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Multicenter Study
.2011 Feb 8;108(6):2456-61.
doi: 10.1073/pnas.1017494108. Epub 2011 Jan 19.

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

Affiliations
Multicenter Study

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

Thomas P Cappola et al. Proc Natl Acad Sci U S A..

Abstract

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 K(a) renal chloride channel (ClC-K(a)). 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)). 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)). 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 variant CLCNKA risk allele, telegraphed by linked variants in the adjacent HSPB7 gene, uncovers a previously overlooked genetic mechanism affecting the cardio-renal axis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
No association between rs1739843 genotype and HSPB7 mRNA expression or splicing in human myocardium. Data are fromn = 111 left-ventricular free-wall specimens from genetically inferred Caucasians with heart failure. (A) HSPB7 RT-qPCR showed no differences in mRNA abundance across genotypes (P = 0.3; diamonds show median with interquartile range). (B) Exon arrays revealed a typical pattern of splicing observed in GenBank that was identical across rs1739843 genotypes (P = 0.8; diamonds show median expression of each exon probeset, spaced along Chr1).
Fig. 2.
Fig. 2.
Genetic characteristics ofCLCNKA. (A) Structure (Upper) and linkage disequilibrium (Lower) at 1p36 for HapMap Caucasian Europeans (CEU). (B) Representative rs10927887 genotypes by Sanger sequencing and associated changes in amino acid coding. (C) Transmembrane structural diagram showing position of heart failure risk variant Arg83Gly (R83G) relative to Bartter's syndrome Cys80 mutation (W80C) and hypertension-associated Ala447 variant (T447A). Analogous position of common ClC-Kb variant T481S is also shown.
Fig. 3.
Fig. 3.
Functional characterization of ClC-Ka Arg and Gly-83. (A) Whole-cell Cl− currents, evoked in response to voltage steps ranging from −165 mV to +85 mV (in 10-mV increments) from a holding potential of 0 mV recorded from tsA201 cells expressing YFP, barttin, ClC-KaArg83 (WT), or ClCKaGly83 (mutant); the voltage clamp paradigm is illustrated adjacent to the current records. (B) Representative whole-cell currents recorded from YFP + barttin + ClC-KaArg83 (WT) and from YFP + barttin + ClC-KaGly83 (mutant)-expressing cells. (C) Mean ± SEM peak inward and outward currents determined from records similar to those illustrated inB plotted as a function of test potential;n = numbers of cells. (D) Representative anti-FLAG immunoblots of tsA201 cells transiently expressing FLAG-tagged ClC-KaArg83 or ClC-KaGly83 alone and in the presence of barttin. Anti-transferrin receptor is loading control. (E andF) Reversal potentials of ClC-Ka Arg83 (E) and Gly83 (F) currents as a function of extracellular Cl− concentration.
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References

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