Causal Associations Between Circulating Adipokines and Cardiovascular Disease: A Mendelian Randomization Study

Abstract

Abstract Context Observational studies have suggested associations between adipokines and cardiovascular disease (CVD), but the roles of certain adipokines remain controversial, and these associations have not yet been ascertained causally. Objective To investigate whether circulating adipokines causally affect the risk of CVD using 2-sample Mendelian randomization (MR). Methods Independent genetic variants strongly associated with adiponectin, resistin, chemerin, and retinol binding protein 4 (RBP4) were selected from public genome-wide association studies. Summary-level statistics for CVD, including coronary artery disease (CAD), myocardial infarction, atrial fibrillation (AF), heart failure (HF), and stroke and its subtypes were collected. The inverse-variance weighted and Wald ratio methods were used for the MR estimates. The MR pleiotropy residual sum and outlier, weighted median, MR-Egger, leave-one-out analysis, MR Steiger, and colocalization analyses were used in the sensitivity analysis. Results Genetically predicted resistin levels were positively associated with AF risk (odds ratio [OR] 1.09; 95% confidence interval [CI], 1.04-1.13; P = 4.1 × 10-5), which was attenuated to null after adjusting for blood pressure. We observed suggestive associations between higher genetically predicted chemerin levels and an increased risk of CAD (OR 1.27; 95% CI, 1.01-1.60; P = 0.040), higher genetically predicted RBP4 levels and an increased risk of HF (OR 1.14; 95% CI, 1.02-1.27; P = 0.024). There was no causal association between genetically predicted adiponectin levels and CVD risk. Conclusions Our findings reveal the causal association between resistin and AF, probably acting through blood pressure, and suggest potential causal associations between chemerin and CAD, RBP4, and HF.