Observational evidence links higher blood levels of copper with higher risk of cardiovascular diseases. However, whether those associations reflect causal links or can be attributed to confounding is still not fully clear. We investigated causal effects of copper on the risk of cardiometabolic endpoints (stroke, coronary artery disease [CAD] and type 2 diabetes) and cardiometabolic risk factors in two-sample Mendelian randomization (MR) studies. The selection of genetic instruments for blood copper levels relied on meta-analysis of genome-wide association studies in three independent studies (European Prospective Investigation into Cancer and Nutrition-Potsdam study, Prospective investigation of the Vasculature in Uppsala Seniors study, Queensland Institute of Medical Research studies). For the selected instruments, outcome associations were drawn from large public genetic consortia on the respective disease endpoints (MEGASTROKE, Cardiogram, DIAGRAM) and cardiometabolic risk factors. MR results indicate an inverse association for genetically higher copper levels with risk of CAD (odds ratio [95% confidence interval] = 0.92 [0.86–0.99], P = 0.022) and systolic blood pressure (beta [standard error (SE)] = −0.238 [0.121]; P = 0.049). Multivariable MR incorporating copper and systolic blood pressure into one model suggested systolic blood pressure as mediating factor between copper and CAD risk. In contrast to previous observational evidence establishing higher blood copper levels as risk-increasing factor for cardiometabolic diseases, this study suggests that higher levels of genetically predicted copper might play a protective role for the development of CAD and systolic blood pressure.

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血铜和心脏代谢疾病的风险：孟德尔随机研究

观察性证据将较高的血液铜含量与较高的心血管疾病风险联系起来。然而，这些关联是否反映了因果关系或可归因于混杂仍不完全清楚。我们在两样本孟德尔随机化 (MR) 研究中调查了铜对心脏代谢终点（中风、冠状动脉疾病 [CAD] 和 2 型糖尿病）和心脏代谢危险因素风险的因果影响。血铜水平遗传工具的选择依赖于三项独立研究中全基因组关联研究的荟萃分析（欧洲癌症和营养前瞻性调查-波茨坦研究、乌普萨拉老年人脉管系统前瞻性研究研究、昆士兰医学研究所研究）。对于选定的乐器，结果关联来自大型公共遗传联盟关于各自的疾病终点（MEGASTROKE、心电图、图表）和心脏代谢风险因素。MR 结果表明，遗传性较高的铜水平与 CAD 风险（优势比 [95% 置信区间] = 0.92 [0.86–0.99]，P = 0.022）和收缩压（β [标准误差 (SE)] = -0.238 [0.121]；P = 0.049）。将铜和收缩压纳入一个模型的多变量 MR 表明，收缩压是铜和 CAD 风险之间的中介因素。与先前的观察证据表明，较高的血铜水平是心脏代谢疾病的风险增加因素，