Submitted to: Pharmacogenetics and Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/10/2007
Publication Date: 5/12/2007
Citation: Lee, C.R., North, K.E., Bray, M.S., Couper, D.J., Heiss, G., Zeldin, D.C. 2007. CYP2J2 and CYP2C8 polymorphisms and coronary heart disease risk: the Atherosclerosis Risk in Communities (ARIC) study. Pharmacogenetics and Genomics. 17(5):349-358. Interpretive Summary: This study investigated the relationship between heart disease and DNA sequence variation in two genes, CYP2J2 and CYP2C8, that are related to heart function. CYP2J2 DNA sequence variation was associated with significantly lower risk of developing heart disease in African-Americans but not in whites. DNA sequence variation in CYP2C8 was associated with the highest risk for heart disease in smokers.
Technical Abstract: The cytochromes P450 epoxygenases CYP2J2 and CYP2C8 synthesize epoxyeicosatrienoic acids, which regulate endothelial function. We sought to determine if genetic variation in CYP2J2 and CYP2C8 was associated with coronary heart disease risk. We genotyped 2065 Atherosclerosis Risk in Communities study participants (1085 incident coronary heart disease cases, 980 noncases) for polymorphisms in CYP2J2 and CYP2C8. Using a case–cohort design, associations between genotype and incident coronary heart disease risk were evaluated using proportional hazards regression. The influence of cigarette smoking on these associations was also evaluated. False discovery rate q-values were estimated to minimize the impact of the multiple statistical comparisons completed. All analyses were race stratified. The CYP2J2 G-50T polymorphism variant – 50T allele was associated with significantly lower risk of incident coronary heart disease in African-Americans (adjusted hazard rate ratio 0.58, 95% confidence interval 0.35 – 0.96, P=0.036, q=0.051); however, no significant association was observed in Caucasians. Overall, the I264M, I269F, and K399R polymorphisms in CYP2C8 were not significantly associated with risk of incident coronary heart disease. In Caucasians, the relationship between the I264M and K399R polymorphisms and incident coronary heart disease risk was significantly modified by cigarette smoking status (P for interaction = 0.008, q = 0.064) with the highest risk observed in smokers carrying at least one variant allete. The G-507 polymorphism in CYP2J2 may be an important risk factor for the development of coronary heart disease events in African-Americans, whereas cigarette smoking may modify the relationship between the I264M and K399R polymorphisms in CYP2C8 and coronary heart disease risk in Caucasians. Confirmation of these findings in an independent population is warranted.