattta tgtagaaaat gaacacaccc cttttccatt taagaccctg 
               
               
                   
               
               
                 1741 ctactgtgtg aagagatgat acttacaagg agtgtcatta cctgtgagct gactgaatgt 
               
               
                   
               
               
                 1801 tggtaggtgc tccattacaa tccaggaaag tctgtgttac tgatatttgt gtggaaatct 
               
               
                   
               
               
                 1861 ttatttcact tcaatttaac cattagatgg taaaattaag atgctacttg ttggtaaaaa 
               
               
                   
               
               
                 1921 ttggtggact ggtttcaatg ggtaaatgtg ttgtggcaaa ttaatgtgtt ggaatattgc 
               
               
                   
               
               
                 1981 tctttgtgaa tttgtgctta agtcaatgaa tgtgtagtat ctccttctga caagcattcc 
               
               
                   
               
               
                 2041 ctattgggat tttaaagcta tgtgcacaga atattagtct cttctacatg ttttattttt 
               
               
                   
               
               
                 2101 ctatttataa ttcccttttt tgttgttata ttttatacac agaatagatc ttttttctaa 
               
               
                   
               
               
                 2161 cacatatttg aactgaataa cagacttaaa gaaagccttt gttcacattg ctatttactt 
               
               
                   
               
               
                 2221 ttgtgtttgg gggaaaatac gagggattga ttttaaataa aaaacattcc atctttcatt 
               
               
                   
               
               
                 2281 taatatcaat atcaaaagaa gaagacaaac atctatcttt ctcatctata tttaagtacc 
               
               
                   
               
               
                 2341 tttttgtaat gtagtatcaa agttttttag gtaatgcaaa attttacaaa tcatttgtgg 
               
               
                   
               
               
                 2401 aatgaatggt aaaactaatc tgatgaaatg gaaaattatt ctgcaatatt gtaattcata 
               
               
                   
               
               
                 2461 gtttgacttt tcataagcaa ataaatccct aggatgtaat caggacttca aatgtgtaat 
               
               
                   
               
               
                 2521 taaatttttt taaaaaaaat cta 
               
             
          
         
       
     
         [0031]    Human KCNMB2 is encoded by the following polypeptide sequence (NCBI Accession No. NP — 852006.1 and SEQ ID NO: 4): 
         [0000]    
       
         
               
             
           
               
                 MFIWTSGRTSSSYRHDEKRNIYQKIRDHDLLDKRKTVTALKAGEDRAIL 
               
               
                   
               
               
                 LGLAMMVCSIMMYFLLGITURSYMQSVWTEESQCTLLNASITETFNCSF 
               
               
                   
               
               
                 SCGPDCWKLSQYPCLQVYVNLTSSGEKLLLYHTEETIKINQKCSYIPKC 
               
               
                   
               
               
                 GKNFEESMSLVNVVMENFRKYQHFSCYSDPEGNQKSVILTKLYSSNVLF 
               
               
                   
               
               
                 HSLFWPTCMMAGGVAIVAMVKLTQYLSLLCERIQRINR 
               
             
          
         
       
     
         [0032]    Human KCNMB2, transcript variant 2, is encoded by the following mRNA sequence (NCBI Accession No. NM — 181361 and SEQ ID NO: 5): 
         [0000]    
       
         
               
               
             
           
               
                    1 gctgggcacc gttctgtttt ctttcttttc ttaatcctat ccaagtatgc agtacgctct 
                   
               
               
                   
               
               
                   61 tgggtcgtct catgagaccc aggggcatgt tggaaagaac tgagagaaag agcaacaaag 
               
               
                   
               
               
                  121 cggcgagtgg tgtgagaggg cagcacgcgc tgtggggccc ttccagagaa atgtactgaa 
               
               
                   
               
               
                  181 aaagtctacg caatgtctgg gatttgctaa acaatacctg gaaagcagac aggtcttttt 
               
               
                   
               
               
                  241 gccattcctc caggacatcc accataagga aaggagaccc tggaccaaca ttctctaagA 
               
               
                   
               
               
                  301 TGtttatatg gaccagtggc cggacctctt catcttatag acatgatgaa aaaagaaata 
               
               
                   
               
               
                  361 tttaccagaa aatcagggac catgacctcc tggacaaaag gaaaacagtc acagcactga 
               
               
                   
               
               
                  421 aggcaggaga ggaccgagct attctcctgg gactggctat gatggtgtgc tccatcatga 
               
               
                   
               
               
                  481 tgtattttct gctgggaatc acactcctgc gctcatacat gcagagcgtg tggaccgaag 
               
               
                   
               
               
                  541 agtctcaatg caccttgctg aatgcgtcca tcacggaaac atttaattgc tccttcagct 
               
               
                   
               
               
                  601 gtggtccaga ctgctggaaa ctttctcagt acccctgcct ccaggtgtac gttaacctga 
               
               
                   
               
               
                  661 cttcttccgg ggaaaagctc ctcctctacc acacagaaga gacaataaaa atcaatcaga 
               
               
                   
               
               
                  721 agtgctccta tatacctaaa tgtggaaaaa attttgaaga atccatgtcc ctggtgaatg 
               
               
                   
               
               
                  781 ttgtcatgga aaacttcagg aagtatcaac acttctcctg ctattctgac ccagaaggaa 
               
               
                   
               
               
                  841 accagaagag tgttatccta acaaaactct acagttccaa cgtgctgttc cattcactct 
               
               
                   
               
               
                  901 tctggccaac ctgtatgatg gctgggggtg tggcaattgt tgccatggtg aaacttacac 
               
               
                   
               
               
                  961 agtacctctc cctactatgt gagaggatcc aacggatcaa tagataaatg caaaaatgga 
               
               
                   
               
               
                 1021 taaaataatt tttgttaaag ctcaaatact gttttctttc attcttcacc aaagaacctt 
               
               
                   
               
               
                 1081 aagtttgtaa cgtgcagtct gttatgagtt ccctaatata ttcttatatg tagagcaata 
               
               
                   
               
               
                 1141 atgcaaaagc tgttctatat gcaaacatga tgtctttatt attcaggaga ataaataact 
               
               
                   
               
               
                 1201 gttttgtgtt ggttggtggt tttcataatc ttatttctgt actggaacta gtactttctt 
               
               
                   
               
               
                 1261 ctctcattcc gccaaaacag ggctcagtta ttcatttgcc aagcttcgtg gaggaatgta 
               
               
                   
               
               
                 1321 ggtgacatca atgtgataaa gtctgtgttc tgagttgtca gatctcttga agacaatatt 
               
               
                   
               
               
                 1381 tttcatcact tattgtttac taaagctaca gccaaaaata tttttttttc ttattctaaa 
               
               
                   
               
               
                 1441 ctgagcccta tagcaagtga agggaccaga tttcctaatt aaaggaagtt aggtactttt 
               
               
                   
               
               
                 1501 cttgtatttt ttaccatatc actgtaaaga agaggggaaa cccagccagc tacttttttt 
               
               
                   
               
               
                 1561 catcactttt tattcataac ttcagatttg taaaactaat ttccaaaata taagctgttt 
               
               
                   
               
               
                 1621 tcattagcca gttctataat atcttcctgt gatttatgta gaaaatgaac acaccccttt 
               
               
                   
               
               
                 1681 tccatttaag accctgctac tgtgtgaaga gatgatactt acaaggagtg tcattacctg 
               
               
                   
               
               
                 1741 tgagctgact gaatgttggt aggtgctcca ttacaatcca ggaaagtctg tgttactgat 
               
               
                   
               
               
                 1801 atttgtgtgg aaatctttat ttcacttcaa tttaaccatt agatggtaaa attaagatgc 
               
               
                   
               
               
                 1861 tacttgttgg taaaaattgg tggactggtt tcaatgggta aatgtgttgt ggcaaattaa 
               
               
                   
               
               
                 1921 tgtgttggaa tattgctctt tgtgaatttg tgcttaagtc aatgaatgtg tagtatctcc 
               
               
                   
               
               
                 1981 ttctgacaag cattccctat tgggatttta aagctatgtg cacagaatat tagtctcttc 
               
               
                   
               
               
                 2041 tacatgtttt atttttctat ttataattcc cttttttgtt gttatatttt atacacagaa 
               
               
                   
               
               
                 2101 tagatctttt ttctaacaca tatttgaact gaataacaga cttaaagaaa gcctttgttc 
               
               
                   
               
               
                 2161 acattgctat ttacttttgt gtttggggga aaatacgagg gattgatttt aaataaaaaa 
               
               
                   
               
               
                 2221 cattccatct ttcatttaat atcaatatca aaagaagaag acaaacatct atctttctca 
               
               
                   
               
               
                 2281 tctatattta agtacctttt tgtaatgtag tatcaaagtt ttttaggtaa tgcaaaattt 
               
               
                   
               
               
                 2341 tacaaatcat ttgtggaatg aatggtaaaa ctaatctgat gaaatggaaa attattctgc 
               
               
                   
               
               
                 2401 aatattgtaa ttcatagttt gacttttcat aagcaaataa atccctagga tgtaatcagg 
               
               
                   
               
               
                 2461 acttcaaatg tgtaattaaa tttttttaaa aaaaatcta 
               
             
          
         
       
     
         [0033]    Human KCNMB2 is encoded by the following polypeptide sequence (NCBI Accession No. NP — 005823.1 and SEQ ID NO: 6): 
         [0000]    
       
         
               
             
           
               
                 MFIWTSGRTSSSYRHDEKRNIYQKIRDHDLLDKRKTVTALKAGEDRAIL 
               
               
                   
               
               
                 LGLAMMVCSIMMYFLLGITLLRSYMQSVWTEESQCTLLNASITETFNCS 
               
               
                   
               
               
                 FSCGPDCWKLSQYPCLQVYVNLTSSGEKLLLYHTEETIKINQKCSYIPK 
               
               
                   
               
               
                 CGKNFEESMSLVNVVMENFRKYQHFSCYSDPEGNQKSVILTKLYSSNVL 
               
               
                   
               
               
                 FHSLFWPTCMMAGGVAIVAMVKLTQYLSLLCERIQRINR 
               
             
          
         
       
     
         [0034]    Human KCNMB3, transcript variant 1, is encoded by the following mRNA sequence (NCBI Accession No. NM — 171828 and SEQ ID NO: 7): 
         [0000]    
       
         
               
               
             
           
               
                    1 gctcccggct gccgaggcgg aaacacaggt gatgaggtgg cggcaagcac agtgcaaaga 
                   
               
               
                   
               
               
                   61 gagagaagca gcttcggctg cagcaaacca cgcaggtcct tcttgatcat ctagaactga 
               
               
                   
               
               
                  121 ccgctccgcc ttgccaggag tctgcagaac cacgtggcta gcctgcctga agttctcacc 
               
               
                   
               
               
                  181 tctccaggaa ggcggggggc ttctaatggc tgcagctgcg ctgggggctg ggggctcccg 
               
               
                   
               
               
                  241 ctgggactcc acttccgtgg atgtctaagc ttcacctttc ttgcgcccgc aggggcatga 
               
               
                   
               
               
                  301 ctcaggtgaa agggagccat tttctcagac ccctggcctc  ATG cagccct tcagcatccc 
               
               
                   
               
               
                  361 cgtgcaaatc acacttcagg gcagccggag gcgccagggg aggacagcct ttcctgcctc 
               
               
                   
               
               
                  421 agggaagaag agagagacag actacagtga tggagaccca ctagatgtgc acaagaggct 
               
               
                   
               
               
                  481 gccatccagt gctggagagg accgagccgt gatgctgggg tttgccatga tgggcttctc 
               
               
                   
               
               
                  541 agtcctaatg ttcttcttgc tcggaacaac cattctaaag ccttttatgc tcagcattca 
               
               
                   
               
               
                  601 gagagaagaa tcgacctgca ctgccatcca cacagatatc atggacgact ggctggactg 
               
               
                   
               
               
                  661 tgccttcacc tgtggtgtgc actgccacgg tcaggggaag tacccgtgtc ttcaggtgtt 
               
               
                   
               
               
                  721 tgtgaacctc agccatccag gtcagaaagc tctcctacat tataatgaag aggctgtcca 
               
               
                   
               
               
                  781 gataaatccc aagtgctttt acacacctaa gtgccaccaa gatagaaatg atttgctcaa 
               
               
                   
               
               
                  841 cagtgctctg gacataaaag aattcttcga tcacaaaaat ggaaccccct tttcatgctt 
               
               
                   
               
               
                  901 ctacagtcca gccagccaat ctgaagatgt cattcttata aaaaagtatg accaaatggc 
               
               
                   
               
               
                  961 tatcttccac tgtttatttt ggccttcact gactctgcta ggtggtgccc tgattgttgg 
               
               
                   
               
               
                 1021 catggtgaga ttaacacaac acctgtcctt actgtgtgaa aaatatagca ctgtagtcag 
               
               
                   
               
               
                 1081 agatgaggta ggtggaaaag taccttatat agaacagcat cagttcaaac tgtgcattat 
               
               
                   
               
               
                 1141 gaggaggagc aaaggaagag cagagaaatc ttaagacggt ggccaaatta aagtgctggc 
               
               
                   
