Association of demographic and clinical factors with risk of acute pancreatitis: An exposure-wide Mendelian randomization study

Background The incidence of acute pancreatitis (AP) is increasing over years, which brings enormous economy and health burden. However, the aetiologies of AP and underlying mechanisms are still unclear. Here, we performed a two-sample Mendelian randomization (MR) analysis to investigate the associations between all reported possible risk factors and AP using publicly available genome-wide association study summary statistics. Methods A series of quality control steps were taken in our analysis to select eligible instrumental single nucleotide polymorphisms which were strongly associated with exposures. To make the conclusions more robust and reliable, we utilized several analytical methods (inverse-variance weighting, MR-PRESSO method, weighted median, MR-Egger regression) that are based on different assumptions of two-sample MR analysis. The MR-Egger intercept test, radial regression and leave-one-out sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on each exposure. A two-step MR method was applied to explore mediators in significant associations. Results Genetic predisposition to cholelithiasis (effect estimate: 17.30, 95% CI: 12.25-22.36, p = 1.95 E-11), body mass index (0.32, 95% CI: 0.13-0.51, p < 0.001), body fat percentage (0.57, 95% CI: 0.31-0.83, p = 1.31 E-05), trunk fat percentage (0.36, 95% CI: 0.14-0.59, p < 0.005), ever smoked (1.61, 95% CI: 0.45-2.77, p = 0.007), and limbs fat percentage (0.55, 95% CI: 0.41-0.69, p < 0.001) were associated with an increased risk of AP. In addition, whole-body fat-free mass (-0.32, 95% CI: -0.55 to -0.10, p = 0.004) was associated with a decrease risk of AP. Conclusion Genetic predisposition to cholelithiasis, obesity and smoking could be causally associated with an increased risk of AP, and whole body fat-free mass could be associated with a decreased risk of AP.