Mediators between body mass index and atrial fibrillation: a Mendelian Randomization study

Background Although obesity is a recognized risk factor of atrial fibrillation (AF), the mechanisms are not fully understood. Thus, we aimed to identify the potential mediators between body mass index (BMI) and AF. Methods We conducted a two-sample Mendelian randomization (MR) analysis using publicly available summary-level data from genome-wide association studies. Univariable MR analyses were applied to identify potential mediators, and then the multivariable MR analyses were conducted to explore the mediated roles of circulating cytokines, metabolic markers and comorbidities in the association between BMI and AF. Results This MR study found a significant causal association between BMI and AF (OR=1.41, 95%CI=1.33-1.50; P<0.001), which was attenuated to 1.21 (95%CI=1.03-1.43) after being adjusted for leptin, in which 48.78% excess risk was mediated. After further adjustment for leptin and sleep apnoea or coronary heart disease, the association was attenuated to null (adjusted for leptin and sleep apnoea: OR=1.05, 95%CI=0.85-1.30; adjusted for leptin and coronary heart disease: OR=1.08, 95%CI=0.90-1.30), resulting in 87.80% and 80.49% excess risk being mediated, respectively. Conclusion These results identified an important mediated role of leptin, particularly for individuals with sleep apnoea or coronary heart disease, providing some clues for the underlying mechanisms behind the impact of obesity on AF risk. Funding Natural Science Foundation of Fujian Province (grant no. 2022J01706) and the Start-up Fund for high-level talents of Fujian Medical University (XRCZX2021026).