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Common heart failure has a strong undefined heritable component. Two recent independent cardiovascular SNP array studies identified a common SNP at 1p36 in intron 2 of theHSPB7 gene as being associated with heart failure.HSPB7 resequencing identified other risk alleles but no functional gene variants. Here, we further show no effect of theHSPB7 SNP on cardiac HSPB7 mRNA levels or splicing, suggesting that the SNP marks the position of a functional variant in another gene. Accordingly, we used massively parallel platforms to resequence all coding exons of the adjacentCLCNKA gene, which encodes theK a renal chloride channel (ClC-K a ). Of 51 exonicCLCNKA variants identified, one SNP (rs10927887, encoding Arg83Gly) was common, in linkage disequilibrium with the heart failure risk SNP inHSPB7 , and associated with heart failure in two independent Caucasian referral populations (n = 2,606 and 1,168; combinedP = 2.25 × 10−6 ). Individual genotyping of rs10927887 in the two study populations and a third independent heart failure cohort (combinedn = 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 ). 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. These findings identify a common, functionally significant genetic risk factor for Caucasian heart failure. The variantCLCNKA risk allele, telegraphed by linked variants in the adjacentHSPB7 gene, uncovers a previously overlooked genetic mechanism affecting the cardio-renal axis.

proceedings of the national academy of sciences of the united states of america

Loss-of-function DNA sequence variant in the <i>CLCNKA</i> chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation