Hall Kathryn T, Nelson Christopher P, Davis Roger B, Buring Julie E, Kirsch Irving, Mittleman Murray A, Loscalzo Joseph, Samani Nilesh J, Ridker Paul M, Kaptchuk Ted J, Chasman Daniel I
From the Program in Placebo Studies, Division of General Medicine and Primary Care, Department of Medicine, Beth Israel Deaconess Medical Center (K.T.H., R.B.D., I.K., T.J.K.), Division of Preventative Medicine, Brigham and Women's Hospital (J.E.B., P.M.R., D.I.C.), and Department of Medicine, Brigham and Women's Hospital (J.L.), Harvard Medical School, Boston, MA (K.T.H., R.B.D., I.K., T.J.K, J.E.B., P.M.R., D.I.C, J.L., M.A.M.); Department of Cardiovascular Sciences, Clinical Research Centre, Glenfield General Hospital, University of Leicester, Leicester, United Kingdom (C.P.N., N.J.S.); Department of Psychology, Plymouth University, Plymouth, United Kingdom (I.K.); and Cardiovascular Epidemiology Research Unit, Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard School of Public Health Boston, MA (M.A.M.).
Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):2160-7. doi: 10.1161/ATVBAHA.114.303845. Epub 2014 Jul 17.
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.
儿茶酚-O-甲基转移酶（COMT）是儿茶酚胺代谢中的关键酶，与心血管、交感神经和内分泌途径有关。本研究旨在证实COMT基因变异与心血管疾病（CVD）发病之间的初步关联。它还旨在评估常用的CVD预防药物阿司匹林是否会改变COMT与CVD发病之间的潜在关联。
我们在女性基因组健康研究（WGHS）中检测了COMT基因多态性rs4680（次要等位基因频率[MAF]，0.47），该基因编码甲硫氨酸到缬氨酸的非同义替换。这是一个基于人群的大型女性队列，与安慰剂相比，随机分配服用阿司匹林或维生素E，并进行10年随访。通过COMT基因多态性rs4818证实了rs4680的作用，并且在冠状动脉疾病全基因组复制和荟萃分析/冠状动脉疾病遗传学联盟（冠状动脉疾病全基因组关联研究联盟）中也进行了检测。在分配到安慰剂组的WGHS女性中（135例事件/n = 5811），相对于甲硫氨酸，rs4680缬氨酸等位基因对CVD发病具有保护作用（风险比[HR；95%置信区间{CI}]，0.66[0.51 - 0.84]；P = 0.0007）；在冠状动脉疾病全基因组复制和荟萃分析以及冠状动脉疾病遗传学联盟中也观察到了这种关联（合并P = 2.4×10⁻⁵）。在WGHS中，随机分配服用阿司匹林消除了rs4680的关联，因此与安慰剂相比，缬氨酸/缬氨酸女性在分配服用阿司匹林时CVD发生率更高（HR[95%CI]，1.85[1.05 - 3.25]；P = 0.033），而甲硫氨酸/甲硫氨酸女性发生率较低（HR[95%CI]，0.60[0.39 - 0.93]；P = 0.023）。与甲硫氨酸/甲硫氨酸女性（HR[95%CI]，0.53[0.34 - 0.84]；P = 0.006）发生率显著较低相比，分配服用维生素E也使缬氨酸/缬氨酸女性的CVD发生率更高但无统计学意义（HR[95%CI]，1.50[0.83 - 2.70]；P = 0.180）。rs4818的结果相似。
常见的COMT基因多态性与CVD发病有关，并且这种关联通过随机分配服用阿司匹林或维生素E而改变。需要对这些发现进行重复验证。
