Using this array, we previously identified in two US Caucasian heart failure referral populations a heart failure risk locus on chromosome 1p36 (rs1739843), within the cardiovascular heat shock protein gene HSPB7 ( 14). The Institute for Translational Medicine and Therapeutics/Broad Institute/Candidate-gene Association Resource (IBC) consortium developed a high-density SNP cardiovascular subgenome array to complement genome-wide platforms in heart disease ( 13). A few population-based cohort studies have implicated genomic regions in heart failure risk ( 9– 11) or mortality ( 12), but specific causative risk alleles are still unknown. Previous efforts to identify genetic risk variants uncovered a rare combination of adrenergic receptor polymorphisms that increases heart failure susceptibility 10-fold among African Americans ( 6), although this particular combination of risk alleles has not yet been replicated ( 7, 8). A fraction of common heart failure may be due to unrecognized monogenic cardiomyopathy ( 5), but most cases are explained by multiple interacting environmental and as-yet unidentified genetic susceptibility factors. Cardiac hypertrophy that predisposes to heart failure is also heritable, suggesting that underlying genetic variation contributes to interindividual variability in heart failure risk ( 4). Framingham Heart Study data show that parental heart failure confers a 70% greater disease risk than in individuals without a family history ( 3). Although rare familial cardiomyopathies can lead to heart failure that is almost entirely attributable to genetic factors, common heart failure has a smaller, poorly defined heritable component. The lifetime risk of developing heart failure is estimated at one in five ( 1, 2). The variant CLCNKA risk allele, telegraphed by linked variants in the adjacent HSPB7 gene, uncovers a previously overlooked genetic mechanism affecting the cardio-renal axis. These findings identify a common, functionally significant genetic risk factor for Caucasian heart failure. Functional characterization of recombinant wild-type Arg83 and variant Gly83 ClC- K a chloride channel currents revealed ≈50% loss-of-function of the variant channel. Individual genotyping of rs10927887 in the two study populations and a third independent heart failure cohort (combined n = 5,489) revealed an additive allele effect on heart failure risk that is independent of age, sex, and prior hypertension (odds ratio = 1.27 per allele copy P = 8.3 × 10 −7). Of 51 exonic CLCNKA variants identified, one SNP (rs10927887, encoding Arg83Gly) was common, in linkage disequilibrium with the heart failure risk SNP in HSPB7, and associated with heart failure in two independent Caucasian referral populations ( n = 2,606 and 1,168 combined P = 2.25 × 10 −6). Accordingly, we used massively parallel platforms to resequence all coding exons of the adjacent CLCNKA gene, which encodes the K a renal chloride channel (ClC- K a). Here, we further show no effect of the HSPB7 SNP on cardiac HSPB7 mRNA levels or splicing, suggesting that the SNP marks the position of a functional variant in another gene. HSPB7 resequencing identified other risk alleles but no functional gene variants. Two recent independent cardiovascular SNP array studies identified a common SNP at 1p36 in intron 2 of the HSPB7 gene as being associated with heart failure. Common heart failure has a strong undefined heritable component.
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