               
               
                 1201 cttcagatgt ctgtgatttc tgcaactgag gacctaatta tgcctgtctg caaactaata 
               
               
                   
               
               
                 1261 atgtaaaagg ta 
               
             
          
         
       
     
         [0035]    Human KCNMB3, transcript variant 1, is encoded by the following polypeptide sequence (NCBI Accession No. NP — 741979.1 and SEQ ID NO: 8): 
         [0000]    
       
         
               
             
           
               
                 MQPFSIPVQITLQGSRRRQGRTAFPASGKKRETDYSDGDPLDVHKRLP 
               
               
                   
               
               
                 SSAGEDRAVMLGFAMMGFSVLMFFLLGTTILKPFMLSIQREESTCTAI 
               
               
                   
               
               
                 HTDIMDDWLDCAFTCGVHCHGQGKYPCLQVFVNLSHPGQKALLHYNEE 
               
               
                   
               
               
                 AVQINPKCFYTPKCHQDRNDLLNSALDIKEFFDHKNGTPFSCFYSPAS 
               
               
                   
               
               
                 QSEDVILIKKYDQMAIFHCLFWPSLTLLGGALIVGMVRLTQHLSLLCE 
               
               
                   
               
               
                 KYSTVVRDEVGGKVPYIEQHQFKLCIMRRSKGRAEKS 
               
             
          
         
       
     
         [0036]    Human KCNMB3, transcript variant 2, is encoded by the following mRNA sequence (NCBI Accession No. NM — 171829 and SEQ ID NO: 9): 
         [0000]    
       
         
               
               
               
             
           
               
                 1 
                 aagagaaaga acaagaaaaa gaaaaagaag aggaaaaaat ccccagtacc catagaaacc 
                   
               
               
                   
               
               
                 61 
                 cttaaagatg tttaaaaaga gttaacttat cagaacacag atttaagtga aattaaggaa 
               
               
                   
               
               
                 121 
                 gaagagcagg taaagtctac tgacagaaag tcagcagtgg aagcccaaaa cgaggtgact 
               
               
                   
               
               
                 181 
                 gaaaatccaa aacagaaaat tgcagcagaa agcagtgaaa atgttgattg tccagagaat 
               
               
                   
               
               
                 241 
                 cctaaaatga agttggatgg aaaacttgac caagaaggca atgatgtaaa aacagcagct 
               
               
                   
               
               
                 301 
                 gaggaggtac tagctggtag agacacatta gattttgagg atgtcacagt tcaatcatca 
               
               
                   
               
               
                 361 
                 ggcccgaggg ctggtggtga agaattagat gaaggtgttg caaaagataa tgctaaaata 
               
               
                   
               
               
                 421 
                 gctggtgcca cttaaagcaa tcctgaagaa ccagagagcg aagatgcaga tcactgcacc 
               
               
                   
               
               
                 481 
                 gtacccaaaa atgaaagtcc ctcacaggac attagtgatg cctgtgaagc agaaagtaca 
               
               
                   
               
               
                 541 
                 gagaggtgtg ggatgtcaga acatccaagt cagaccatca ggaaagcttt agacagcaat 
               
               
                   
               
               
                 601 
                 agcctaaaaa accatgactt gttggcacca ggaggagagc cgggggactt caatccagaa 
               
               
                   
               
               
                 661 
                 agcagagaag ataccagagg agggaacgag aagggcaaaa gcaaagaaga ccgtaccatg 
               
               
                   
               
               
                 721 
                 tcctaagctg aggcaggcgg caggcgtggt gcacaggaag tctgagtgtg aggggctctt 
               
               
                   
               
               
                 781 
                 ttctctccac tgcca ATG ac agcctttcct gcctcaggga agaagagaga gacagactac 
               
               
                   
               
               
                 841 
                 agtgatggag acccactaga tgtgcacaag aggctgccat ccagtgctgg agaggaccga 
               
               
                   
               
               
                 901 
                 gccgtgatgc tggggtttgc catgatgggc ttctcagtcc taatgttctt cttgctcgga 
               
               
                   
               
               
                 961 
                 acaaccattc taaagccttt tatgctcagc attcagagag aagaatcgac ctgcactgcc 
               
               
                   
               
               
                 1021 
                 atccacacag atatcatgga cgactggctg gactgtgcct tcacctgtgg tgtgcactgc 
               
               
                   
               
               
                 1081 
                 cacggtcagg ggaagtaccc gtgtcttcag gtgtttgtga acctcagcca tccaggtcag 
               
               
                   
               
               
                 1141 
                 aaagctctcc tacattataa tgaagaggct gtccagataa atcccaagtg cttttacaca 
               
               
                   
               
               
                 1201 
                 cctaagtgcc accaagatag aaatgatttg ctcaacagtg ctctggacat aaaagaattc 
               
               
                   
               
               
                 1261 
                 ttcgatcaca aaaatggaac ccccttttca tgcttctaca gtccagccag ccaatctgaa 
               
               
                   
               
               
                 1321 
                 gatgtcattc ttataaaaaa gtatgaccaa atggctatct tccactgttt attttggcct 
               
               
                   
               
               
                 1381 
                 tcactgactc tgctaggtgg tgccctgatt gttggcatgg tgagattaac acaacacctg 
               
               
                   
               
               
                 1441 
                 tccttactgt gtgaaaaata tagcactgta gtcagagatg aggtaggtgg aaaagtacct 
               
               
                   
               
               
                 1501 
                 tatatagaac agcatcagtt caaactgtgc attatgagga ggagcaaagg aagagcagag 
               
               
                   
               
               
                 1561 
                 aaatcttaag acggtggcca aattaaagtg ctggccttca gatgtctgtg atttctgcaa 
               
               
                   
               
               
                 1621 
                 ctgaggacct aattatgcct gtctgcaaac taataatgta aaaggtaata attaaagtat 
               
               
                   
               
               
                 1681 
                 catattttca tgtgggaaaa aatttaaaa 
               
             
          
         
       
     
         [0037]    Human KCNMB3, transcript variant 2, is encoded by the following polypeptide sequence (NCBI Accession No. NP — 741980.1 and SEQ ID NO: 10): 
         [0000]    
       
         
               
             
           
               
                 MTAFPASGKKRETDYSDGDPLDVHKRLPSSAGEDRAVMLGFAMMGFSV 
               
               
                   
               
               
                 LMFFLLGTTILKPFMLSIQREESTCTAIHTDIMDDWLDCAFTCGVHCH 
               
               
                   
               
               
                 GQGKYPCLQVFVNLSHPGQKALLHYNEEAVQINPKCFYTPKCHQDRND 
               
               
                   
               
               
                 LLNSALDIKEFFDHKNGTPFSCFYSPASQSEDVILIKKYDQMAIFHCL 
               
               
                   
               
               
                 FWPSLTLLGGALIVGMVRLTQHLSLLCEKYSTVVRDEVGGKVPYIEQH 
               
               
                   
               
               
                 QFKLCIMRRSKGRAEKS 
               
             
          
         
       
     
         [0038]    Human KCNMB3, transcript variant 3, is encoded by the following mRNA sequence (NCBI Accession No. NM — 171830 and SEQ ID NO: 11): 
         [0000]    
       
         
               
               
               
             
           
               
                 1 
                 cccagctact agggaggctg aggcaggaga atcgcttgaa cctgggaggc ggaggaggtt 
                   
               
               
                   
               
               
                 61 
                 gcagtgaact gagatcgtac ccagcctggg caacagtgcg aggttccgtc tcaaaaaaaa 
               
               
                   
               
               
                 121 
                 ccaaaaaaca caaaaacaaa aaacgacaga gaaggccaaa caaaacacat ctgtgggctg 
               
               
                   
               
               
                 181 
                 gatgccgcca tgcccaccgg tttgcgacct ttgtgttgga ctcttctgtt caccagacac 
               
               
                   
               
               
                 241 
                 cctgccctgc gagaatgtat ctcatccttt gctggagcag gtttgcaggc acagtggaga 
               
               
                   
               
               
                 301 
                 gaggagagaa gaaatgaagg gacacttatg cagaaccatg agtggccaga gaggaggaga 
               
               
                   
               
               
                 361 
                 aggagggtga gaggagcaaa gaagccatga caacttcata attctgagtg gactgggcag 
               
               
                   
               
               
                 421 
                 tggccagaaa ttctggtggt ggatatgctg cctttccaac aggtgaatat gaaagaataa 
               
               
                   
               
               
                 481 
                 gtcaaaccct gttcaggacg ctgttaattc caaatgtgaa ctttttgagt cattctttcc 
               
               
                   
               
               
                 541 
                 atgtggaatt caaaggagaa tgtaaacaaa ttttcaggag ggacgtgcaa tatccctgaa 
               
               
                   
               
               
                 601 
                 agataacaaa gttcgtaaca cttatttaca tacaacattc tctagttatt gattaaacag 
               
               
                   
               
               
                 661 
                 atctctacag acttgcatga ggcaacattt cttaggcttg tttgctacaa tatctttaaa 
               
               
                   
               
               
                 721 
                 aatacttgat tacacatcac tttagcttat ttagatggac ttttcaccaa gctctgaact 
               
               
                   
               
               
                 781 
                 gggatttcat tttgttgcat tcatcctgct cacgagacac aggtaggcag caaatgagat 
               
               
                   
               
               
                 841 
                 tatccctcca gtccccatgg attggaaATG ttcccccttc tttatgagct cactgcagta 
               
               
                   
               
               
                 901 
                 tctccttctc cctttcccca aaggacagcc tttcctgcct cagggaagaa gagagagaca 
               
               
                   
               
               
                 961 
                 gactacagtg atggagaccc actagatgtg cacaagaggc tgccatccag tgctggagag 
               
               
                   
               
               
                 1021 
                 gaccgagccg tgatgctggg gtttgccatg atgggcttct cagtcctaat gttcttcttg 
               
               
                   
               
               
                 1081 
                 ctcggaacaa ccattctaaa gccttttatg ctcagcattc agagagaaga atcgacctgc 
               
               
                   
               
               
                 1141 
                 actgccatcc acacagatat catggacgac tggctggact gtgccttcac ctgtggtgtg 
               
               
                   
               
               
                 1201 
                 cactgccacg gtcaggggaa gtacccgtgt cttcaggtgt ttgtgaacct cagccatcca 
               
               
                   
               
               
                 1261 
                 ggtcagaaag ctctcctaca ttataatgaa gaggctgtcc agataaatcc caagtgcttt 
               
               
                   
               
               
                 1321 
                 tacacaccta agtgccacca agatagaaat gatttgctca acagtgctct ggacataaaa 
               
               
                   
               
               
                 1381 
                 gaattcttcg atcacaaaaa tggaaccccc ttttcatgct tctacagtcc agccagccaa 
               
               
                   
               
               
                 1441 
                 tctgaagatg tcattcttat aaaaaagtat gaccaaatgg ctatcttcca ctgtttattt 
               
               
                   
               
               
                 1501 
                 tggccttcac tgactctgct aggtggtgcc ctgattgttg gcatggtgag attaacacaa 
               
               
                   
               
               
                 1561 
                 cacctgtcct tactgtgtga aaaatatagc actgtagtca gagatgaggt aggtggaaaa 
               
               
                   
               
               
                 1621 
                 gtaccttata tagaacagca tcagttcaaa ctgtgcatta tgaggaggag caaaggaaga 
               
               
                   
               
               
                 1681 
                 gcagagaaat cttaagacgg tggccaaatt aaagtgctgg ccttcagatg tctgtgattt 
               
               
                   
               
               
                 1741 
                 ctgcaactga ggacctaatt atgcctgtct gcaaactaat aatgtaaaag gtaataatta 
               
               
                   
               
               
                 1801 
                 aagtatcata ttttcatgtg ggaaaaaatt taaaa 
               
             
          
         
       
     
         [0039]    Human KCNMB3, transcript variant 3, is encoded by the following polypeptide sequence (NCBI Accession No. NP — 741981.1 and SEQ ID NO: 12): 
         [0000]    
       
         
               
             
           
               
                 MFPLLYELTAVSPSPFPQRTAFPASGKKRETDYSDGDPLDVHKRLPSS 
               
               
                   
               
               
                 AGEDRAVMLGFAMMGFSVLMFFLLGTTILKPFMLSIQREESTCTAIHT 
               
               
                   
               
               
                 DIMDDWLDCAFTCGVHCHGQGKYPCLQVFVNLSHPGQKALLHYNEEAV 
               
               
                   
               
               
                 QINPKCFYTPKCHQDRNDLLNSALDIKEFFDHKNGTPFSCFYSPASQS 
               
               
                   
               
               
                 EDVILIKKYDQMAIFHCLFWPSLTLLGGALIVGMVRLTQHLSLLCEKY 
               
               
                   
               
               
                 STVVRDEVGGKVPYIEQHQFKLCIMRRSKGRAEKS 
               
             
          
         
       
     
         [0040]    Human KCNMB3, transcript variant 4, is encoded by the following mRNA sequence (NCBI Accession No. NM — 014407 and SEQ ID NO: 13): 
         [0000]    
       
         
               
               
               
             
           
               
                 1 
                 tgccctgcga gaatgtatct catcctttgc tggagcaggt ttgcaggcac agtggagaga 
                   
               
               
                   
               
               
                 61 
                 ggagagaaga aatgaaggga cacttatgca gaaccatgag tggccagaga ggaggagaag 
               
               
                   
               
               
                 121 
                 gagggtgaga ggagcaaaga agccatgaca acttcataat tctgagtgga ctgggcagtg 
               
               
                   
               
               
                 181 
                 gccagaaatt ctggtggtgg atatgctgcc tttccaacag gtgaatatga aagaataagt 
               
               
                   
               
               
                 241 
                 caaaccctgt tcaggacgct gttaattcca aatgtgaact ttttgagtca ttctttccat 
               
               
                   
               
               
                 301 
                 gtggaattca aaggagaatg taaacaaatt ttcaggaggg acgtgcaata tccctgaaag 
               
               
                   
               
               
                 361 
                 ataacaaagt tcgtaacact tatttacata caacattctc tagttattga ttaaacagat 
               
               
                   
               
               
                 421 
                 ctctacagac ttgcatgagg caacatttct taggcttgtt tgctacaata tctttaaaaa 
               
               
                   
               
               
                 481 
                 tacttgatta cacatcactt tagcttattt ag ATG gactt ttcaccaagc tctgaactgg 
               
               
                   
               
               
                 541 
                 gatttcattt tgttgcattc atcctgctca cgagacacag gacagccttt cctgcctcag 
               
               
                   
               
               
                 601 
                 ggaagaagag agagacagac tacagtgatg gagacccact agatgtgcac aagaggctgc 
               
               
                   
               
               
                 661 
                 catccagtgc tggagaggac cgagccgtga tgctggggtt tgccatgatg ggcttctcag 
               
               
                   
               
               
                 721 
                 tcctaatgtt cttcttgctc ggaacaacca ttctaaagcc ttttatgctc agcattcaga 
               
               
                   
               
               
                 781 
                 gagaagaatc gacctgcact gccatccaca cagatatcat ggacgactgg ctggactgtg 
               
               
                   
               
               
                 841 
                 ccttcacctg tggtgtgcac tgccacggtc aggggaagta cccgtgtctt caggtgtttg 
               
               
                   
               
               
                 901 
                 tgaacctcag ccatccaggt cagaaagctc tcctacatta taatgaagag gctgtccaga 
               
               
                   
               
               
                 961 
                 taaatcccaa gtgcttttac acacctaagt gccaccaaga tagaaatgat ttgctcaaca 
               
               
                   
               
               
                 1021 
                 gtgctctgga cataaaagaa ttcttcgatc acaaaaatgg aacccccttt tcatgcttct 
               
               
                   
               
               
                 1081 
                 acagtccagc cagccaatct gaagatgtca ttcttataaa aaagtatgac caaatggcta 
               
               
                   
               
               
                 1141 
                 tcttccactg tttattttgg ccttcactga ctctgctagg tggtgccctg attgttggca 
               
               
                   
               
               
                 1201 
                 tggtgagatt aacacaacac ctgtccttac tgtgtgaaaa atatagcact gtagtcagag 
               
               
                   
               
               
                 1261 
                 atgaggtagg tggaaaagta ccttatatag aacagcatca gttcaaactg tgcattatga 
               
               
                   
               
               
                 1321 
                 ggaggagcaa aggaagagca gagaaatctt aagacggtgg ccaaattaaa gtgctggcct 
               
               
                   
               
               
                 1381 
                 tcagatgtct gtgatttctg caactgagga cctaattatg cctgtctgca aactaataat 
               
               
                   
               
               
                 1441 
                 gtaaaaggta ataattaaag tatcatattt tcatgtggga aaaaatttaa aa 
               
             
          
         
       
     
         [0041]    Human KCNMB3, transcript variant 4, is encoded by the following polypeptide sequence (NCBI Accession No. NP — 055222.3 and SEQ ID NO: 14): 
         [0000]    
       
         
               
             
           
               
                 MDFSPSSELGFHFVAFILLTRHRTAFPASGKKRETDYSDGDPLDVHKR 
               
               
                   
               
               
                 LPSSAGEDRAVMLGFAMMGFSVLMFFLLGTTILKPFMLSIQREESTCT 
               
               
                   
               
               
                 AIHTDIMDDWLDCAFTCGVHCHGQGKYPCLQVFVNLSHPGQKALLHYN 
               
               
                   
               
               
                 EEAVQINPKCFYTPKCHQDRNDLLNSALDIKEFFDHKNGTPFSCFYSP 
               
               
                   
               
               
                 ASQSEDVILIKKYDQMAIFHCLFWPSLTLLGGALIVGMVRLTQHLSLL 
               
               
                   
               
               
                 CEKYSTVVRDEVGGKVPYIEQHQFKLCIMRRSKGRAEKS 
               
             
          
         
       
     
         [0042]    Human KCNMA1, transcript variant 1, is encoded by the following mRNA sequence (NCBI Accession No. NM — 001014797 and SEQ ID NO: 15): 
         [0000]    
       
         
               
               
               
             
           
               
                 1 
                 cgccaggtcg cgcacagcgc cccgagccca ggcgcctccc cgcccccctc ccgcgctccg 
                   
               
               
                   
               
               
                 61 
                 cggcggcggc ggcggcggca gcagtagcag caatatggct gttgatgggt gtttggggtg 
               
               
                   
               
               
                 121 
                 gcgctggcgg cgggaggagc tcccccgagc ccctgcgccg gctgcccgtt gctagct ATG   
               
               
                   
               
               
                 181 
                 gcaaatggtg gcggcggcgg cggcggcagc agcggcggcg gcggcggcgg cggaggcagc 
               
               
                   
               
               
                 241 
                 agtcttagaa tgagtagcaa tatccacgcg aaccatctca gcctagacgc gtcctcctcc 
               
               
                   
               
               
                 301 
                 tcctcctcct cctcttcctc ttcttcttct tcctcctcct cttcctcctc gtcctcggtc 
               
               
                   
               
               
                 361 
                 cacgagccca agatggatgc gctcatcatc ccggtgacca tggaggtgcc gtgcgacagc 
               
               
                   
               
               
                 421 
                 cggggccaac gcatgtggtg ggctttcctg gcctcctcca tggtgacttt cttcgggggc 
               
               
                   
               
               
                 481 
                 ctcttcatca tcttgctctg gcggacgctc aagtacctgt ggaccgtgtg ctgccactgc 
               
               
                   
               
               
                 541 
                 gggggcaaga cgaaggaggc ccagaagatt aacaatggct caagccaggc ggatggcact 
               
               
                   
               
               
                 601 
                 ctcaaaccag tggatgaaaa agaggaggca gtggccgccg aggtcggctg gatgacctcc 
               
               
                   
               
               
                 661 
                 gtgaaggact gggcgggggt gatgatatcc gcccagacac tgactggcag agtcctggtt 
               
               
                   
               
               
                 721 
                 gtcttagtct ttgctctcag catcggtgca cttgtaatat acttcataga ttcatcaaac 
               
               
                   
               
               
                 781 
                 ccaatagaat cctgccagaa tttctacaaa gatttcacat tacagatcga catggctttc 
               
               
                   
               
               
                 841 
                 aacgtgttct tccttctcta cttcggcttg cggtttattg cagccaacga taaattgtgg 
               
               
                   
               
               
                 901 
                 ttctggctgg aagtgaactc tgtagtggat ttcttcacgg tgccccccgt gtttgtgtct 
               
               
                   
               
               
                 961 
                 gtgtacttaa acagaagttg gcttggtttg agatttttaa gagctctgag actgatacag 
               
               
                   
               
               
                 1021 
                 ttttcagaaa ttttgcagtt tctgaatatt cttaaaacaa gtaattccat caagctggtg 
               
               
                   
               
               
                 1081 
                 aatctgctct ccatatttat cagcacgtgg ctgactgcag ccgggttcat ccatttggtg 
               
               
                   
               
               
                 1141 
                 gagaattcag gggacccatg ggaaaatttc caaaacaacc aggctctcac ctactgggaa 
               
               
                   
               
               
                 1201 
                 tgtgtctatt tactcatggt cacaatgtcc accgttggtt atggggatgt ttatgcaaaa 
               
               
                   
               
               
                 1261 
                 accacacttg ggcgcctctt catggtcttc ttcatcctcg ggggactggc catgtttgcc 
               
               
                   
               
               
                 1321 
                 agctacgtcc ctgaaatcat agagttaata ggaaaccgca agaaatacgg gggctcctat 
               
               
                   
               
               
                 1381 
                 agtgcggtta gtggaagaaa gcacattgtg gtctgcggac acatcactct ggagagtgtt 
               
               
                   
               
               
                 1441 
                 tccaacttcc tgaaggactt tctgcacaag gaccgggatg acgtcaatgt ggagatcgtt 
               
               
                   
               
               
                 1501 
                 tttcttcaca acatctcccc caacctggag cttgaagctc tgttcaaacg acattttact 
               
               
                   
               
               
                 1561 
                 caggtggaat tttatcaggg ttccgtcctc aatccacatg atcttgcaag agtcaagata 
               
               
                   
               
               
                 1621 
                 gagtcagcag atgcatgcct gatccttgcc aacaagtact gcgctgaccc ggatgcggag 
               
               
                   
               
               
                 1681 
                 gatgcctcga atatcatgag agtaatctcc ataaagaact accatccgaa gataagaatc 
               
               
                   
               
               
                 1741 
                 atcactcaaa tgctgcagta tcacaacaag gcccatctgc taaacatccc gagctggaat 
               
               
                   
               
               
                 1801 
                 tggaaagaag gtgatgacgc aatctgcctc gcagagttga agttgggctt catagcccag 
               
               
                   
               
               
                 1861 
                 agctgcctgg ctcaaggcct ctccaccatg cttgccaacc tcttctccat gaggtcattc 
               
               
                   
               
               
                 1921 
                 ataaagattg aggaagacac atggcagaaa tactacttgg aaggagtctc aaatgaaatg 
               
               
                   
               
               
                 1981 
                 tacacagaat atctctccag tgccttcgtg ggtctgtcct tccctactgt ttgtgagctg 
               
               
                   
               
               
                 2041 
                 tgttttgtga agctcaagct cctaatgata gccattgagt acaagtctgc caaccgagag 
               
               
                   
               
               
                 2101 
                 agccgaagcc gaaagcgtat attaattaat cctggaaacc atcttaagat ccaagaaggt 
               
               
                   
               
               
                 2161 
                 actttaggat ttttcatcgc aagtgatgcc aaagaagtta aaagggcatt tttttactgc 
               
               
                   
               
               
                 2221 
                 aaggcctgtc atgatgacat cacagatccc aaaagaataa aaaaatgtgg ctgcaaacgg 
               
               
                   
               
               
                 2281 
                 cttgaagatg agcagccgtc aacactatca ccaaaaaaaa agcaacggaa tggaggcatg 
               
               
                   
               
               
                 2341 
                 cggaactcac ccaacacctc gcctaagctg atgaggcatg accccttgtt aattcctggc 
               
               
                   
               
               
                 2401 
                 aatgatcaga ttgacaacat ggactccaat gtgaagaagt acgactctac tgggatgttt 
               
               
                   
               
               
                 2461 
                 cactggtgtg cacccaagga gatagagaaa gtcatcctga ctcgaagtga agctgccatg 
               
               
                   
               
               
                 2521 
                 accgtcctga gtggccatgt cgtggtctgc atctttggcg acgtcagctc agccctgatc 
               
               
                   
               
               
                 2581 
                 ggcctccgga acctggtgat gccgctccgt gccagcaact ttcattacca tgagctcaag 
               
               
                   
               
               
                 2641 
                 cacattgtgt ttgtgggctc tattgagtac ctcaagcggg aatgggagac gcttcataac 
               
               
                   
               
               
                 2701 
                 ttccccaaag tgtccatatt gcctggtacg ccattaagtc gggctgattt aagggctgtc 
               
               
                   
               
               
                 2761 
                 aacatcaacc tctgtgacat gtgcgttatc ctgtcagcca atcagaataa tattgatgat 
               
               
                   
               
               
                 2821 
                 acttcgctgc aggacaagga atgcatcttg gcgtcactca acatcaaatc tatgcagttt 
               
               
                   
               
               
                 2881 
                 gatgacagca tcggagtctt gcaggctaat tcccaagggt tcacacctcc aggaatggat 
               
               
                   
               
               
                 2941 
                 agatcctctc cagataacag cccagtgcac gggatgttac gtcaaccatc catcacaact 
               
               
                   
               
               
                 3001 
                 ggggtcaaca tccccatcat cactgaacta gtgaacgata ctaatgttca gtttttggac 
               
               
                   
               
               
                 3061 
                 caagacgatg atgatgaccc tgatacagaa ctgtacctca cgcagccctt tgcctgtggg 
               
               
                   
               
               
                 3121 
                 acagcatttg ccgtcagtgt cctggactca ctcatgagcg cgacgtactt caatgacaat 
               
               
                   
               
               
                 3181 
                 atcctcaccc tgatacggac cctggtgacc ggaggagcca cgccggagct ggaggctctg 
               
