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BACKGROUND:Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. METHODS AND RESULTS:Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3. CONCLUSIONS:We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

Original publication

DOI

10.1161/CIRCGENETICS.109.895763

Type

Journal article

Journal

Circulation. Cardiovascular genetics

Publication Date

06/2010

Volume

3

Pages

256 - 266

Addresses

Cardiovascular Health Study: Department of Epidemiology, University of Washington, Seattle, WA 98105, USA. nlsmith@u.washington.edu

Keywords

Humans, Endopeptidases, Incidence, Risk, Cohort Studies, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, African Americans, European Continental Ancestry Group, Female, Male, Heart Failure, Genome-Wide Association Study, Ubiquitin-Specific Proteases