Multi-Omics Analysis Reveals Potential Therapeutic Targets and Genetic Mechanisms in Primary Biliary Cholangitis

Background Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease with limited treatment options. This study employs multi-omics approaches to investigate its genetic mechanisms and identify potential therapeutic targets. Methods We performed univariable and multivariable Mendelian Randomization (MR) analyses using GWAS datasets to assess methylation, gene expression, and protein abundance related to PBC. Pathway enrichment, mouse genome informatics(MGI), protein-protein interaction (PPI) networks, DGIdb and GeneCards databases were further utilized to investigate potential mechanisms and targets. Results We identified 2,415 PBC risk snps that affect genome methylation using GoDMC mQTL dataset, among which 22 genetic variants were associated with blood gene expression in eQTLGen dataset. Genes affected by these risk SNPs include FAM177A1, HLA-DPB1, AIF1, IRF6, IL10RB and CANT1 (the latter four were firstly associated with PBC). Additionally, those risk SNPs affecting AIF1 and FAM177A1 were also associated with the protein abundance of these genes using multiple pQTL datasets. AIF1 and FAM177A1 participate in intestinal immune networks and metabolic-related pathways,suggested by KEGG/GO and previous studies. MGI showed that ablation of all six genes resulted in PBC symptoms. DGIdb and GeneCards databases showed that three unique drugs or compounds targeting AIF1 and one targeting FAM177A1. Conclusion We identified six key genes linked to PBC through methylation and gene expression. Meanwhile, we pinpointed two critical genes, AIF1 , a newly discovered gene affecting PBC, and FAM177A1 , strongly associated with methylation, gene expression, and protein abundance, emerged as promising therapeutic targets. These findings provide novel insights into the genetic mechanisms underlying PBC and potentially uncover novel therapeutic targets.