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

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.