title: 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.affiliation: Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, 660 S. Eucliud Avenue, St. Louis, Missouri 63110, USA.
authors.forename: Scot J
authors.initials: SJ
authors.lastname: Matkovich
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Van Booven
authors.forename: Anna
authors.initials: A
authors.lastname: Hindes
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kang
authors.forename: Todd E
authors.initials: TE
authors.lastname: Druley
authors.forename: Francesco L M
authors.initials: FL
authors.lastname: Vallania
authors.forename: Robi D
authors.initials: RD
authors.lastname: Mitra
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
mesh_terms: D000328:Adult; D000368:Aged; D044383:Black People; D005787:Gene Frequency; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D054143:Heart Failure, Systolic / Q000208:ethnology / Q000235:genetics*; D006360:Heat-Shock Proteins; D006801:Humans; D008875:Middle Aged; D018832:Molecular Chaperones; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D044465:White People
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones