banner_advertise_728

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

Authors:
Thomas P Cappola
Thomas P Cappola
Penn Cardiovascular Institute
United States
Scot J Matkovich
Scot J Matkovich
Center for Pharmacogenomics
Dr. Wei Wang, MD
Dr. Wei Wang, MD
College of Life Science
China
Mingyao Li
Mingyao Li
University of Pennsylvania
Philadelphia | United States
Xuexia Wang
Xuexia Wang
Michigan Technological University
United States
Liming Qu
Liming Qu
University of Pennsylvania
Philadelphia | United States
Nancy K Sweitzer
Nancy K Sweitzer
University of Pennsylvania School of Medicine
United States

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.

Download full-text PDF

Source
http://www.pnas.org/content/108/6/2456.full.pdf
Web Search
http://www.pnas.org/cgi/doi/10.1073/pnas.1017494108
Publisher Site
http://dx.doi.org/10.1073/pnas.1017494108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038744PMC
banner_advertise_728
February 2011
19 Reads

Publication Analysis

Top Keywords

heart failure
32
chloride channel
12
failure risk
12
heart
8
associated heart
8
hspb7 gene
8
variant clcnka
8
failure
8
cardio-renal axis
8
hspb7
6
risk
6
snp
6
variant
5
gene
5
common linkage
4
arg83gly common
4
snp rs10927887
4
rs10927887 encoding
4
encoding arg83gly
4
variant channel
4

Similar Publications