Genetic mechanisms of primary biliary cholangitis and its association with immune cells using mendelian randomization...

The incidence of primary biliary cholangitis (PBC) is on the rise, attributed to autoimmune-mediated bile duct damage in genetically susceptible individuals triggered by environmental factors. The close association between immune cell infiltration around the intrahepatic bile ducts and bile duct damage, and the causal and potential relationships of immune cells in the pathogenesis of PBC, remain unclear. Utilizing summary statistics from published genome-wide association studies, we evaluated the association between 731 immune cell traits and PBC through 2-sample Mendelian randomization (MR) analysis. Through pathway enrichment and functional analysis of associated genes, we aim to predict potential mechanisms. Genomic risk loci for PBC were identified, and summary data-based Mendelian randomization (SMR) analysis was conducted to pinpoint potential genes and therapeutic targets. Our analysis revealed a significant association between the elevated proportion of IgD- CD27- %lymphocytes and reduced risk of PBC after FDR adjustment in the B-cell panels (β = -0.381, confidence interval = -0.564 to -0.199, P = 4.19 × 10-5, FDR = 0.031). SMR analysis, MAGMA Gene-set analysis, and genes mapped on the Functional Mapping and Annotation platform jointly identified HLA-DQA1, HLA-DQB1, IL12RB2, and AIF1. Molecular docking studies forecasted prospective drug-target engagements, reinforcing their therapeutic promise. Our study indicates that an increased proportion of IgD- CD27- %lymphocytes lowers the risk of PBC and explores the potential pathogenic mechanisms of PBC through genetic means, charting a course for the discovery of novel pharmacological targets and delineating new prospects for drug development.