               
                   
               
               
                 3241 
                 attgctgagg aaaacgccct tagaggtggc tacagcaccc cgcagacact ggccaatagg 
               
               
                   
               
               
                 3301 
                 gaccgctgcc gcgtggccca gttagctctg ctcgatgggc catttgcgga cttaggggat 
               
               
                   
               
               
                 3361 
                 ggtggttgtt atggtgatct gttctgcaaa gctctgaaaa catataatat gctttgtttt 
               
               
                   
               
               
                 3421 
                 ggaatttacc ggctgagaga tgctcacctc agcaccccca gtcagtgcac aaagaggtat 
               
               
                   
               
               
                 3481 
                 gtcatcacca acccgcccta tgagtttgag ctcgtgccga cggacctgat cttctgctta 
               
               
                   
               
               
                 3541 
                 atgcagtttg accacaatgc cggccagtcc cgggccagcc tgtcccattc ctcccactcg 
               
               
                   
               
               
                 3601 
                 tcgcagtcct ccagcaagaa gagctcctct gttcactcca tcccatccac agcaaaccga 
               
               
                   
               
               
                 3661 
                 cagaaccggc ccaagtccag ggagtcccgg gacaaacaga acagaaaaga aatggtttac 
               
               
                   
               
               
                 3721 
                 agatgaaccg gataatgcct atcccagaaa cattcaaatc aagcccatga gtacccacat 
               
               
                   
               
               
                 3781 
                 ggctaaccag atcaaccaat ataaatccac aagcagcttg attccaccaa tcagagaagt 
               
               
                   
               
               
                 3841 
                 tgaagatgaa tgttgactcc caggagacca gaactatttt tttaaagcct gacaaacttc 
               
               
                   
               
               
                 3901 
                 ataaatggtg atgtgacttt tcttcttaca tgctgaatca ctggtggaaa cgttaggata 
               
               
                   
               
               
                 3961 
                 agcaagaatt gccagaaaat aaagtagaca gatctttctc tttgtctgcc ttgaatattg 
               
               
                   
               
               
                 4021 
                 cttccatgta ttttggaaaa gaaaatgatt tcatttataa atgaacatac taaaatagtc 
               
               
                   
               
               
                 4081 
                 atgtatagcc tctagcattt taaattattt ttatttatta gaaagaaaat atattttttc 
               
               
                   
               
               
                 4141 
                 ttttcattgt caaatatctt ccctatatct aaacaatgca aaatctaaat gaataagtgg 
               
               
                   
               
               
                 4201 
                 tcagactcct taatgtgttt ttctcttctt tctctctttt tctttgagga gaatgatggt 
               
               
                   
               
               
                 4261 
                 caccaccaca attaattgta attaagggaa atgaattatt aaaacaattt taaaatggcc 
               
               
                   
               
               
                 4321 
                 aatgatgtat acatgtattt tagtaaatcc agaaaagaag actaagggga caggtgaata 
               
               
                   
               
               
                 4381 
                 cctgctcctc gcctggatgg gtgtgtattt tgatctgcat tgacaccagc tcttaataaa 
               
               
                   
               
               
                 4441 
                 tggaaactta tttattttca cagttgaaag tcatattttt gtagttctag ttttcattct 
               
               
                   
               
               
                 4501 
                 gtagttctca cccctttgtt catattttta aagggaagac cttctgctgc ttttctacaa 
               
               
                   
               
               
                 4561 
                 ttggcagatc aggtttgtct ggccaactaa ggacaccagg agggttgtgg gcacacctgg 
               
               
                   
               
               
                 4621 
                 gatgtggaag ctgaggacca gatgcacaca aggcattgct ctgtttgctg ttctagtggt 
               
               
                   
               
               
                 4681 
                 ggagactcct acgtgctgtt atgcttctca ttttatattt ccaaaccacc tgagcgagta 
               
               
                   
               
               
                 4741 
                 atgtcaactt cgggagggtc tggtggactt tctccccact ccccaagtct cagagctttt 
               
               
                   
               
               
                 4801 
                 agcctggaag tttgtaaaac tgattagtag ttttacttta ccataggatg tgagagggca 
               
               
                   
               
               
                 4861 
                 gtcattcttc tcactgagtt tttgtttaaa aaccaggaaa tttctacaat catggagaca 
               
               
                   
               
               
                 4921 
                 gattttaatt tgcatgctct cctttattta gttgctgggg ccaaacacat gaacttgtta 
               
               
                   
               
               
                 4981 
                 caacaattta aaaataataa taacaaaagg aaagcaacga atgcacttca tatagactgt 
               
               
                   
               
               
                 5041 
                 tagaaaaggc ctttgaaaat taccagcagt gaaatcaaat aaattagcca ctttaaactg 
               
               
                   
               
               
                 5101 
                 cggtcaaaag atttttctag ccatcagatg caattacgat gtctcagagc tctgctatcg 
               
               
                   
               
               
                 5161 
                 cttgcatgct cggtgtacag tctcccggca actgttttgt tccaatcaac ttagcaagtc 
               
               
                   
               
               
                 5221 
                 tttcaacttt aaaattatca atctttgata tgatcatcaa ggtctctgga gaagcatgga 
               
               
                   
               
               
                 5281 
                 tgtaatagtg atttctattt tcttaaaaaa tgtaaactgt ggacacttaa tggaaccaag 
               
               
                   
               
               
                 5341 
                 ctaaccaaag tatctccccg aagtttcatg atatctagtc cattaactct ttgggccatg 
               
               
                   
               
               
                 5401 
                 acctgtggta cctagttatg gtagtgcaaa tcagatcaga gcaaagcaat gagatcatca 
               
               
                   
               
               
                 5461 
                 tgaagacata tgtccactaa gtactccaat taccagcgta ggcaaaatga gcttccacct 
               
               
                   
               
               
                 5521 
                 ctgtccactc cctgcagagc caatatagtc gtgcttccac ctcgtaggca ttgtcctgca 
               
               
                   
               
               
                 5581 
                 gtgatttgtc ggactgtggt tactctgtcg tcacattttg tagaattagt tctataaaag 
               
               
                   
               
               
                 5641 
                 tattgtgaat acaatgtatg tccaattgga ttgtttaaaa actacttata attaatcact 
               
               
                   
               
               
                 5701 
                 agcctactca gcagactaaa atgatgtcaa cagtctatat tcaggcttat aaacatttct 
               
               
                   
               
               
                 5761 
                 tggtttccaa cagaagtcaa atgtgtttgt ggggagaacg ttttgctagg attttgacaa 
               
               
                   
               
               
                 5821 
                 ctttcctgaa agctaggcct tttttacata atgattttgc attggggtca ccttagtata 
               
               
                   
               
               
                 5881 
                 ttcacgtcaa tccacgctct tctttccttc gtgaaccata gtgggctctt cactcctgct 
               
               
                   
               
               
                 5941 
                 cgtaataacc acctccaaat ttgttagagt gatttggtct cctctggcag gctgtggtgg 
               
               
                   
               
               
                 6001 
                 ccacataaag gatcttccat tagagggaca caggacacaa agctccattc ccatgaccct 
               
               
                   
               
               
                 6061 
                 ctcttccctg tgtctcccct aacaaggcaa tctggaagca gaaatgcaaa ctccagcccc 
               
               
                   
               
               
                 6121 
                 accacacatc caccgatgca tttgtggcta gaaattttaa tctaaacttt ttttaaaaaa 
               
               
                   
               
               
                 6181 
                 aatcataata gttaggatag tttcctatag caaagggctc cttgattcat aagcacctcc 
               
               
                   
               
               
                 6241 
                 cccccaaaaa aaccaaattg gtaaaaattc attttctttt aaatagagca ataagttcat 
               
               
                   
               
               
                 6301 
                 actgtgttgc cgttgtaata atgaattgtt ctggactaga aaacaaaatg aggcattttg 
               
               
                   
               
               
                 6361 
                 ttaagggggt aggaaaatga ctgattgttg ggccctttgg caaaagctgg tgcctggtaa 
               
               
                   
               
               
                 6421 
                 gtagaaacga aatggaaaca gaaataacat ttgtgaaatc actggagggc tcaagcaaat 
               
               
                   
               
               
                 6481 
                 gccagagctt ctccctggct tgttcctact tgttgagctc tttggccctg agtcccatcc 
               
               
                   
               
               
                 6541 
                 atctccactg caacagtctg tctttctgcc tacatccgcc tgagaccaag gagggtcttt 
               
               
                   
               
               
                 6601 
                 ggtacagtcc acattatgag gctctgattt cctatcccag tttagggctc cagaaaagcc 
               
               
                   
               
               
                 6661 
                 attctcccaa actaatgatt cttgggtgct gtgggtcacc aacaggctgt ttacaaagca 
               
               
                   
               
               
                 6721 
                 gaaaatatca tcaccatcat aacctttctc cttgagaaaa cttttatttt tgtctaagca 
               
               
                   
               
               
                 6781 
                 attttatatt ttagaatatc atcttgaacc attataaaac accttaaata aaagtgattg 
               
               
                   
               
               
                 6841 
                 tgactaaggc acgttggaga acattccaat ctttcctccc aagggttctg gcaccttatg 
               
               
                   
               
               
                 6901 
                 atgtactttg taaaaaaatt gattgaagat tttaaataaa caggaaatta gaagtgttag 
               
               
                   
               
               
                 6961 
                 ggttagataa aggaaaagtg aaaaagcata agaaatttgg gactttttca tgttgaaagg 
               
               
                   
               
               
                 7021 
                 agaaaaagca caagttccct agttaccatt taatatgagg gtgcaagagc cacatttaca 
               
               
                   
               
               
                 7081 
                 aacaacaaac ttgatcttta aaaatgtttt taaaactctc tgagtctcag tgacttcatt 
               
               
                   
               
               
                 7141 
                 tgtaaatgag agtgattcat ctagatgact ctaaggtctc tttcaggtcc caggggacgt 
               
               
                   
               
               
                 7201 
                 gatctaagtt aggagtggga acatgggagt ggctgcttct ccttggctaa gcccatgcag 
               
               
                   
               
               
                 7261 
                 actattgtgt ccaggactgg aataaaggtc ctttttgctg catcacccag gcaacactcc 
               
               
                   
               
               
                 7321 
                 cagccttact caggagtggt gaacattttc tgctctggac atagaatagg taggttcatt 
               
               
                   
               
               
                 7381 
                 cctggtcttt tcactttaga ttctctttag gttcaagatg cagatttctc aatttggaca 
               
               
                   
               
               
                 7441 
                 cacctgcatc acgttggtca aattttgctg cctgtttcta gggttttctt ctcagtttca 
               
               
                   
               
               
                 7501 
                 tccctgcctt cccttttttg ttgttttttt tttggttcaa ggcccagctt cagttaatcc 
               
               
                   
               
               
                 7561 
                 cttcatctct atgccatgtc tccaattcct agtatgtaac tagaggttca agagacccca 
               
               
                   
               
               
                 7621 
                 aattcctgcc attttcccca tttatgtttc cccatgtgaa tcttcaggaa gtaaccagtc 
               
               
                   
               
               
                 7681 
                 ttccttctca cttcatttcc tgtcctctgt ttatttggtt attttctttc attaataaac 
               
               
                   
               
               
                 7741 
                 taaccatctc ttagctactt acattcacaa atgtaatttt aatctattgt gtttcattgt 
               
               
                   
               
               
                 7801 
                 gaaagagaat ctcattgaag gaaggaagga agaaattgag gaataaaggt aggaagggag 
               
               
                   
               
               
                 7861 
                 agaaacaaag actatccaac caattgactg agatgtgagc cggcttgact cctaggagac 
               
               
                   
               
               
                 7921 
                 taagtagatc cattcagctt gaacactgag ttccagggca gaatctgtcc attttctgtt 
               
               
                   
               
               
                 7981 
                 ttgttcttac ttgctgcttt tggaatggtg gtaaagccac cagtcaccat gagccttgaa 
               
               
                   
               
               
                 8041 
                 aggaccttca ctaatgagga cttgactcac cctctttaaa aagcaaaaga aacagaattt 
               
               
                   
               
               
                 8101 
                 acttacaatc ttctggtaaa ttacctttct gatcctctcc ttattcccaa aaggcaattt 
               
               
                   
               
               
                 8161 
                 ttttaatcca gcagagatga tttagcatat aaatcccagg tcatttgagg aggtgatgac 
               
               
                   
               
               
                 8221 
                 gctatttgga tttatttatg agacagtagt aattataaat gattcctagg cagtttgtac 
               
               
                   
               
               
                 8281 
                 tagtttggtc atattggttg tttaagtgga gtctcttctg attgtttgtt tccaataaag 
               
               
                   
               
               
                 8341 
                 tatcagttgt taataatttc aagatttcca taaaaataag aaaacttgga aaacattttt 
               
               
                   
               
               
                 8401 
                 aattttattt cttaagagac cacagagcct aattttcaat ttttatggta agcttgctta 
               
               
                   
               
               
                 8461 
                 aaacatgtat aaaaagaagc ctacatgctc aaaggcagag gcacctttag ccctacaaca 
               
               
                   
               
               
