Submitted to: Human Molecular Genetics
Publication Type: Peer reviewed journal
Publication Acceptance Date: 3/28/2006
Publication Date: 4/4/2006
Citation: Lee, C.R., North, K.E., Bray, M.S., Fornage, M., Seubert, J.M., Newman, J.W., Hammock, B.D., Couper, D.J., Heiss, G., Zeldin, D.C. 2006. Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study. Human Molecular Genetics. 15(10):1640-1649. Interpretive Summary: We tested whether DNA sequence variation in the soluble epoxide hydrolase (EPHX2) gene was associated with the risk of coronary heart disease in subjects from the Atherosclerosis Risk in Communities study. Approximately 1,085 individuals who developed coronary heart disease and 980 individuals who remained free of disease were tested for 10 previously identified DNA sequence variants in EPHX2. Individuals with one of the sequence variants (K55R) had higher activity of the EPHX2 enzyme. This DNA sequence variant was associated with significantly higher risk for developing coronary heart disease in whites but not African Americans, identifying EPHX2 as a potential cardiovascular disease gene.
Technical 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.