A Two-step Bayesian Mendelian Randomization Study on Cholecystitis and Dermatitis

Abstract: Background: Cholecystitis is an inflammatory disease involving the gallbladder, often associated with digestive disorders and systemic immune response. This systemic immune response could potentially influence the immune status of the skin, particularly in conditions like dermatitis. Despite extensive research on dermatitis, the causal relationship between cholecystitis and dermatitis subtypes (DSs) remains unclear. Objective: The aim of this study was to investigate the causal relationship between cholecystitis and DSs. Methods: Two-sample Mendelian randomization (MR) was used to analyze the causal relationship between cholecystitis and DSs. We then utilized the Bayesian Weighted Mendelian Randomization (BWMR) method to validate our findings and applied bidirectional MR analysis to confirm the causal direction. After establishing the associations between traits, we delved into the underlying mechanisms of this interesting finding. Subsequently, we used 91 inflammatory proteins as mediators and performed summary data-based mendelian randomization (SMR) analysis to further investigate the pathogenesis of DSs. Results: MR results evidently showed that cholecystitis can significantly reduce the risk of allergic contact dermatitis (ACD) (IVW, OR=0.8834, p=0.0368) and exfoliative dermatitis (ED) (IVW, OR=0.5738, p=0.0126). BWMR also provided secondary validation of the casual associations. In the subsequent reverse direction MR analyses, reverse causality was not present, so cholecystitis had a unidirectional effect and existed as a protective factor for ACD and ED. Interestingly, cholecystitis appears to lower the risk of ACD and ED by downregulating IL-6, IL-7, and IFN-γ. Additionally, the genes HCG27 and HLA-DRB5 may play a significant role in the pathogenesis of ACD. Conclusion: This study used a two-step MR analysis of genetic summary data to investigate to what extent inflammatory proteins impact the protective role of cholecystitis on dermatitis. We also identified several proteins and genes that could serve as potential drug targets.