                 8521 
                 gttggaagct ccatgatatc acagccccac atggatagat tggagaaaga attctgactt 
               
               
                   
               
               
                 8581 
                 agaccacctg tagcagacct tcctcttttg gcatattttt ttaatcacaa aaaggacctg 
               
               
                   
               
               
                 8641 
                 agactcccta tctgaagata agccaaactt ggggtataca ttaagaatct gggaagaaag 
               
               
                   
               
               
                 8701 
                 aaaaaaaaga aaaagatata ataagcagta ttttaaaata ccatgagtta tgggcatgca 
               
               
                   
               
               
                 8761 
                 tatggtacaa agagtagttc tttgggttga aagaaagaag agtttgcatt gaactgcgta 
               
               
                   
               
               
                 8821 
                 ggctggcaag aatgcagagg tatacaatgt ttgatgggct ttggaggcat ttcaatagta 
               
               
                   
               
               
                 8881 
                 aatgggtgac aggactggaa agatgtggaa tatgagggtt ttccagggag atgggactta 
               
               
                   
               
               
                 8941 
                 atgggccatg atgtatttgt aggaatgtga tttcaataga ttgactattt tgtctactgt 
               
               
                   
               
               
                 9001 
                 gataagtttg tgtaggggaa ctgaggaaaa ctgagatgag acttcatgga aggggctaca 
               
               
                   
               
               
                 9061 
                 aagtacagtc taaaggccta gataaagttt gaaacttgat ttagaaagtc atgaaaagcc 
               
               
                   
               
               
                 9121 
                 actcagagtt ttaagcaaag agtgatgggg cagcaatggc tgtgcatttt tcaggttgaa 
               
               
                   
               
               
                 9181 
                 agtagtgaga tgtcagttct tcctggaaga tatcatgaga atgcacacaa aactgaacat 
               
               
                   
               
               
                 9241 
                 tttctcagca gcaaggagtg ctaaagggtg cacactccaa gtcaacaact caccgtgtgc 
               
               
                   
               
               
                 9301 
                 agcaccttcc tcacacattt tgctttgctt tctgtcacag gaccatcaga cgtagaacgt 
               
               
                   
               
               
                 9361 
                 cctgactctc ctgaattact agaatgtcag caacaaactc acaaagtaga ttagagggta 
               
               
                   
               
               
                 9421 
                 ggaatagata cataaatttt taaaaacctg ccaatcatac tgttttctag acagtaatat 
               
               
                   
               
               
                 9481 
                 aataagaaca tgaggcagga catccacaaa tagtagagaa taattaatag tccagaactg 
               
               
                   
               
               
                 9541 
                 ccaaatagga attcccctta tgaaaacacc cttgcagcta atcaggtagc ccttgtttag 
               
               
                   
               
               
                 9601 
                 aaaccaatta gcactcataa aatatttgta caaggagtga gtgggggaga aatgagcaca 
               
               
                   
               
               
                 9661 
                 atatgggttc tgccatcaat cagcttataa tacaactaaa gaaagaaaac atgctcaaag 
               
               
                   
               
               
                 9721 
                 caccattaga gaaagggtga gccctaatga catagtttca cattcaatat ggtaggagtt 
               
               
                   
               
               
                 9781 
                 gaaacaaggg agaaatgctg tggtttgaag tggttcaaca aggtaggatt tctagagaaa 
               
               
                   
               
               
                 9841 
                 ggggggttta ggagttagat aagtagagga tcagcattct aggtatgaag gcaggattat 
               
               
                   
               
               
                 9901 
                 ctggcatgtg gcagggtgaa tgatgttaat cagtaactgc taattgatat ttactgagca 
               
               
                   
               
               
                 9961 
                 gctgctgtgt cctcacgatg gtaagactat tagaggaaga cagcccacct gcctaactgg 
               
               
                   
               
               
                 10021 
                 gaacacaagg cacacatata ttggaaagat catgttgcac aaaacaggtg ttcaataaat 
               
               
                   
               
               
                 10081 
                 aatttttgaa taaatgtgaa cactgaatag caaataaatg ttatagatcg taatagttgt 
               
               
                   
               
               
                 10141 
                 agaagattgg ttgggattgt agggactgga tgtggggcaa tggctgtggg tctagagtat 
               
               
                   
               
               
                 10201 
                 attcattgtg cagtggacac acacctaatc tgtcctcaag gacagaacca tgtggaggaa 
               
               
                   
               
               
                 10261 
                 taggaaaaca agagaagcag gcaagaagcg gaggcagtga gtacagcagc taagaaatgt 
               
               
                   
               
               
                 10321 
                 tacattgggt tcatccagag caagaaaagc tgagagctgt ccgtgaggga aggccacaca 
               
               
                   
               
               
                 10381 
                 ggcaagagga gtgggacagg ggagtaaagg agtgggctac aacaggccct gcagatgtgg 
               
               
                   
               
               
                 10441 
                 aagccagacc cacagaggca cttagaaagt gaggatcctg gatgaattat tttagggaga 
               
               
                   
               
               
                 10501 
                 aagtgtaggt ttagatcagc tggcagatgt gtttgtgggc tacagccaag tttttcagga 
               
               
                   
               
               
                 10561 
                 ctaagaagga gcaaaataag tagaacttct tgggacagga gatctagggt actccagaac 
               
               
                   
               
               
                 10621 
                 cagggaaatg agaaacaaga ggggaatttt aagaaagaga gggaagatca tctatgaggt 
               
               
                   
               
               
                 10681 
                 tggagatgaa aggtgttgga gatggtgagg cacaagtcaa aagactcact cgaagggcag 
               
               
                   
               
               
                 10741 
                 gaactctgct tatttgtcca tattcccaga gtttgtcatg aggtctggcc cacgtgggca 
               
               
                   
               
               
                 10801 
                 gtcactcggc cactatgtat cactgtggct gccatggtgg atggaggctg gacagaacct 
               
               
                   
               
               
                 10861 
                 gtggtgatcg gcagtctttc tggaggactc accagggagg ggtctcaggg tgggcatctc 
               
               
                   
               
               
                 10921 
                 ctttcacctt cctgtgcatg tcactgcact gttcttcttc cctccctgaa cagcacacac 
               
               
                   
               
               
                 10981 
                 actgcatcct tagtttcagg ggtctgaaaa caaatgctac gaccaccttg ctttggtggc 
               
               
                   
               
               
                 11041 
                 ttttctgaac aggcattgtg agaagagatg ttctggccag gtgaaagtgg actttatttt 
               
               
                   
               
               
                 11101 
                 taggtaggtt tttcagttta gaaaggtttc ctttgcttat cccttgagga cttctgtgct 
               
               
                   
               
               
                 11161 
                 gctgcttctc ctccatcttg ctagttaaca gaacaggggc agaagtgaca ccaatgctct 
               
               
                   
               
               
                 11221 
                 cggccatgcc tgccttggga agcactaccg ggccccactg tttagaatct tagatggaaa 
               
               
                   
               
               
                 11281 
                 tgtacacaag gcattgacac acgcctgcgg gagtgaccca gtgcttccct cccatgggac 
               
               
                   
               
               
                 11341 
                 tcagggtcag cgtgggaagg cagctggcag ggacaggagc cccgcccgca aggtggactg 
               
               
                   
               
               
                 11401 
                 agcctcactt ccacacaaaa ccagagtccc atctgcccca gagcgctcgc tctcctcccc 
               
               
                   
               
               
                 11461 
                 ttccttccgc tcaatgcagc ctgacacgcc tttgaccaga actgcaacat ttcaaacaca 
               
               
                   
               
               
                 11521 
                 aacccagatc tgttgggaaa tcctaattaa aaacgttgca ttcccaggtg gcacaatcac 
               
               
                   
               
               
                 11581 
                 atcctgccta aaacttctgg cccacatccc accacccaga tgttgaaaag aaacctttct 
               
               
                   
               
               
                 11641 
                 ctgcttaaca ccaaaacctg cacttcaagg tttctttagg ggacaaagaa aaaaaaagta 
               
               
                   
               
               
                 11701 
                 cacacatgca gagttcagcc tacatgttca ttgaggaaaa agagcgtggc ttattcatct 
               
               
                   
               
               
                 11761 
                 ttcaatcttt tgattgttgg cattatgatt atgattatga ttaattactc tgacctgaca 
               
               
                   
               
               
                 11821 
                 ggaattgaag aagagactat atgctggtgc tctgaaatga tctacccaac tctgtcatct 
               
               
                   
               
               
                 11881 
                 gtaacaacca gtgataactc tcttgtcttg taaaaagggt ttgtacataa cttgtacatg 
               
               
                   
               
               
                 11941 
                 gtttcatttt gtatttttcg cagattaaaa atttatgtat ttgtgttcta aaa 
               
             
          
         
       
     
         [0043]    Human KCNMA1, transcript variant 1, is encoded by the following polypeptide sequence (NCBI Accession No. NP — 001014797.1 and SEQ ID NO: 16): 
         [0000]    
       
         
               
             
           
               
                 MANGGGGGGGSSGGGGGGGGSSLRMSSNIHANHLSLDASSSSSSSSSS 
               
               
                   
               
               
                 SSSSSSSSSSSSVHEPKMDALIIPVTMEVPCDSRGQRMWWAFLASSMV 
               
               
                   
               
               
                 TFFGGLFIILLWRTLKYLWTVCCHCGGKTKEAQKINNGSSQADGTLKP 
               
               
                   
               
               
                 VDEKEEAVAAEVGWMTSVKDWAGVMISAQTLTGRVLVVLVFALSIGAL 
               
               
                   
               
               
                 VIYFIDSSNPIESCQNFYKDFTLQIDMAFNVFFLLYFGLRFIAANDKL 
               
               
                   
               
               
                 WFWLEVNSVVDFFTVPPVFVSVYLNRSWLGLRFLRALRLIQFSEILQF 
               
               
                   
               
               
                 LNILKTSNSIKLVNLLSIFISTWLTAAGFIHLVENSGDPWENFQNNQA 
               
               
                   
               
               
                 LTYWECVYLLMVTMSTVGYGDVYAKTTLGRLFMVFFILGGLAMFASYV 
               
               
                   
               
               
                 PEIIELIGNRKKYGGSYSAVSGRKHIVVCGHITLESVSNFLKDFLHKD 
               
               
                   
               
               
                 RDDVNVEIVFLHNISPNLELEALFKRHFTQVEFYQGSVLNPHDLARVK 
               
               
                   
               
               
                 IESADACLILANKYCADPDAEDASNIMRVISIKNYHPKIRIITQMLQY 
               
               
                   
               
               
                 HNKAHLLNIPSWNWKEGDDAICLAELKLGFIAQSCLAQGLSTMLANLF 
               
               
                   
               
               
                 SMRSFIKIEEDTWQKYYLEGVSNEMYTEYLSSAFVGLSFPTVCELCFV 
               
               
                   
               
               
                 KLKLLMIAIEYKSANRESRSRKRILINPGNHLKIQEGTLGFFIASDAK 
               
               
                   
               
               
                 EVKRAFFYCKACHDDITDPKRIKKCGCKRLEDEQPSTLSPKKKQRNGG 
               
               
                   
               
               
                 MRNSPNTSPKLMRHDPLLIPGNDQIDNMDSNVKKYDSTGMFHWCAPKE 
               
               
                   
               
               
                 IEKVILTRSEAAMTVLSGHVVVCIFGDVSSALIGLRNLVMPLRASNFH 
               
               
                   
               
               
                 YHELKHIVFVGSIEYLKREWETLHNFPKVSILPGTPLSRADLRAVNIN 
               
               
                   
               
               
                 LCDMCVILSANQNNIDDTSLQDKECILASLNIKSMQFDDSIGVLQANS 
               
               
                   
               
               
                 QGFTPPGMDRSSPDNSPVHGMLRQPSITTGVNIPIITELVNDTNVQFL 
               
               
                   
               
               
                 DQDDDDDPDTELYLTQPFACGTAFAVSVLDSLMSATYFNDNILTLIRT 
               
               
                   
               
               
                 LVTGGATPELEALIAEENALRGGYSTPQTLANRDRCRVAQLALLDGPF 
               
               
                   
               
               
                 ADLGDGGCYGDLFCKALKTYNMLCFGIYRLRDAHLSTPSQCTKRYVIT 
               
               
                   
               
               
                 NPPYEFELVPTDLIFCLMQFDHNAGQSRASLSHSSHSSQSSSKKSSSV 
               
               
                   
               
               
                 HSIPSTANRQNRPKSRESRDKQNRKEMVYR 
               
             
          
         
       
     
         [0044]    Human KCNMA1, transcript variant 2, is encoded by the following mRNA sequence (NCBI Accession No. NM — 002247 and SEQ ID NO: 17): 
         [0000]    
       
         
               
               
               
             
           
               
                 1 
                 cgccaggtcg cgcacagcgc cccgagccca ggcgcctccc cgcccccctc ccgcgctccg 
                   
               
               
                   
               
               
                 61 
                 cggcggcggc ggcggcggca gcagtagcag caatatggct gttgatgggt gtttggggtg 
               
               
                   
               
               
                 121 
                 gcgctggcgg cgggaggagc tcccccgagc ccctgcgccg gctgcccgtt gctagct ATG   
               
