Abstract
BACKGROUND: Previous research has established a correlation between immune cells and an increased likelihood of Chronic pancreatitis (CP). However, studies investigating the causal relationship remain limited. METHODS: This study utilized publicly available genome-wide association study (GWAS) databases and conducted a two-sample Mendelian randomization (MR) analysis to examine the causal relationships (CRs) among 731 immune cells, 1,400 metabolites, and CP. Mediation MR analysis was also performed to assess whether metabolites serve as mediators in the relationship between immune cells and CP. RESULTS: Our study identified four immune cell types that act as risk factors for CP, with odds ratios (OR) ranging between 1.076 and 1.177. In contrast, three immune cell types were found to serve as protective factors, exhibiting OR values between 0.846 and 0.913. Additionally, four metabolites were implicated as risk factors for CP, with OR values ranging from 1.243 to 1.334. On the other hand, eight metabolites were discovered to have a protective effect, with OR values between 0.580 and 0.871. Mediation analysis revealed that cholesterol levels mediate the causal relationship between immune cell cells and CP, with a mediation effect of 0.00918, accounting for 9.18% of the total effect. CONCLUSIONS: Our findings provide valuable insights into the genetic underpinnings of CP, highlighting the role of immune cells and plasma metabolites in its pathogenesis. The mediation analysis further suggests that the presence of CD25 on IgD-CD38-B cells may facilitate CP development through the elevation of cholesterol levels. These results not only deepen our understanding of CP but also suggest potential biological targets for therapeutic intervention. Future clinical research should focus on these mediators to develop more effective treatment strategies for CP.