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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 6; pp. 2456 - 2461
• Main Authors: Cappola, Thomas P, Matkovich, Scot J, Wang, Wei, van Booven, Derek, Li, Mingyao, Wang, Xuexia, Qu, Liming, Sweitzer, Nancy K, Fang, James C, Reilly, Muredach P, Hakonarson, Hakon, Nerbonne, Jeanne M, Dorn, Gerald W. II
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08.02.2011; National Acad Sciences
• Subjects: Age; Alleles; Amino Acid Substitution; Bartter syndrome; Biological Sciences; Cardiomyopathies; Chloride channels; Chloride Channels - genetics; Chloride Channels - metabolism; Cohort Studies; Deoxyribonucleic acid; DNA; Exons; Female; Genes; Genotype; Genotypes; Genotyping; Heart; Heart diseases; Heart failure; Heart Failure - genetics; Heart Failure - metabolism; HSP27 Heat-Shock Proteins - genetics; HSP27 Heat-Shock Proteins - metabolism; Humans; Hypertension; Introns; Kidney; Linkage disequilibrium; Male; Medical genetics; mRNA; Mutation, Missense; Myocardium; Nucleotide sequence; Polymorphism, Single Nucleotide; Population genetics; Population studies; Ribonucleic acid; Risk Factors; RNA; Sex; Single-nucleotide polymorphism; Splicing; White people
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1017494108

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 the HSPB7 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 the HSPB7 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 adjacent CLCNKA gene, which encodes the Ka renal chloride channel (ClC-Ka). 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 x 10⁻⁶). 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 x 10⁻⁷). Functional characterization of recombinant wild-type Arg83 and variant Gly83 ClC-Ka chloride channel currents revealed [almost equal to]50% loss-of-function of the variant channel. These findings identify a common, functionally significant genetic risk factor for Caucasian heart failure. 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.