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 3

Comparative analysis of SNP allele frequencies in population subgroups.

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Comparative analysis of SNP allele frequencies in population subgroups. ...
(A) Comparison of target gene SNP allele frequencies in African Americans versus Caucasians. Vertical axis is African American allele frequency/Caucasian allele frequency, plotted on a log10 scale. Horizontal axis shows target gene with SNPs positioned accordingly, as in Figure 1. Red symbols denote novel SNPs. The shaded area indicates less than 2-fold difference in relative allele frequency. Symbols at the extreme top and bottom represent alleles seen exclusively in African Americans and Caucasians, respectively (see Table 2). (B) Linkage analysis of HSPB7 SNPs in Caucasians and association with systolic heart failure. HSPB7 SNP positions are shown within the gene (schematic as in Figure 1; boxes denote SNPs present in HapMap). Allele frequencies were compared across pools of 100 individuals. Red shading in the linkage plot denotes r2 ≥ 0.90; blue shading denotes r2 > 0.70; no shading denotes r2 < 0.70. Numbers within plot show r2 values (×100). Asterisks denote SNPs significantly associated with Caucasian heart failure (P < 0.0014; see Table 4).