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Loss-Of-Function DNA Sequence Variant in the CLCNKA Chloride Channel Implicates the Cardio-Renal Axis in Interindividual Heart Failure Risk Variation

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Loss-Of-Function DNA Sequence Variant in the CLCNKA 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 Thomas P. Cappolaa,1, Scot J. Matkovichb, Wei Wangc, Derek van Boovenb, Mingyao Lid, Xuexia Wangd, Liming Qud, Nancy K. Sweitzere, James C. Fangf, Muredach P. Reillya, Hakon Hakonarsong, Jeanne M. Nerbonnec, and Gerald W. Dorn IIb,1 aPenn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; bCenter for Pharmacogenomics, Department of Medicine, and cDepartment of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110; dCenter for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; eDivision of Cardiovascular Medicine, University of Wisconsin, Madison, WI 53792; fDivision of Cardiovascular Medicine, Case Western Reserve University, Cleveland, OH 44106; and gCenter for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104 Edited* by Jonathan G. Seidman, Harvard Medical School, Boston, MA, and approved December 20, 2010 (received for review November 22, 2010) Common heart failure has a strong undefined heritable component. The Institute for Translational Medicine and Therapeutics/ Two recent independent cardiovascular SNP array studies identified Broad Institute/Candidate-gene Association Resource (IBC) con- a common SNP at 1p36 in intron 2 of the HSPB7 gene as being asso- sortium developed a high-density SNP cardiovascular subgenome ciated with heart failure. HSPB7 resequencing identified other risk array to complement genome-wide platforms in heart disease (13). alleles but no functional gene variants. Here, we further show no Using this array, we previously identified in two US Caucasian heart effect of the HSPB7 SNP on cardiac HSPB7 mRNA levels or splicing, failure referral populations a heart failure risk locus on chromo- suggesting that the SNP marks the position of a functional variant in some 1p36 (rs1739843), within the cardiovascular heat shock pro- another gene. Accordingly, we used massively parallel platforms to tein gene HSPB7 (14). A European consortium using the IBC array resequence all coding exons of the adjacent CLCNKA gene, which recently reported that the identical variant was their strongest ge- K K CLCNKA encodes the a renal chloride channel (ClC- a). Of 51 exonic netic predictor of nonfamilial dilated cardiomyopathy (15). Thus, MEDICAL SCIENCES variants identified, one SNP (rs10927887, encoding Arg83Gly) was taken together, rs1739843 has been linked with heart failure in six common, in linkage disequilibrium with the heart failure risk SNP in independent populations on two continents, establishing it as a HSPB7, and associated with heart failure in two independent Cauca- bona fide heart failure risk variant. rs1739843 occurs in intron 2 sian referral populations (n = 2,606 and 1,168; combined P =2.25× of HSPB7 and has no predicted affect on its protein sequence −6 10 ). Individual genotyping of rs10927887 in the two study popula- or function. Accordingly, we previously resequenced the entire tions and a third independent heart failure cohort (combined HSPB7 gene to screen for nearby functional variants (16). Al- n = 5,489) revealed an additive allele effect on heart failure risk though these experiments further confirmed the rs1739843 as- that is independent of age, sex, and prior hypertension (odds ratio = sociation and revealed 11 additional heart failure-associated P × −7 1.27 per allele copy; =8.3 10 ). Functional characterization of SNPs in tight linkage disequilibrium, the additional HSPB7 SNPs K recombinant wild-type Arg83 and variant Gly83 ClC- a chloride chan- were also intronic or synonymous. As such, the causative gene ≈ nel currents revealed 50% loss-of-function of the variant channel. variant(s) remain unknown, suggesting either that rs1739843 fi fi These ndings identify a common, functionally signi cant genetic marks an expression quantitative trait locus (eQTL) that modifies CLCNKA risk factor for Caucasian heart failure. The variant risk allele, HSPB7 expression (17) or that it marks the position of a geneti- HSPB7 telegraphed by linked variants in the adjacent gene, uncovers cally linked functional variant located outside of HSPB7. a previously overlooked genetic mechanism affecting the cardio- Here we demonstrate that there is no association between renal axis. rs1739843 genotype and HSPB7 mRNA expression levels or splicing in human myocardium, making an eQTL mechanism cardiomyopathy | genetic association unlikely. For this reason, we resequenced the coding exons of the neighboring gene, CLCNKA, which is within the same linkage- he lifetime risk of developing heart failure is estimated at one disequilibrium block as HSPB7.Of51CLCNKA sequence var- Tin five (1, 2). Although rare familial cardiomyopathies can iants identified, rs10927887 (encoding Arg83Gly) is positively lead to heart failure that is almost entirely attributable to genetic associated with heart failure risk in three independent Caucasian factors, common heart failure has a smaller, poorly defined her- heart failure populations. Functional analysis shows the Gly83 itable component. Framingham Heart Study data show that pa- variant channel to exhibit markedly abnormal chloride currents, rental heart failure confers a 70% greater disease risk than in suggesting that this common loss of function variant in CLCNKA individuals without a family history (3). Cardiac hypertrophy that at 1p36 confers heart failure risk in Caucasians and accounts for predisposes to heart failure is also heritable, suggesting that un- derlying genetic variation contributes to interindividual variability in heart failure risk (4). A fraction of common heart failure may Author contributions: T.P.C., J.M.N., and G.W.D. designed research; T.P.C., S.J.M., W.W., be due to unrecognized monogenic cardiomyopathy (5), but most D.v.B., M.L., X.W., L.Q., N.K.S., J.C.F., M.P.R., H.H., J.M.N., and G.W.D. performed research; T.P.C., S.J.M., W.W., D.v.B., M.L., N.K.S., J.C.F., M.P.R., H.H., J.M.N., and G.W.D. contributed cases are explained by multiple interacting environmental and as- new reagents/analytic tools; T.P.C., S.J.M., W.W., D.v.B., M.L., X.W., L.Q., M.P.R., H.H., J.M.N., yet unidentified genetic susceptibility factors. Previous efforts to and G.W.D. analyzed data; and T.P.C., S.J.M., H.H., and G.W.D. wrote the paper. identify genetic risk variants uncovered a rare combination of The authors declare no conflict of interest. adrenergic receptor polymorphisms that increases heart failure *This Direct Submission article had a prearranged editor. susceptibility 10-fold among African Americans (6), although this Freely available online through the PNAS open access option. particular combination of risk alleles has not yet been replicated 1To whom correspondence may be addressed. E-mail: [email protected] (7, 8). A few population-based cohort studies have implicated or [email protected]. – genomic regions in heart failure risk (9 11) or mortality (12), but This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. specific causative risk alleles are still unknown. 1073/pnas.1017494108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1017494108 PNAS Early Edition | 1of6 Downloaded by guest on September 23, 2021 the previously described association between some HSPB7 SNPs variants marked heart failure risk alleles within the broader ge- and heart failure. netic region. Accordingly, we resequenced all 19 coding exons and intron–exon boundaries of the adjacent CLCNKA gene in Results 1,742 DNA samples from the Cincinnati Heart Failure Study rs1739843 Is Not Associated with Altered Myocardial HSPB7 Expression (18, 19). (Detailed clinical characteristics of the study pop- or Splicing. The rs1739843 intronic HSPB7 SNP has been associated ulations are in Table S1.) Polymorphism screening by pooled with heart failure in multiple independent cohorts. Neither it nor resequencing identified 51 nonprivate exonic CLCNKA SNPs other linked polymorphisms alter protein coding. To examine (nine in dbSNP and 42 previously unreported; 11 synonymous whether this SNP might instead confer HSPB7 dysfunction by al- and 40 nonsynonymous; Table S2). Only seven of these SNPs tering transcription, we measured HSPB7 mRNA levels from human (five nonsynonymous) are common, defined as having an allele left-ventricular heart specimens of 111 Caucasian heart failure sub- frequency of ≥0.05. Thus, the CLCNKA gene exhibits limited jects genotyped for rs1739843. Using microarrays, we found no dif- polymorphic variability. ference in HSPB7 expression across rs1739843 genotypes, and we To determine whether CLCNKA polymorphisms were associ- verified this finding using RT–quantitative PCR (RT-qPCR) (Fig. ated with heart failure, allele frequencies for the 51 SNPs were 1A). HSPB7 exon expression revealed identical splicing patterns compared between 1,117 Caucasian heart failure cases and 625 regardless of rs1739843 genotype (Fig. 1B). Thus, the association unaffected controls. Nine SNPs (seven nonsynonymous) had between rs1739843 and heart failure risk is unlikely to be caused by significant associations with heart failure (P < 0.001, corre- an eQTL mechanism or by alterations in HSPB7 splicing. sponding to a Bonferroni-adjusted P < 0.05). In all but one in- stance allele frequencies for these SNPs were <0.05, whereas that A Common Nonsynonymous CLCNKA SNP Is Associated with Systolic for the marker HSPB7 SNP was ≈0.5 (14, 16). However, the allele Heart Failure. HapMap data reveal the HSPB7 locus on 1p36 to be frequency of rs10927887 was ≈0.50 in controls and ≈0.57 in heart − an area of high linkage disequilibrium (Fig. 2A). Because the failure cases (P = 7.09 × 10 5; Table S2), which is similar to the HSPB7 heart failure-associated SNPs do not alter protein coding marker HSPB7 SNP. This CLCNKA variant encodes a change HSPB7 or cardiac gene expression, we hypothesized that the risk from Arg to Gly at amino acid 83 (exon 3) of the renal ClC-Ka chloride channel (Fig.
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