Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease.

Authors:
Scot J Matkovich
Scot J Matkovich
Center for Pharmacogenomics
Anna Hindes
Anna Hindes
Washington University School of Medicine in St. Louis
Saint Louis | United States
Min Young Kang
Min Young Kang
Korea University
Todd E Druley
Todd E Druley
Washington University School of Medicine
United States
Robi D Mitra
Robi D Mitra
Washington University School of Medicine
United States
Muredach P Reilly
Muredach P Reilly
Cardiovascular Institute
United States

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. In 2,606 individuals examined, we identified a total of 129 separate SNPs in the 4 cardiac signaling genes, including 23 nonsynonymous SNPs that we believe to be novel. Comparison of allele frequencies between 625 Caucasian nonaffected controls and 1,117 Caucasian individuals with systolic heart failure revealed 12 SNPs in the cardiovascular heat shock protein gene HSPB7 with greater proportional representation in the systolic heart failure group; all 12 SNPs were confirmed in an independent replication study. These SNPs were found to be in tight linkage disequilibrium, likely reflecting a single genetic event, but none altered amino acid sequence. These results establish the power and applicability of pooled resequencing for comparative SNP association analysis of target subgenomes in large populations and identify an association between multiple HSPB7 polymorphisms and heart failure.

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http://dx.doi.org/10.1172/JCI39085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798680PMC

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January 2010
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