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, Scot J. Matkovich, Wei Wang, Derek Van Booven, Mingyao Li, Xuexia Wang, Liming Qu, Nancy K Sweitzer, James C. Fang, Muredach P. Reilly, Hakon Hakonarson, Jeanne M. Nerbonne, Gerald W. Dorn

Research output: Contribution to journalArticle

52 Citations (Scopus)

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 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 × 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 recombinantwild-typeArg83 and variant Gly83 ClC-Ka 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 cardiorenal axis.

Original languageEnglish (US)
Pages (from-to)2456-2461
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number6
DOIs
StatePublished - Feb 8 2011
Externally publishedYes

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Chloride Channels
Heart Failure
Single Nucleotide Polymorphism
Kidney
Alleles
Genes
Linkage Disequilibrium
Introns
Population
Exons
Referral and Consultation
Odds Ratio
Hypertension
Messenger RNA

Keywords

  • Cardiomyopathy
  • Genetic association

ASJC Scopus subject areas

  • General

Cite this

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 6, 08.02.2011, p. 2456-2461.

Research output: Contribution to journalArticle

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. / Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 6. pp. 2456-2461.
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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 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 × 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 recombinantwild-typeArg83 and variant Gly83 ClC-Ka 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 cardiorenal axis.",
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AU - Wang, Wei

AU - Van Booven, Derek

AU - Li, Mingyao

AU - Wang, Xuexia

AU - Qu, Liming

AU - Sweitzer, Nancy K

AU - Fang, James C.

AU - Reilly, Muredach P.

AU - Hakonarson, Hakon

AU - Nerbonne, Jeanne M.

AU - Dorn, Gerald W.

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N2 - 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 × 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 recombinantwild-typeArg83 and variant Gly83 ClC-Ka 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 cardiorenal axis.

AB - 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 × 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 recombinantwild-typeArg83 and variant Gly83 ClC-Ka 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 cardiorenal axis.

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