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Human Molecular Genetics Advance Access published online on April 4, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl085
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Published by Oxford University Press 2006
Received January 30, 2006
Revised March 28, 2006
Accepted March 28, 2006

Article

Genetic Variation in Soluble Epoxide Hydrolase (EPHX2) and Risk of Coronary Heart Disease: The Atherosclerosis Risk in Communities (ARIC) Study

Craig R. Lee 1, Kari E. North 2, Molly S. Bray 3, Myriam Fornage 4, John M. Seubert 5, John W. Newman 6, Bruce D. Hammock 6, David J. Couper 7, Gerardo Heiss 2, and Darryl C. Zeldin 8 *

1 Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC; Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC
2 Departments of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC
3 Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX
4 Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center, Houston, TX
5 Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC
6 Department of Entomology, University of California-Davis Cancer Research Center, Davis, CA
7 Biostatistics, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
8 Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA

* To whom correspondence should be addressed.
Darryl C. Zeldin, E-mail: zeldin{at}niehs.nih.gov


  Abstract

Background. 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 if genetic variation in soluble epoxide hydrolase (EPHX2) was associated with risk of CHD.

Methods. We genotyped 2065 Atherosclerosis Risk in Communities study participants (1085 incident CHD cases, 980 non-cases) for ten previously identified polymorphisms in EPHX2. Using a case-cohort design, associations between incident CHD risk and both nonsynonymous EPHX2 polymorphisms and phase reconstructed haplotypes were evaluated using proportional hazards regression.

Results. 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 compared to 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 to 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 compared to non-cases (P = 0.001). Significant differences in haplotype distribution were not observed in African-Americans (P = 0.315).

Conclusions. 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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