Abstract 2386: Genetic Variation in CYP2J2 and Risk of Coronary Heart Disease: the Atherosclerosis Risk in Communities (ARIC) Study
Background. CYP2J2 metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs) which regulate endothelial function and serve as a reserve system to endothelial nitric oxide synthase (NOS3). We sought to determine if genetic variation in CYP2J2 was associated with risk of coronary heart disease (CHD) events.
Methods. Using a case-cohort design, 2065 participants (30% African-American) of the biethnic, multicenter ARIC study (all 1085 incident CHD cases occurring from 1987–98; 980 noncases from a cohort representative sample) were genotyped for 6 CYP2J2 polymorphisms, including the reduced function G-50T promoter variant. Haplotypes were reconstructed using the phase reconstruction method. Associations between genotype/haplotype and incident CHD risk were evaluated by proportional hazards regression with covariate adjustment. The putative interaction between the NOS3 T-786C and CYP2J2 G-50T polymorphisms was also assessed. False discovery rate q-values were estimated to account for multiple comparisons. All analyses were race stratified.
Results. In African-Americans, the variant -50T allele was less common in CHD cases vs. noncases (20.9% vs. 29.3%, P=0.043). Presence of at least one -50T allele was associated with significantly lower risk of CHD relative to two -50G alleles [adjusted hazard rate ratio (aHRR) 0.58, 95% CI 0.35– 0.96, P=0.036, q=0.051]. A common haplotype that includes the -50T allele was also associated with significantly lower CHD risk [aHRR 0.51, 95% CI 0.29 – 0.91, P=0.023, q=0.041]. The T-786C polymorphism in NOS3 appeared to modify the association between G-50T and CHD risk (interaction P=0.053), with the lowest risk observed in individuals carrying both the variant -50T and -786C alleles relative to those with both the wild-type -50G and -786T alleles [aHRR 0.24, 95% CI 0.08 – 0.72]. In Caucasians, no significant association between the variant -50T allele and CHD risk was observed [11.4% vs. 12.1%, P=0.719; aHRR 1.15, 95% CI 0.78 –1.70, P=0.472].
Conclusions. The variant -50T allele in CYP2J2 is associated with lower risk of incident CHD in African-Americans, particularly in those with the variant -786C allele in NOS3, suggesting presence of a potential gene-gene interaction. Confirmatory studies are necessary.