Blood copper and risk of cardiometabolic diseases-A Mendelian randomization study.

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 and type 2 diabetes) and cardiometabolic risk factors in two-sample Mendelian randomization studies. 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 (EPIC)-Potsdam Study, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, Queensland Institute of Medical Research (QIMR) 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. Mendelian randomization results indicate an inverse association for genetically higher copper levels with risk of coronary artery disease (Odds ratio [95% CI] = 0.92 [0.86-0.99], p = 0.022) and systolic blood pressure (beta [SE] = -0.238 [0.121]; p = 0.049). Multivariable Mendelian randomization incorporating copper and systolic blood pressure into one model suggested systolic blood pressure as mediating factor between copper and coronary artery disease 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 coronary artery disease and systolic blood pressure.