Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease
Scot J. Matkovich, Derek J. Van Booven, Anna Hindes, Min Young Kang, Todd E. Druley, Francesco L.M. Vallania, Robi D. Mitra, Muredach P. Reilly, Thomas P. Cappola, Gerald W. Dorn II
Scot J. Matkovich, Derek J. Van Booven, Anna Hindes, Min Young Kang, Todd E. Druley, Francesco L.M. Vallania, Robi D. Mitra, Muredach P. Reilly, Thomas P. Cappola, Gerald W. Dorn II
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Research Article Cardiology

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

Abstract

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.

Authors

Scot J. Matkovich, Derek J. Van Booven, Anna Hindes, Min Young Kang, Todd E. Druley, Francesco L.M. Vallania, Robi D. Mitra, Muredach P. Reilly, Thomas P. Cappola, Gerald W. Dorn II

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Figure 2

Allele frequency comparisons with Illumina resequencing of pooled DNA.

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Allele frequency comparisons with Illumina resequencing of pooled DNA. (...
(A) Comparison of SNP allele frequencies from 2 independent runs of identical sequencing libraries made from 12 pools of 2,606 individual DNAs. (B) Comparison of SNP allele frequencies from 2 independent runs of separate libraries made from the same DNA pools. (C) Comparison of SNP allele frequencies from 2 independent runs of libraries made from replicate DNA pools. (D) Comparison of SNP allele frequencies obtained from resequencing the same 2,606 individual DNAs, grouped into pools of approximately 250 individual DNAs (12 pools) versus approximately 100 individual DNAs (29 pools). Formulae for regression line and Pearson correlation coefficient are indicated for each analysis.