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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.
    Proc Natl Acad Sci U S A 2011 Feb 19;108(6):2456-61. Epub 2011 Jan 19.
    Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
    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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    A CLCNKA polymorphism (rs10927887; p.Arg83Gly) previously linked to heart failure is associated with the estimated glomerular filtration rate in the RENASTUR cohort.
    Gene 2013 Sep 9;527(2):670-2. Epub 2013 Jul 9.
    Genética Molecular-Laboratorio Medicina, HUCA, Oviedo, Spain.
    A total of 569 individuals aged 55-85 and Caucasian were genotyped for SNP rs10927887 in the Ka renal chloride channel gene (CLCNKA). The following variables were significantly associated with an estimated glomerular filtration rate of (eGFR) <60 ml/min./1. Read More
    Common variants in HSPB7 and FRMD4B associated with advanced heart failure.
    Circ Cardiovasc Genet 2010 Apr 2;3(2):147-54. Epub 2010 Feb 2.
    Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, USA.
    Background: Heart failure results from abnormalities in multiple biological processes that contribute to cardiac dysfunction. We tested the hypothesis that inherited variation in genes of known importance to cardiovascular biology would thus contribute to heart failure risk.

    Methods And Results: We used the ITMAT/Broad/CARe cardiovascular single-nucleotide polymorphism array to screen referral populations of patients with advanced heart failure for variants in approximately 2000 genes of predicted importance to cardiovascular biology. Read More
    Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease.
    J Clin Invest 2010 Jan 14;120(1):280-9. Epub 2009 Dec 14.
    Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, 660 S. Eucliud Avenue, St. Louis, Missouri 63110, USA.
    Sporadic heart failure is thought to have a genetic component, but the contributing genetic events are poorly defined. Here, we used ultra-high-throughput resequencing of pooled DNAs to identify SNPs in 4 biologically relevant cardiac signaling genes, and then examined the association between allelic variants and incidence of sporadic heart failure in 2 large Caucasian populations. Resequencing of DNA pools, each containing DNA from approximately 100 individuals, was rapid, accurate, and highly sensitive for identifying common and rare SNPs; it also had striking advantages in time and cost efficiencies over individual resequencing using conventional Sanger methods. Read More