Celiac disease as a risk factor for pancreatitis: Evidence from multivariable Mendelian randomization and mediation analysis.

Previous studies have suggested a potential link between celiac disease (CeD) and an increased risk of pancreatitis. However, the causal relationship and underlying mechanisms remain unclear. This study utilizes multivariable Mendelian randomization (MVMR) and mediation analysis to explore the causal link and underlying pathways between CeD and pancreatitis. Inverse variance weighting (IVW) was employed as the primary analysis method in MR analysis. To account for the potential confounding effects of cholelithiasis and triglycerides (TG), MVMR was further conducted. Furthermore, the mediating role of Sjögren syndrome (SS) in the relationship between CeD and pancreatitis was examined. Finally, multiple sensitivity analyses were utilized to assess the robustness of the results. Meta-analysis of the IVW results indicated that CeD is a potential risk factor for acute pancreatitis (AP) (pooled ORIVW = 1.05, 95% CI = 1.03-1.08, P < .001) and chronic pancreatitis (CP) (pooled ORIVW = 1.07, 95% CI = 1.04-1.10, P < .001). The MVMR result suggested the causal effects of CeD on AP (ORIVW = 1.05, 95% CI = 1.03-1.08, P < .001) and CP (ORIVW = 1.07, 95% CI = 1.03-1.10, P < .001) remain significant even after adjusting for cholelithiasis and TG. Further mediation analysis revealed that SS plays a mediating role in the causal effect of CeD on AP (OR = 1.01, 95% CI = 1.00-1.02, P = .033). The final sensitivity analysis showed no significant heterogeneity or horizontal pleiotropy. This study strongly supports a causal link between CeD and pancreatitis, both AP and CP, with SS potentially mediating the CeD-AP relationship.