               
                   
               
               
                 181 
                 gcaaatggtg gcggcggcgg cggcggcagc agcggcggcg gcggcggcgg cggaggcagc 
               
               
                   
               
               
                 241 
                 agtcttagaa tgagtagcaa tatccacgcg aaccatctca gcctagacgc gtcctcctcc 
               
               
                   
               
               
                 301 
                 tcctcctcct cctcttcctc ttcttcttct tcctcctcct cttcctcctc gtcctcggtc 
               
               
                   
               
               
                 361 
                 cacgagccca agatggatgc gctcatcatc ccggtgacca tggaggtgcc gtgcgacagc 
               
               
                   
               
               
                 421 
                 cggggccaac gcatgtggtg ggctttcctg gcctcctcca tggtgacttt cttcgggggc 
               
               
                   
               
               
                 481 
                 ctcttcatca tcttgctctg gcggacgctc aagtacctgt ggaccgtgtg ctgccactgc 
               
               
                   
               
               
                 541 
                 gggggcaaga cgaaggaggc ccagaagatt aacaatggct caagccaggc ggatggcact 
               
               
                   
               
               
                 601 
                 ctcaaaccag tggatgaaaa agaggaggca gtggccgccg aggtcggctg gatgacctcc 
               
               
                   
               
               
                 661 
                 gtgaaggact gggcgggggt gatgatatcc gcccagacac tgactggcag agtcctggtt 
               
               
                   
               
               
                 721 
                 gtcttagtct ttgctctcag catcggtgca cttgtaatat acttcataga ttcatcaaac 
               
               
                   
               
               
                 781 
                 ccaatagaat cctgccagaa tttctacaaa gatttcacat tacagatcga catggctttc 
               
               
                   
               
               
                 841 
                 aacgtgttct tccttctcta cttcggcttg cggtttattg cagccaacga taaattgtgg 
               
               
                   
               
               
                 901 
                 ttctggctgg aagtgaactc tgtagtggat ttcttcacgg tgccccccgt gtttgtgtct 
               
               
                   
               
               
                 961 
                 gtgtacttaa acagaagttg gcttggtttg agatttttaa gagctctgag actgatacag 
               
               
                   
               
               
                 1021 
                 ttttcagaaa ttttgcagtt tctgaatatt cttaaaacaa gtaattccat caagctggtg 
               
               
                   
               
               
                 1081 
                 aatctgctct ccatatttat cagcacgtgg ctgactgcag ccgggttcat ccatttggtg 
               
               
                   
               
               
                 1141 
                 gagaattcag gggacccatg ggaaaatttc caaaacaacc aggctctcac ctactgggaa 
               
               
                   
               
               
                 1201 
                 tgtgtctatt tactcatggt cacaatgtcc accgttggtt atggggatgt ttatgcaaaa 
               
               
                   
               
               
                 1261 
                 accacacttg ggcgcctctt catggtcttc ttcatcctcg ggggactggc catgtttgcc 
               
               
                   
               
               
                 1321 
                 agctacgtcc ctgaaatcat agagttaata ggaaaccgca agaaatacgg gggctcctat 
               
               
                   
               
               
                 1381 
                 agtgcggtta gtggaagaaa gcacattgtg gtctgcggac acatcactct ggagagtgtt 
               
               
                   
               
               
                 1441 
                 tccaacttcc tgaaggactt tctgcacaag gaccgggatg acgtcaatgt ggagatcgtt 
               
               
                   
               
               
                 1501 
                 tttcttcaca acatctcccc caacctggag cttgaagctc tgttcaaacg acattttact 
               
               
                   
               
               
                 1561 
                 caggtggaat tttatcaggg ttccgtcctc aatccacatg atcttgcaag agtcaagata 
               
               
                   
               
               
                 1621 
                 gagtcagcag atgcatgcct gatccttgcc aacaagtact gcgctgaccc ggatgcggag 
               
               
                   
               
               
                 1681 
                 gatgcctcga atatcatgag agtaatctcc ataaagaact accatccgaa gataagaatc 
               
               
                   
               
               
                 1741 
                 atcactcaaa tgctgcagta tcacaacaag gcccatctgc taaacatccc gagctggaat 
               
               
                   
               
               
                 1801 
                 tggaaagaag gtgatgacgc aatctgcctc gcagagttga agttgggctt catagcccag 
               
               
                   
               
               
                 1861 
                 agctgcctgg ctcaaggcct ctccaccatg cttgccaacc tcttctccat gaggtcattc 
               
               
                   
               
               
                 1921 
                 ataaagattg aggaagacac atggcagaaa tactacttgg aaggagtctc aaatgaaatg 
               
               
                   
               
               
                 1981 
                 tacacagaat atctctccag tgccttcgtg ggtctgtcct tccctactgt ttgtgagctg 
               
               
                   
               
               
                 2041 
                 tgttttgtga agctcaagct cctaatgata gccattgagt acaagtctgc caaccgagag 
               
               
                   
               
               
                 2101 
                 agccgtatat taattaatcc tggaaaccat cttaagatcc aagaaggtac tttaggattt 
               
               
                   
               
               
                 2161 
                 ttcatcgcaa gtgatgccaa agaagttaaa agggcatttt tttactgcaa ggcctgtcat 
               
               
                   
               
               
                 2221 
                 gatgacatca cagatcccaa aagaataaaa aaatgtggct gcaaacggct tgaagatgag 
               
               
                   
               
               
                 2281 
                 cagccgtcaa cactatcacc aaaaaaaaag caacggaatg gaggcatgcg gaactcaccc 
               
               
                   
               
               
                 2341 
                 aacacctcgc ctaagctgat gaggcatgac cccttgttaa ttcctggcaa tgatcagatt 
               
               
                   
               
               
                 2401 
                 gacaacatgg actccaatgt gaagaagtac gactctactg ggatgtttca ctggtgtgca 
               
               
                   
               
               
                 2461 
                 cccaaggaga tagagaaagt catcctgact cgaagtgaag ctgccatgac cgtcctgagt 
               
               
                   
               
               
                 2521 
                 ggccatgtcg tggtctgcat ctttggcgac gtcagctcag ccctgatcgg cctccggaac 
               
               
                   
               
               
                 2581 
                 ctggtgatgc cgctccgtgc cagcaacttt cattaccatg agctcaagca cattgtgttt 
               
               
                   
               
               
                 2641 
                 gtgggctcta ttgagtacct caagcgggaa tgggagacgc ttcataactt ccccaaagtg 
               
               
                   
               
               
                 2701 
                 tccatattgc ctggtacgcc attaagtcgg gctgatttaa gggctgtcaa catcaacctc 
               
               
                   
               
               
                 2761 
                 tgtgacatgt gcgttatcct gtcagccaat cagaataata ttgatgatac ttcgctgcag 
               
               
                   
               
               
                 2821 
                 gacaaggaat gcatcttggc gtcactcaac atcaaatcta tgcagtttga tgacagcatc 
               
               
                   
               
               
                 2881 
                 ggagtcttgc aggctaattc ccaagggttc acacctccag gaatggatag atcctctcca 
               
               
                   
               
               
                 2941 
                 gataacagcc cagtgcacgg gatgttacgt caaccatcca tcacaactgg ggtcaacatc 
               
               
                   
               
               
                 3001 
                 cccatcatca ctgaactagt gaacgatact aatgttcagt ttttggacca agacgatgat 
               
               
                   
               
               
                 3061 
                 gatgaccctg atacagaact gtacctcacg cagccctttg cctgtgggac agcatttgcc 
               
               
                   
               
               
                 3121 
                 gtcagtgtcc tggactcact catgagcgcg acgtacttca atgacaatat cctcaccctg 
               
               
                   
               
               
                 3181 
                 atacggaccc tggtgaccgg aggagccacg ccggagctgg aggctctgat tgctgaggaa 
               
               
                   
               
               
                 3241 
                 aacgccctta gaggtggcta cagcaccccg cagacactgg ccaataggga ccgctgccgc 
               
               
                   
               
               
                 3301 
                 gtggcccagt tagctctgct cgatgggcca tttgcggact taggggatgg tggttgttat 
               
               
                   
               
               
                 3361 
                 ggtgatctgt tctgcaaagc tctgaaaaca tataatatgc tttgttttgg aatttaccgg 
               
               
                   
               
               
                 3421 
                 ctgagagatg ctcacctcag cacccccagt cagtgcacaa agaggtatgt catcaccaac 
               
               
                   
               
               
                 3481 
                 ccgccctatg agtttgagct cgtgccgacg gacctgatct tctgcttaat gcagtttgac 
               
               
                   
               
               
                 3541 
                 cacaatgccg gccagtcccg ggccagcctg tcccattcct cccactcgtc gcagtcctcc 
               
               
                   
               
               
                 3601 
                 agcaagaaga gctcctctgt tcactccatc ccatccacag caaaccgaca gaaccggccc 
               
               
                   
               
               
                 3661 
                 aagtccaggg agtcccggga caaacagaag tacgtgcagg aagagcggct ttgatatgtg 
               
               
                   
               
               
                 3721 
                 tatccaccgc cactgtgtga aactgtatct gccactcatt tccccagttg gtgtttccaa 
               
               
                   
               
               
                 3781 
                 caaagtaact ttccctgttt tcccctgtag tccccccctt tttttttaca catatttgca 
               
               
                   
               
               
                 3841 
                 tatgtatgat agtgtgcatg tggttgtcat ttttatttca ccaccataaa acccttgagc 
               
               
                   
               
               
                 3901 
                 acaacagcaa ataagcagac ggaccaaaag ttatttatga ttctggggga aaaataaccc 
               
               
                   
               
               
                 3961 
                 aaaggcatgc tccagacata aatagctcac tgcaggaacg agttcacaga ttagaaggga 
               
               
                   
               
               
                 4021 
                 gcacttgtga tcaacgtcag ttaggcagag caagtttatt taatgtaaaa gaaaagttga 
               
               
                   
               
               
                 4081 
                 ttctgattta tcaggattat cagggtgctt tgggttttga ttttgttgtt gttgttgttt 
               
               
                   
               
               
                 4141 
                 tcctttcttt ctttttttat acacacaata agttagcaca tgtttatttg aaacaagcaa 
               
               
                   
               
               
                 4201 
                 ccaaacagca atgaaaacat attgattgtt tccagtctct gggccgaagt attgcgaagc 
               
               
                   
               
               
                 4261 
                 atttgaaaag ctttcacgat ttgtgtagat gattatgaag gacctgcttg ttgcaagaga 
               
               
                   
               
               
                 4321 
                 acatcagtga tttttttagt tactcaccaa ggccttttgt cccagagcca gttccctctg 
               
               
                   
               
               
                 4381 
                 ggagttctta tgaacatttc tcaccttaat atggaggaga gaatagtatt ccaatcatgg 
               
               
                   
               
               
                 4441 
                 atgtatcaaa ttctagtcat ttagtttaag tgaaaagagg tttgattgca tattaaattg 
               
               
                   
               
               
                 4501 
                 ttattctgtc tccttatgtt gccatatgaa tagctatttt ttttctttca cttttgacat 
               
               
                   
               
               
                 4561 
                 ttgggatgaa aagccatatg tatcataaat atcagatgta agtcattaaa aactgccttc 
               
               
                   
               
               
                 4621 
                 ctgggacttt tacatctttt aaaaggtgaa ttacttacct tatgtacaga ataaataatg 
               
               
                   
               
               
                 4681 
                 ctcaggaaag agcaagtatt tttccatgca ttctcagggg atctttttac tcccctttgt 
               
               
                   
               
               
                 4741 
                 ttgattagtt agggccccaa tgccaggtag gaggaagggc tggggcaatg gtagagtgag 
               
               
                   
               
               
                 4801 
                 aggaagacaa acccagctgc agatcatgct tttctaggag ccgacatgct aaataaatta 
               
               
                   
               
               
                 4861 
                 gaatgtagga ggatcagcca cagttgactc aacaaagaca aaagccagcc accaccttca 
               
               
                   
               
               
                 4921 
                 actgttggca cagctgtgcg gtgctggctg tcccaatgca gaaagctggt gggaaggaat 
               
               
                   
               
               
                 4981 
                 tcctcatcat cactttcttt aatgtagcca atttaggcag ggtaatgacg gcaatagaga 
               
               
                   
               
               
                 5041 
                 gctgctcctt gtcattatga gacgtgggat aagaagagtg caacagtgag ccaaacacat 
               
               
                   
               
               
                 5101 
                 tttggtatag ttattttttt cttcttttgt tttctttctt ttttaacact tagtaagcat 
               
               
                   
               
               
                 5161 
                 gagaggagag gtagaaaaat accctttttt caacatatag ttgtcagatg ctttgtgcat 
               
               
                   
               
               
                 5221 
                 gcaaatcatg ctttaggcag tgcggtattt cttaaaaact ggccaattca ccataaccaa 
               
               
                   
               
               
                 5281 
                 tttcccttat ggatggacta ggctggtata tacatatttg aaaagtttta cttcaaagaa 
               
               
                   
               
               
                 5341 
                 ttccatcgaa tagaataggg gtaaaaggga ggaggaaaac atgtcacagc tgtaccatct 
               
