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Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study.

Authors
Lee-CR; North-KE; Bray-MS; Fornage-M; Seubert-JM; Newman-JW; Hammock-BD; Coupe-DJ; Heiss-G; Zeldin-DC
Source
Hum Mol Genet 2006 May; 15(10):1640-1649
NIOSHTIC No.
20033295
Abstract
Endothelial dysfunction contributes to the development of coronary heart disease (CHD). Soluble epoxide hydrolase metabolizes epoxyeicosatrienoic acids in the vasculature and regulates endothelial function. We sought to determine whether genetic variation in soluble epoxide hydrolase (EPHX2) was associated with the risk of CHD. We genotyped 2,065 Atherosclerosis Risk in Communities study participants (1,085 incident CHD cases, 980 non-cases) for 10 previously identified polymorphisms in EPHX2. Using a case-cohort design, associations between incident CHD risk and both non-synonymous EPHX2 polymorphisms and phase-reconstructed haplotypes were evaluated using proportional hazards regression. Individuals carrying the K55R polymorphism variant allele demonstrated higher apparent soluble epoxide hydrolase activity in vivo. Presence of the K55R variant allele was significantly more common among Caucasian CHD cases when compared with non-cases (20.8% versus 15.3%, respectively, P=0.012), and was associated with significantly higher risk of incident CHD (adjusted hazard rate ratio 1.45, 95% confidence interval 1.05-2.01, P=0.026). A significant association between the K55R variant allele and risk of CHD was not observed in African-Americans. The distribution of reconstructed haplotypes were significantly different in Caucasian cases when compared with non-cases (P=0.021). Significant differences in haplotype distribution were not observed in African-Americans (P=0.315). Genetic variation in EPHX2 was significantly associated with risk of incident CHD in Caucasians, implicating EPHX2 as a potential cardiovascular disease-susceptibility gene.
Keywords
Heart; Genetic-disorders; Genetic-factors; Genetics; Epoxides; Epoxy-compounds; Blood-gas-analysis; Blood-pressure; Blood-vessels; Gamma-rays; Genetics; Genotoxic-effects; Genotoxicity; Risk-analysis; Risk-factors; Cardiovascular-system-disease; Cardiovascular-system-disorders
Contact
C. R. Lee, National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709
CODEN
HMGEE5
Publication Date
20060515
Document Type
Journal Article
Email Address
zeldin@niehs.nih.gov
Funding Type
Agriculture; Cooperative Agreement
Fiscal Year
2006
NTIS Accession No.
NTIS Price
Identifying No.
Cooperative-Agreement-Number-U50-OH-007550
Issue of Publication
10
ISSN
0964-6906
Source Name
Human Molecular Genetics
State
CA; NC; TX
Performing Organization
University of California - Davis
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