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

Research Article
Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease
Scot J. Matkovich1, Derek J. Van Booven1, Anna Hindes1, Min Young Kang1, Todd E. Druley2,3, Francesco L.M. Vallania3, Robi D. Mitra3, Muredach P. Reilly4, Thomas P. Cappola4 and Gerald W. Dorn, II1

1Center for Pharmacogenomics, Department of Medicine,
2Division of Pediatric Hematology and Oncology, Department of Pediatrics, and
3Center for Genome Sciences, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
4Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Address correspondence to: Gerald W. Dorn II, Washington University Center for Pharmacogenomics, 660 S. Euclid Ave., Campus Box 8220, St. Louis, Missouri 63110, USA. Phone: (314) 362-4892; Fax: (314) 362-8844; E-mail: gdorn@dom.wustl.edu.

Published December 14, 2009
Received for publication July 8, 2009, and accepted in revised form October 14, 2009.

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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Journal of Clinical Investigation -- Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease