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.
PDF Download - Full Text Link
( Please be advised that this article is hosted on an external website not affiliated with PubFacts.com)
Source Status
http://dx.doi.org/10.1172/JCI39085DOI ListingPossible
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798680PMCFound
January 2010
7 Reads

Similar Publications

Common variants in HSPB7 and FRMD4B associated with advanced heart failure.

Circ Cardiovasc Genet 2010 Apr 2;3(2):147-54. Epub 2010 Feb 2.

Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, USA.

Background: Heart failure results from abnormalities in multiple biological processes that contribute to cardiac dysfunction. We tested the hypothesis that inherited variation in genes of known importance to cardiovascular biology would thus contribute to heart failure risk.

Methods And Results: We used the ITMAT/Broad/CARe cardiovascular single-nucleotide polymorphism array to screen referral populations of patients with advanced heart failure for variants in approximately 2000 genes of predicted importance to cardiovascular biology. Read More

View Article
April 2010

Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy.

PLoS Genet 2010 Oct 21;6(10):e1001167. Epub 2010 Oct 21.

Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany.

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. Read More

View Article
October 2010

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation.

Proc Natl Acad Sci U S A 2011 Feb 19;108(6):2456-61. Epub 2011 Jan 19.

Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Common heart failure has a strong undefined heritable component. Two recent independent cardiovascular SNP array studies identified a common SNP at 1p36 in intron 2 of the HSPB7 gene as being associated with heart failure. HSPB7 resequencing identified other risk alleles but no functional gene variants. Read More

View Article
February 2011

Single nucleotide polymorphisms in bone turnover-related genes in Koreans: ethnic differences in linkage disequilibrium and haplotype.

BMC Med Genet 2007 Nov 26;8:70. Epub 2007 Nov 26.

Center for Genome Science, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, Republic of Korea.

Background: Osteoporosis is defined as the loss of bone mineral density that leads to bone fragility with aging. Population-based case-control studies have identified polymorphisms in many candidate genes that have been associated with bone mass maintenance or osteoporotic fracture. To investigate single nucleotide polymorphisms (SNPs) that are associated with osteoporosis, we examined the genetic variation among Koreans by analyzing 81 genes according to their function in bone formation and resorption during bone remodeling. Read More

View Article
November 2007