Uncovering potential therapeutic targets for autoimmune hepatitis using proteome-wide Mendelian randomization

Autoimmune hepatitis (AIH) is a chronic inflammatory disorder caused by an aberrant immune response directed against liver tissues. However, current treatments for AIH are insufficient in preventing disease progression, managing relapses, and minimizing adverse effects. Therefore, new treatments are urgently needed to improve the management of AIH. Protein quantitative trait loci data for 2940 plasma proteins were obtained from the UK Biobank Pharma Proteomics Project. Genetic association data for AIH were obtained from the FinnGen Consortium (including 264 AIH patients and 3,72,273 healthy controls) and from the study by Sakaue et al (including 821 AIH cases and 4,84,422 controls) and were considered as the discovery and validation sets, respectively. Summary-based Mendelian randomization and colocalization analyses were undertaken to pinpoint target proteins and to reveal the shared drivers between plasma proteins and AIH, respectively. In addition, we performed enrichment analysis, protein-protein interaction analysis, and drug availability analysis of AIH-related proteins to further explore the genetic mechanisms of AIH susceptibility and the potential of proteins as drug targets. Four plasma proteins, namely advanced glycosylation end product-specific receptor, butyrophilin subfamily 2 member A1, butyrophilin subfamily 3 member A2, and human leukocyte antigen E, were found to be significant in both the discovery set and validation sets, and their association with AIH was supported by both co-localization and sensitivity analyses. Phenome-wide association study analysis assessed the side effect profile of the 4 identified proteins; enrichment analysis and protein-protein interaction network showed that these proteins affected the occurrence of AIH by regulating immune response. Drug formation analysis suggested that advanced glycosylation end product-specific receptor and human leukocyte antigen E had the potential to be drug targets. This study highlights the important role of 4 plasma proteins in AIH risk. Further study of these proteins may reveal their potential in the prevention and treatment of AIH.