Mediation analysis of the causal pathway from gastroesophageal reflux disease to pancreatitis: A Mendelian randomization study

Although gastroesophageal reflux disease (GERD) and pancreatitis are both common gastrointestinal disorders, few studies have investigated their potential causal relationship. Clarifying whether GERD contributes to the development of acute pancreatitis (AP) and chronic pancreatitis (CP), and the possible mediating role of cholelithiasis, may provide new insights into shared pathogenic mechanisms. A univariable Mendelian randomization (UVMR) analysis was performed to assess the causal effects of GERD on AP and CP. To improve statistical power, the results from the discovery and replication cohorts were combined through meta-analysis. Multivariable Mendelian randomization (MVMR) was subsequently applied to adjust for the potential confounding effect of cholelithiasis. Finally, mediation analysis was conducted to evaluate the mediating role of cholelithiasis in the causal pathway from GERD to AP and CP. Multiple analyses, including heterogeneity analysis and horizontal pleiotropy analysis, were performed for sensitivity assessment. This study provides genetic evidence supporting a causal relationship between GERD and pancreatitis. The findings further highlight cholelithiasis as a partial mediator in this pathway, offering novel insights into shared mechanisms and potential preventive strategies for pancreatitis. UVMR suggested a positive causal association between GERD and both AP (discovery cohort: odds ratio [OR], 1.46; 95% confidence interval [CI], 1.29-1.65; P < .001; replication cohort: OR, 1.63; 95% CI, 1.37-1.93; P < .001) and CP (discovery cohort: OR, 1.47; 95% CI, 1.24-1.73; P < .001; replication cohort: OR, 1.50; 95% CI, 1.15-1.96; P = .003). Meta-analysis confirmed consistent and robust causal estimates across the discovery and replication datasets (AP: pooled OR, 1.52; 95% CI, 1.37-1.68; P < .001; CP: pooled OR, 1.48; 95% CI, 1.28-1.70; P < .001). After adjustment for cholelithiasis using MVMR, the causal effects were attenuated but remained statistically significant (AP: OR, 1.24; 95% CI, 1.06-1.44; P = .006; CP: OR, 1.39; 95% CI, 1.12-1.72; P = .003). Mediation analysis indicated that cholelithiasis partially mediated the causal effect of GERD on AP (mediation proportion [95% CI]: 42.4% [27.7-57.2%], P < .001) and CP (mediation proportion [95% CI]: 21.9% [0.1-43.7%], P = .048), suggesting that gallstone formation may be an important biological link between reflux disease and pancreatic inflammation. No significant evidence was detected in the sensitivity analyses (All P > .050).