Genetically predicted osteoprotegerin levels and the risk of cardiovascular diseases: A Mendelian randomization study

Purpose: The relationship between circulating osteoprotegerin (OPG) levels and the risk of cardiovascular dis-eases (CVDs) has been the subject of conflicting results in previous observational and experimental studies. To assess the causal effect of genetically predicted OPG levels on the risk of a wide range of CVDs, we used the Mendelian randomization design.Design: We initially extracted information of genetic variants on OPG levels and their corresponding effect values from the summary data based on the European ancestry genome-wide association study. Subsequently, we performed two-sample Mendelian randomization analyses to assess the causal effect of genetically predicted OPG levels on CVDs by using inverse variance weighting (IVW), MR-Egger, weighted median, and MR-PRESSOmethods. We also conducted sensitivity analyzes as well as complementary analyses with a more relaxed threshold for the exposure genetic instrumental variable (P < 5 x 10(-6)) to test the robustness of our results.Results: Our results indicated that genetically predicted OPG levels causally reduce the risk of atrial fibrillation (IVW OR = 0.84; 95% CI = 0.72-0.98; P = 0.0241), myocardial infarction(IVW OR = 0.89; 95% CI = 0.80-0.98; P = 0.0173) and coronary heart disease (IVW: OR = 0.90; 95% CI = 0.82-0.99; P = 0.0286). Further comple-mentary analyses also confirmed the above results remain robust and we also identified a potential causal as-sociation of OPG levels with a reduced risk of hypertensive diseases(IVW OR = 0.94;95% CI = 0.88-1.00; P = 0.0394).Conclusion: This study provides compelling evidence for a causal relationship between genetically predicted OPG levels and risk reduction of coronary heart disease, myocardial infarction, and atrial fibrillation, indicating that OPG could potentially serve as a cardiovascular risk marker in clinical practice.