               
                   
               
               
                 5401 
                 ctaaaaaggt gtttttatgg tgaatgtttt ggatttagat tttggatccc ccgtcccctc 
               
               
                   
               
               
                 5461 
                 aagcatgata gttttggata tttgcttgct gtgtgaattg acaagcactt ttactgacaa 
               
               
                   
               
               
                 5521 
                 atggtgaggc tcagtcagaa cctccaccct cccccacacc aaagacaggg gcagcgtagt 
               
               
                   
               
               
                 5581 
                 attcaaacca gtattgtggt ggggaataat tgtatacatg taaattatca agccctatga 
               
               
                   
               
               
                 5641 
                 gtggaagaat tttttcaaat tatttttgtc cctctatata ttgatttata ttatgtataa 
               
               
                   
               
               
                 5701 
                 ctatctcttt atataaacta tatataatta tatatatata actatataat tatatatata 
               
               
                   
               
               
                 5761 
                 taactatata tataactata tatatgtatc ccctagtatt ggatcatgaa gagctcttca 
               
               
                   
               
               
                 5821 
                 tgcattcttt gcaaaggagg ttataaagtt acgccctcag aacatttata actataagaa 
               
               
                   
               
               
                 5881 
                 tgtgccagtt aaagtgctca acaggaaata tgacagttta aaagcattgt aaaactcaca 
               
               
                   
               
               
                 5941 
                 tagcttactt ctctctctaa agtgcaacaa ggatgaatag aatgggccaa ggtatgacaa 
               
               
                   
               
               
                 6001 
                 ttaatggttc tgcatgacct agccactgct gggggttttc ttctataacg ttgtccttgt 
               
               
                   
               
               
                 6061 
                 gaaaactttt gtgaaattaa aaaaaaagga gttacaaatt tta 
               
             
          
         
       
     
         [0045]    Human KCNMA1, transcript variant 2, is encoded by the following polypeptide sequence (NCBI Accession No. NP — 002238.2 and SEQ ID NO: 18): 
         [0000]    
       
         
               
             
           
               
                 MANGGGGGGGSSGGGGGGGGSSLRMSSNIHANHLSLDASSSSSSSSSS 
               
               
                   
               
               
                 SSSSSSSSSSSSVHEPKMDALIIPVTMEVPCDSRGQRMWWAFLASSMV 
               
               
                   
               
               
                 TFFGGLFIILLWRTLKYLWTVCCHCGGKTKEAQKINNGSSQADGTLKP 
               
               
                   
               
               
                 VDEKEEAVAAEVGWMTSVKDWAGVMISAQTLTGRVLVVLVFALSIGAL 
               
               
                   
               
               
                 VIYFIDSSNPIESCQNFYKDFTLQIDMAFNVFFLLYFGLRFIAANDKL 
               
               
                   
               
               
                 WFWLEVNSVVDFFTVPPVFVSVYLNRSWLGLRFLRALRLIQFSEILQF 
               
               
                   
               
               
                 LNILKTSNSIKLVNLLSIFISTWLTAAGFIHLVENSGDPWENFQNNQA 
               
               
                   
               
               
                 LTYWECVYLLMVTMSTVGYGDVYAKTTLGRLFMVFFILGGLAMFASYV 
               
               
                   
               
               
                 PEIIELIGNRKKYGGSYSAVSGRKHIVVCGHITLESVSNFLKDFLHKD 
               
               
                   
               
               
                 RDDVNVEIVFLHNISPNLELEALFKRHFTQVEFYQGSVLNPHDLARVK 
               
               
                   
               
               
                 IESADACLILANKYCADPDAEDASNIMRVISIKNYHPKIRIITQMLQY 
               
               
                   
               
               
                 HNKAHLLNIPSWNWKEGDDAICLAELKLGFIAQSCLAQGLSTMLANLF 
               
               
                   
               
               
                 SMRSFIKIEEDTWQKYYLEGVSNEMYTEYLSSAFVGLSFPTVCELCFV 
               
               
                   
               
               
                 KLKLLMIAIEYKSANRESRILINPGNHLKIQEGTLGFFIASDAKEVKR 
               
               
                   
               
               
                 AFFYCKACHDDITDPKRIKKCGCKRLEDEQPSTLSPKKKQRNGGMRNS 
               
               
                   
               
               
                 PNTSPKLMRHDPLLIPGNDQIDNMDSNVKKYDSTGMFHWCAPKEIEKV 
               
               
                   
               
               
                 ILTRSEAAMTVLSGHVVVCIFGDVSSALIGLRNLVMPLRASNFHYHEL 
               
               
                   
               
               
                 KHIVFVGSIEYLKREWETLHNFPKVSILPGTPLSRADLRAVNINLCDM 
               
               
                   
               
               
                 CVILSANQNNIDDTSLQDKECILASLNIKSMQFDDSIGVLQANSQGFT 
               
               
                   
               
               
                 PPGMDRSSPDNSPVHGMLRQPSITTGVNIPIITELVNDTNVQFLDQDD 
               
               
                   
               
               
                 DDDPDTELYLTQPFACGTAFAVSVLDSLMSATYFNDNILTLIRTLVTG 
               
               
                   
               
               
                 GATPELEALIAEENALRGGYSTPQTLANRDRCRVAQLALLDGPFADLG 
               
               
                   
               
               
                 DGGCYGDLFCKALKTYNMLCFGIYRLRDAHLSTPSQCTKRYVITNPPY 
               
               
                   
               
               
                 EFEINPTDLIFCLMQFDHNAGQSRASLSHSSHSSQSSSKKSSSVHSIP 
               
               
                   
               
               
                 STANRQNRPKSRESRDKQKYVQEERL 
               
             
          
         
       
