Catechol-O-Methyltransferase and Cardiovascular Disease: MESA

Abstract

Background Genetic variation in catechol-O-methyltransferase (COMT), a key enzyme in estrogen and catecholamine metabolism, has plausible physiological links to cardiovascular disease (CVD) and its risk factors. In WHS (Women's Health Study), COMT variants rs4818 and rs4680 were associated with a lower risk of CVD among women receiving placebo but not aspirin, suggesting a possible role of COMT in thrombosis. Methods and Results To evaluate potential pathways linking COMT with CVD, and COMT effect modification of aspirin in prevention, we examined COMT association with CVD risk and subclinical measures, coronary artery calcium, and carotid intima-media thickness in MESA (Multi-Ethnic Study of Atherosclerosis). In 65 957 person-years of follow-up, during which 498 events occurred, COMT rs4818 was associated with lower CVD risk (hazard ratio, 0.85; 95% CI, 0.74-0.97 [P=0.02]). This association remained virtually unchanged after adjusting for common CVD risk factors. Fibrinogen was the only risk factor associated with rs4818 (β, -3.65; SE, 1.35 mg/dL [P=0.007]). Results were directionally similar but not significant for rs4680. Adjusted hazard ratios for COMT rs4818 CVD association were 0.79 (95% CI, 0.65-0.95; P=0.02) among individuals who used aspirin <3 days per week and 0.89 (95% CI, 0.71-1.13; P=0.34) among more frequent users (P_interaction=0.39). Neither intima-media thickness nor coronary artery calcium was associated with COMT. Conclusions In a multiethnic prospective cohort of men and women, the COMT rs4818G allele was associated with lower CVD risk and lower fibrinogen levels but not with radiographic measures of subclinical atherosclerosis. These results suggest a plausible role of COMT in the latter stages of CVD.

Keywords: aspirin; cardiovascular disease risk factors; catecholamine; catecholaminergic polymorphic ventricular tachycardia; catechol‐O‐methyltransferase.

Figure 1

Kaplan–Meier curves of cardiovascular disease event‐free survival probability over the duration of MESA (Multi‐Ethnic Study of Atherosclerosis) (in years) by catechol‐O‐methyltransferase (COMT) (A) rs4818 and (B) rs4680 genotypes.