Abstract
Over the past 2 decades, the prevalence of cholecystitis has increased significantly, a trend believed to be influenced by improvements in quality of life and changes in lifestyle habits. However, the precise etiology of cholecystitis remains unclear. Although gallstones are commonly associated with this condition, recent studies suggest that immune cells also play a critical role in their development. This study investigated the relationship between cholecystitis and CD45 on CD33br HLA-DR+ immune cells, focusing on the mediating role of glycine levels, using Mendelian randomization (MR). The primary analytical approach employed was inverse variance weighting (IVW) complemented by additional methods, such as MR-Egger, weighted median, simple mode, and weighted mode. Horizontal pleiotropy and heterogeneity were evaluated to ensure the robustness of the MR findings, and a "leave-one-out" analysis was conducted to explore potential mediating effects. IVW analysis revealed that the association between cholecystitis and CD45 on CD33br HLA-DR+ immune cells yielded an odds ratio of 1.039 (95% confidence interval: 1.012-1.067, P = .004). Mediation analysis further indicated that glycine levels mediated this relationship, with a significant mediating effect of 6.87% (P = .0046). Notably, cholecystitis did not exhibit a reverse causal effect of CD45 on CD33br HLA-DR+ levels (P = .545; IVW odds ratio = 1.044, 95% confidence interval: 0.907-1.201). These findings suggested that the association between CD45 on CD33br HLA-DR+ immune cells and cholecystitis is mediated by glycine levels. This study provides novel insights into cholecystitis pathogenesis, highlighting the potential role of metabolic factors in immune-mediated inflammation. These results offer a new perspective on the underlying mechanisms of cholecystitis and suggest potential metabolic intervention targets for its prevention.