     
       The E65K Polymorphism 
       [0046]    The human β-regulatory subunit gene includes a non-synonymous polymorphism that converts a glutamic acid to a lysine reside at codon 65 (KCNMB1-E65K) associated with the single nucleotide polymorphism (SNP) rs11739136. The E65K polymorphism (also referred to as the “K allele”) increases the probability of BK channel opening in response to calcium stimulation. With greater calcium responsiveness, BK channels that comprise the E65K mutant protein were found to increase vascular smooth muscle cell relaxation leading to greater vasorelaxation and lower blood pressure, including reduced diastolic blood pressure. 
         [0047]    Genetic variants that influence large conductance calcium-activated potassium channel&#39;s function may alter arterial function and contribute to the known heritability of arterial stiffness and blood pressure. The β1-subunit (KCNMB1) of the large conductance calcium-activated potassium channel includes two coding region polymorphisms. E65K, a gain-of-function polymorphism, was predicted to enhance large conductance calcium-activated potassium channel opening and vasorelaxation, whereas V110L has no known effect. This mechanism was tested in humans. The data is consistent with the mechanism of E65K polymorphism reducing muscular artery stiffness. This effect was observed in muscular arteries that are relevant to blood pressure control. 
         [0048]    To test whether E65K has a favorable effect on arterial function, arterial tonometry and brachial artery phenotypes were examined relative to genotypes in 1100 Framingham Offspring Study participants with available genotypes and phenotypes (53% women; mean age 61.5±9.4 years). 
         [0049]    The minor allele frequency was 0.10 for E65K and 0.09 for V110L; both were in Hardy-Weinberg equilibrium (χ 2  P&gt;0.05), and haplotype analysis found R 2 =0.01. E65K was associated with lower augmented pressure (7.4±3.3 versus 9.0±3.8 mmHg, P+0.01) and central pulse pressure (47.1±7.3 versus 50.7±7.8 mmHg, P=0.01) in multivariable analyses. No association was noted between E65K and mean arterial pressure, carotid-femoral pulse wave velocity or brachial artery diameter, flow velocity or volume flow. V110L was not associated with tonometry or brachial measures. 
         [0050]    A diminished augmented pressure in K-carriers indicated a reduced or delayed wave reflection and supports the finding that E65K reduces arterial impedance mismatch in the arterial tree. The data indicated that this polymorphism increases the likelihood of the BK-channel being open in the vascular smooth muscle cell. As a consequence of greater probability of the channel being open, the polymorphism causes greater vascular smooth muscle cell relaxation. And as a consequence of greater cellular relaxation, the polymorphism leads to greater blood vessel relaxation, which in turn leads to lower blood pressure. Therefore, E65K polymorphism causes the blood pressure to be lower and has a favorable effect on arterial function and pulsatile hemodynamic load. 
       Genotyping 
       [0051]    The term “genotyping” refers to the process of determining the genotype of an individual. Standard, art-recognized, methods include, but are not limited to, polymerase chain reaction (PCR), DNA sequencing, and hybridization of sample genetic material to microarrays or beads. The term “single nucleotide polymorphism (SNP)” refers to a DNA sequence variation occurring when a single nucleotide in genomic DNA differs between individuals or between paired chromosomes within an individual. The term “allele” refers to a DNA region that occupies a given locus, or position, on a chromosome. Alleles are sequences that often code for a gene. The genotype of an individual for any given gene comprises a combination of two alleles that correlate to sequences found on either chromosome of the diploid pair. For example, an individual can have two copies of a mutation, one wild type and one mutant copy, or two wild type copies of a gene. The number of mutant copies can indicate the severity of a condition. 
         [0052]    In one embodiment of the present invention, the choice of antihypertensive therapy varies according to the number of mutations carried by that individual. For example, an individual carrying two mutant alleles receives a different antihypertensive treatment than an individual carrying one mutant allele. Alternatively, an individual carrying two mutant alleles receives a different dose of the same antihypertensive treatment given to an individual carrying one mutant allele. 
         [0053]    Subjects&#39; genomic DNA was extracted from peripheral blood leukocytes using standard methods. The KCNMB1 polymorphism rs11739136 was genotyped using Taqman Assay (ABP Prism 7900HT; Applied Biosystems), using primers: 5′ ggtactggggcaccttcttgcccttcagct 3′ and 3′ ctcctggtccctgatgttggtctcaatcag 5′. Given the low frequency of the K-allele, the assay was validated by sequence confirmation (ABI Prism Big Dye Terminator 3.0, Applied Biosystems). Genotyping rates were 98.7% for Heart SCORE and 99.6% for FHS. 
       Study Population: Heart SCORE Cohort 
       [0054]    Heart SCORE is a prospective, community study based in Western Pennsylvania and designed to enroll equal numbers of Caucasian and African American participants. Subjects were enrolled at baseline; eligibility criteria included age 45 to 74 years, residence in the greater Pittsburgh metropolitan area, ability to undergo baseline and annual follow-up visits, and absence of known co-morbidity expected to limit life expectancy to less than 5 years. Among the 2,000 subjects enrolled at baseline, 1,191 had DNA available for analysis. 
         [0055]    Assessment of demographics, past medical history, medication use, and physical examination were documented at the baseline enrollment visit. Physical examination included measurement of blood pressure and anthropometric measures of height and weight. Blood samples were drawn to measure fasting levels of glucose and other cardiovascular risk factors. Laboratory tests were performed using standard techniques in the clinical laboratory. For the present study, Heart SCORE subjects with history of cardiovascular disease were excluded, leaving n=1075 available for analysis. 
       Study Population: Framingham Heart Study 
       [0056]    The FHS Offspring cohort is a community-based study of healthy Caucasian-Americans that has previously been described in detail (Kannel W B et al. Am J. Epidemiol. 1979; 110:281-90). Among the 3,370 unrelated participants who attended the sixth clinic examination (1996-1998), analysis was restricted to 1,635 subjects with DNA available. 
         [0057]    Medical history, medication use, laboratory tests and physical examinations were documented at examination cycle six. Systolic and diastolic blood pressure values were averaged from two physician-obtained measurements. Subjects with a history of cardiovascular disease were excluded leaving n=1519 for analysis. 
       Blood Pressure-Lowering Drugs 
       [0058]    One or more blood pressure-lowering drugs that are used individually or combinatorially to treat hypertension. Exemplary drugs include, but are not limited to, diuretics, angiotensin-coverting enzyme (ACE) inhibitors, angiotensin-2 receptor antagonists, beta blockers, calcium channel blockers, alpha blockers, and antiandrenergics. 
         [0059]    Beta blockers are also referred to as beta-adrenergic blocking agents, beta-adrenergic antagonists, or beta antagonists. Beta blockers inhibit the action of endogenous catecholamines on β-adrenergic receptors. Exemplary catecholamines include, but are not limited to, epinephrine (also known as adrenaline) and norepinephrine (also known as noradrenaline). β-adrenergic receptors comprise a component of the sympathic nervous system which mediates the commonly named “flight or fight” response. 
         [0060]    The present invention comprises beta blockers that target and/or inhibit the action of any β-adrenergic receptor. Exemplary receptors include β 1 -, β 2 -, and β 3 -adrenergic receptors. Selective and non-selective beta blockers comprise the present invention. Exemplary non-selective agents include, but are not limited to, alprenolol, carteolol, levobunolol, metipreanolol, nadolol, oxprenolol, penbutolol, pindolol, propanolol, sotalol, and timolol. Exemplary β 1 -selective agents include, but are not limited to, acebutolol, atenolol, betoxolol, bisoprolol, esmolol, metoprolol, and nebivolol. Exemplary β 2 -selective agents include, but are not limited to, butaxamine. Some beta blockers also antagonize α 1 -adrenegic receptors providing additional arteriolar vasodilation. Exemplary mixed α 1 /β-adrenergic antagonists include, but are not limited to, carvedilol, celiprolol, and labetalol. 
         [0061]    Diuretics include, but are not limited to, Amiloride (Midamor®), Bumetanide (Bumex®), Chlorothiazide (Diuril®), Chlorthalidone (Chlorthalidone Tablets®, Hygroton®, Thalitone®), Ethacrynic Acid (Edecrin®), Furosemide (Lasix®), Hydrochlorothiazide (Aldactazide®, Capozide®, Dyazide®, Esidrix®, HydroDIURIL®, Inderide®, Lopressor® HCT, Maxzide®, Microzide®, Moduretic®, Timolide®, Vaseretic® and combination drugs), Indapamide (Lozol®), Metolazone (Mykrox®, Zaroxolyn®), Spironolactone (Aldactone®, Aldactazide® as a combination product also containing Hydrochlorthiazide), Torsemide (Demadex Oral®), and Triamterene (Dyrenium®). 
         [0062]    Angiotensin-coverting enzyme (ACE) inhibitors include, but are not limited to, Benazepril (Lotensin®), Captopril (Capoten®), Enalapril (Vasotec®), Fosinopril (Monopril®), Lisinopril (Prinivil®, Zestril®), Moexipril (Univasc®), Perindopril (Aceon®), Quinapril (Accupril®), Ramipril (Altace®), and Trandolapril (Mavik®). 
         [0063]    Combinations of ACE inhibitors and diuretics are encompassed by the invention. Exemplary combinations include, but are not limited to, Benazepril and hydrochlorothiazide (Lotensin® HCT), Enalapril and hydrochlorothiazide (Vaseretic®), Fosinopril and hydrochlorothiazide (Monopril® HCT), Lisinopril and hydrochlorothiazide (Prinzide®, Zestoretic®), Moexipril and hydrochlorothiazide (Uniretic®), and Quinapril and hydrochlorothiazide (Accuretic®). 
         [0064]    Angiotensin-2 receptor antagonists include, but are not limited to, Candesartan (Atacand®), Eprosartan (Teveten®), Irbesartan (Avapro®), Losartan (Cozaar®), Telmisartan (Micardis®), and Valsartan (Diovan®). 
         [0065]    Combinations of angiotensin-2 receptor antagonists and diuretics are encompassed by the invention. Exemplary combinations include, but are not limited to, Eprosartan and hydrochlorothiazide (Teveten® HCT), Irbesartan and hydrochlorothiazide (Avalide®), Losartan and hydrochlorothiazide (Hyzaar®), Telmisartan and hydrochlorothiazide (Micardis® HCT), and Valsartan and hydrochlorothiazide (Diovan® HCT). 
         [0066]    Beta blockers comprise: 1) Non-selective beta blockers that block both the Beta-1 and Beta-2 adrenergic receptors, including, but not limited to, Carteolol (Cartrol®), Nadolol (Corgard®, Corzide® as a combination product also containing Bendroflumethiazide), Propranolol (Inderal®, Innopran® XL, Propranolol Hydrochloride Intensol®); 2) Beta blockers that selectively block the Beta-1 adrenergic receptors, including, but not limited to, Atenolol (Tenormin®), Betaxolol Hydrochloride (Kerlone®), Bisoprolol (Zebeta®), Metoprolol (Lopressor®, Toprol XL®), Timolol (Blocadren®); 3) Beta blockers with intrinsic sympathomimetic activity, including, but not limited to, Acebutolol (Sectral®), and 4) Combination Beta and Alpha Adrenergic Receptor blocker activity, including, but not limited to, Carvedilol (Coreg®). 
         [0067]    Beta blockers include, but are not limited to, Acebutolol (Sectral®), Atenolol (Tenormin®), Betaxolol Hydrochloride (Kerlone®), Bisoprolol (Zebeta®), Carteolol (Cartrol®), Metoprolol (Lopressor®, Toprol XL®), Nadolol (Corgard®, Corzide® as a combination product also containing Bendroflumethiazide), Penbutolol (Levatol®), Pindolol (Visken®), Propranolol (Inderal®, Innopran® XL, Propranolol Hydrochloride Intensol®), Sotalol (Betapace®, Sorine®), and Timolol (Blocadren®). 
         [0068]    Combinations of beta blockers and diuretics are encompassed by the invention. Exemplary combinations include, but are not limited to Atenolol and Chlorthalidone (Tenoretic®), Bisoprolol and Hydrochlorothiazide (Ziac®), Propranolol and Hydrochlorothiazide (Inderide®), and Timolol and Hydrochlorothiazide (Timolide®). 
         [0069]    Calcium channel blockers include, but are not limited to, Amlodipine (Norvasc®, Caduet® as a combination product also containing Atorvastatin for cholesterol), Bepridil (Vascor®), Diltiazem (Cardizem®, Cartia XT®, Dilacor XR®, Diltia XT®, Tiazac®), Felodipine (Plendil®), Isradipine (DynaCirc®), Nifedipine (Adalat®, Nifedical® XL, Procardia®), Nimodipine (Nimotop®), Nisoldipine (Sular®), and Verapamil (Calan®, Covera-HS®, Isoptin®, Verelan®). 
         [0070]    Combinations of ACE inhibitors and calcium channel blockers are encompassed by the invention. Exemplary combinations include, but are not limited to, Amlodipine and benazepril (Lotrel®), Enalapril and felodipine (Lexxel®), and Trandolapril and verapamil (Tarka®). 
         [0071]    Alpha blockers include, but are not limited to, Doxazosin mesylate (Cardura®), Prazosin hydrochloride (Minipress®), Prazosin and polythiazide (Minizide®), and Terazosin hydrochloride (Hytrin®). 
         [0072]    Central alpha agonists, either given individually or combinatorially, include, but are not limited to, Clonidine hydrochloride (Catapres®, Duraclon®), Clonidine hydrochloride and chlorthalidone (Clorpres®), Guanabenz Acetate (Wytensin®), Guanfacine hydrochloride (Tenex®), Methyldopa (Aldomet®), Methyldopa and chlorothiazide (Aldochlor®), and Methyldopa and hydrochlorothiazide (Aldoril®). 
         [0073]    Combinations of alpha and beta blockers are encompassed by the invention. Exemplary combinations include, but are not limited to, Carvedilol (Coreg®) and Labetalol hydrochloride (Normodyne®, Trandate®). 
         [0074]    Adrenergics include, but are not limited to, Hylorel®. 
       Statistical Analysis 
       [0075]    served genotype frequencies were compared with those expected under Hardy-Weinberg equilibrium (HWE) using a χ2 test. Given the low prevalence of minor alleles, a dominant mode of inheritance was used in all analyses (E=wild type, K=substitution). Analyses were performed separately by race, and Caucasian genotype frequencies were similar in both cohorts. Analysis of covariance (ANOVA) was used to assess whether E65K was associated with adjusted mean systolic, diastolic and pulse pressure. Similarly, logistic regression was used to estimate the adjusted odds of being in the upper quartile of systolic, diastolic, or pulse pressure in relation to the E65K polymorphism. Models controlled for known and suspected blood pressure confounders, including current anti-hypertensive treatment. The interaction between E65K with anti-hypertensive medications, age and gender were tested a priori by the addition of a multiplicative term to the full multivariate model. 
         [0076]    Analysis using pooled cohorts provides greater statistical power than independent cohort validation. The direction of the E65K-effect was similar in both cohorts; therefore, Caucasians were pooled in order to increase statistical power in order to detect a genetic interaction. All analyses were performed using SAS software (SAS Institute, Inc., Cary, N.C.). A two-sided p-value of &lt;0.05 was considered statistically significant for all primary and secondary analyses. No adjustment for multiple testing was performed. 
       EXAMPLES 
     Example 1 
     E65K Polymorphism and Blood Pressure in Heart SCORE Study 
       [0077]    An association between the E65K polymorphism and blood pressure was tested in the Heart SCORE (n=1,075). Study cohorts composed of individuals who are not diagnosed with cardiovascular disease. 
         [0078]    In Heart SCORE Caucasians (n=687), but not African-Americans (n=388), analysis of covariance revealed an association between E65K and lower systolic (E=wild type, K=substitution) (adjusted-mean mmHg (+SD) for E:133.7 (±7.3), K 130.6 (±8.4), p=0.02) and diastolic pressures (E 79.7 (±2.6), K 77.6 (±3.1), p=0.02). In logistic regression, Caucasian K-carriers were at lower risk for elevated systolic (OR=0.55, 95% CI: 0.33-0.91) and diastolic (OR=0.47, 95% CI: 0.28-0.79) blood pressure. The protective effect of E65K was primarily evident among subjects receiving anti-hypertensive therapy. 
       Example 2 
     E65K Polymorphism and Blood Pressure in Framingham Heart Study 
       [0079]    An association between the E65K polymorphism and blood pressure was tested in the Framingham Heart Study (n=1,519) cohorts composed of individuals who are not diagnosed with cardiovascular disease. 
         [0080]    In the Framingham Heart Study, the E65K polymorphism was not associated with blood pressure or hypertension, although a similar trend was noted. In pooled Caucasian Heart SCORE and Framingham Heart Study subjects we found that in subjects receiving beta-blockade, K-carriers had lower systolic and diastolic pressure (p=0.09, 0.03, respectively). In summary, Caucasian wild-type carriers are less responsive to beta-blockade treatment than subjects harboring the E65K allele. 
       Example 3 
     E65K Interacts with Age and Blood Pressure Treatment 
       [0081]    To evaluate whether E65K interacts with and antihypertensive therapy, age and gender, data from the Heart SCORE Caucasian and FHS cohorts was pooled to maximize power for detection. No interaction with gender was found. In adults receiving antihypertensive therapy, K-carriers had significantly lower adjusted SBP and DBP (p=0.03, 0.01, respectively) solely in the setting of anti-hypertensive treatment ( FIG. 1 ). There was no difference in subjects not receiving antihypertensive therapy (p=0.27, 0.76, for SBP, DBP respectively). Testing for interaction between E65K and anti-hypertensive therapy was significant (p=0.049 DBP model). 
         [0082]    There was no difference in the frequency of antihypertensive therapy use by E65K genotype (p=0.28). The distribution of major anti-hypertensive classes in treated subjects (n=619) was as follows: 54.6% reported receiving diuretics (n=338); 40.2% reported use of renin-angiotensin-system blocking agents (n=249); 37.8% reported beta-blockade use (n=234); and 25.5% reported using calcium-channel blockers (n=158), with a significant proportion (44.7%, n=277) receiving multiple agents. 
         [0083]    When differences in systolic and diastolic pressure by E65K status were examined by medication class, lower pressure was found amongst K-carriers receiving beta-blockade ( FIG. 2 ), in all subjects and more pronounced in older subjects (age&gt;58 years). No significant difference in blood pressure was noted by genotype status amongst renin-angiotensin-system blockade, calcium-channel blockers or diuretic classes (Table 4). Given that nearly 50% pf subject reported using multiple classes of antihypertensive medications, the analysis was limited to the use of a single agent, and results were similar ( FIG. 2 ). Formal tests for interaction between beta-blockade and E65K genotype were not significant (p=0.29 and 0.15, SBP and DBP models, respectively). There was no difference in beta-blockade use by E65K status (p=0.28). 
       Example 4 
     The KCNMB1 E65K Carrier Status Identifies Patients with Hypertension that Respond Favorably to Beta Blocker Treatment 
       [0084]    The relationship between the coding non-synonymous polymorphism (E65K) in the KCNMB1 gene and blood pressure in two independent community-based cohorts without cardiovascular disease was examined. Heart SCORE Caucasian K-allele carriers exhibited lower systolic and diastolic pressure, however, these effects were not found in Framingham Heart Study participants. This association is driven by the response in K-carriers receiving beta-blockade therapy. 
         [0085]    The increased calcium-triggered BK activity of the mutant β 1 -subunit protein preserves BK channel-dependent vasodilation in the setting of reduced overall (β 1 -subunit expression. This effect was observed to be preferential in the setting of beta-blockade. Alternatively, the E65K polymorphism lowers blood pressure by modifying vascular remodeling or sensitivity to antihypertensive therapy in the setting of hypertension. 
       Example 5 
     Additional Polymorphisms in BK Channel Components 
       [0086]    While it is possible that other KCNMB1 SNPs or haplotypes may have a stronger blood pressure association, E65K was tested for several reasons. First, only the E65K polymorphism has a biological function. Second, polymorphism screening of the KCNMB1 gene has not identified additional functional polymorphisms. Third, the KCNMB1 gene has a relatively low level of linkage disequilibrium. 
       Other Embodiments 
       [0087]    While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. 
         [0088]    The patent and scientific literature referred to herein establishes the knowledge that is available to those with skill in the art. All United States patents and published or unpublished United States patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. Genbank and NCBI submissions indicated by accession number cited herein are hereby incorporated by reference. All other published references, documents, manuscripts and scientific literature cited herein are hereby incorporated by reference. 
         [0089]    While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.