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Published on: July 21, 2023
Blood copper and risk of cardiometabolic diseases: a Mendelian randomization study
Susanne Jäger1,2,3, Maria Cabral1,2,3, Johannes F Kopp3,4
1Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal 14558, Germany.
Insights
Higher blood copper levels may protect against coronary artery disease (CAD) and lower systolic blood pressure, contrary to previous observational studies. This Mendelian randomization study suggests a potential causal protective role for copper in cardiovascular health.
Area of Science:
- Cardiovascular Genetics
- Metabolic Disease Research
- Trace Element Metabolism
Background:
- Observational studies suggest a link between elevated blood copper and increased cardiovascular disease risk.
- The causal relationship and potential confounding factors in the copper-cardiometabolic disease association remain unclear.
Purpose of the Study:
- To investigate the causal effect of genetically predicted copper levels on cardiometabolic endpoints, including coronary artery disease (CAD), stroke, and type 2 diabetes.
- To examine the impact of copper on key cardiometabolic risk factors, specifically systolic blood pressure.
Main Methods:
- Utilized two-sample Mendelian randomization (MR) studies to assess causality.
- Employed genome-wide association study meta-analyses for genetic instruments of blood copper levels.
- Extracted outcome data from large public genetic consortia for CAD, stroke, type 2 diabetes, and blood pressure.
Main Results:
- Genetically predicted higher copper levels showed an inverse association with the risk of coronary artery disease (CAD).
- Higher genetically predicted copper levels were associated with lower systolic blood pressure.
- Multivariable MR indicated that systolic blood pressure may mediate the relationship between copper and CAD risk.
Conclusions:
- Contrary to observational findings, genetically predicted higher copper levels may have a protective effect against CAD.
- The study suggests a potential protective role for copper in maintaining healthy systolic blood pressure levels.
- Systolic blood pressure is identified as a potential mediator in the pathway between copper and CAD risk.
Abstract:
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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