Causal Effects of Multiple Obesity Indices on Atrial Fibrillation and the Mediating Roles of Adipokines: Evidence from Mendelian Randomization and Mediation Analyses.

INTRODUCTION: The causal associations between various obesity indices and Atrial Fibrillation (AF) have not been well established. We aimed to investigate these causal relationships and explore the potential mediating roles of adipokines (leptin, resistin, and adiponectin). METHODS: General obesity was assessed via Body Fat Percentage (BFP) and Body Mass Index (BMI), while Waist Circumference (WC), Waist-to-Hip Ratio (WHR), and Hip Circumference (HC) represented central obesity. Bidirectional and two-step Mendelian Randomization (MR) were performed using the Inverse Variance Weighted (IVW), weighted median, and MR-Egger methods to assess causality and mediation effects. RESULTS: All obesity indicators (including BMI-adjusted WC/HC) were causally related to AF risk (each P < 0.05 for the IVW method). The two-step MR analysis indicated that leptin could mediate the causal relationships between several obesity indices and AF risk, including general (BMI and BFP) and central (WC and HC) obesity indices (P < 0.05). Leptin's mediating effect persisted in the relationship between central obesity and AF risk, even when using data adjusted by BMI, as particularly evidenced by the weighted median method (P < 0.05). DISCUSSION: Our findings suggest that both overall adiposity and fat distribution contribute to AF risk. The identification of leptin as a key mediator indicates that the relationship between obesity and AF may be partly explained by leptin-related biological mechanisms. CONCLUSION: Both general and central obesity are causally associated with AF risk, with leptin acting as an important mediator.