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Human Molecular Genetics Advance Access originally published online on April 4, 2006
Human Molecular Genetics 2006 15(10):1640-1649; doi:10.1093/hmg/ddl085
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Published by Oxford University Press 2006

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

Craig R. Lee1,2, Kari E. North3, Molly S. Bray5, Myriam Fornage6, John M. Seubert1, John W. Newman7, Bruce D. Hammock7, David J. Couper4, Gerardo Heiss3 and Darryl C. Zeldin1,*

1Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA, 2Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, 3Department of Epidemiology and 4Department of Biostatistics, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 5Department of Pediatrics, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA, 6Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center, Houston, TX, USA and 7Department of Entomology, University of California-Davis Cancer Research Center, Davis, CA, USA

* To whom correspondence should be addressed at: National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA. Tel: +1 9195411169; Fax: +1 9195414133; Email: zeldin{at}niehs.nih.gov.

Received January 30, 2006; Accepted March 28, 2006

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 2065 Atherosclerosis Risk in Communities study participants (1085 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.


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