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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 (?, -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 (Pinteraction=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.

SUBMITTER: Hall KT

PROVIDER: S-EPMC6951085 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Project description:Catechol-O-methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD.We examined COMT polymorphism rs4680 (MAF [minor allele frequency], 0.47), encoding a nonsynonymous methionine-to-valine substitution, in the Women's Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E when compared with placebo and 10-year follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis/The Coronary Artery Disease Genetics Consortium, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/n=5811), the rs4680 valine allele was protective against incident CVD relative to the methionine (hazard ratio [HR; 95% confidence interval {CI}], 0.66 [0.51-0.84]; P=0.0007); an association also observed in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis and The Coronary Artery Disease Genetics Consortium (combined P=2.4×10(-5)). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that valine/valine women experienced higher CVD rates with aspirin allocation when compared with placebo (HR [95% CI], 1.85 [1.05-3.25]; P=0.033), whereas methionine/methionine women experienced lower rates (HR [95% CI], 0.60 [0.39-0.93]; P=0.023). Allocation to vitamin E also conferred higher but nonsignificant CVD rates on valine/valine (HR [95% CI], 1.50 [0.83-2.70]; P=0.180) when compared with significantly lower rates on methionine/methionine (HR [95% CI], 0.53 [0.34-0.84]; P=0.006) women. Rs4818 results were similar.Common COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required.

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Catechol-O-Methyltransferase and Cardiovascular Disease: MESA.

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