DNA Methylation-mediated BTN3A2 Regulation via CD14+CD16+ Monocytes Protects Against Primary Sclerosing Cholangitis

INTRODUCTION: Primary Sclerosing Cholangitis (PSC) remains a significant challenge in hepatology with an unclear pathogenesis and limited treatment options. This study employed Mendelian Randomization (MR) to explore novel pathogenic mechanisms of PSC. METHODS: We analyzed publicly available datasets, including cis-eQTL, cis-pQTL, 731 immune cell profiles, DNA methylation data, and PSC GWAS summary statistics. Using Inverse Variance Weighted (IVW) as our primary method, we identified genes causally associated with PSC. Subsequent mediation analyses elucidated how DNA methylation regulates gene expression and how these genes influence PSC through specific immune cell subpopulations. RESULTS: Our analysis revealed a significant protective effect of BTN3A2 expression against PSC risk (IVW OR 0.838, 95% CI 0.792-0.887, P = 1.12E-09). Mediation analysis indicated that methylation at cg23465465 had a largely mediated effect on PSC risk through BTN3A2 regulation (89.3% mediated effect). Additionally, BTN3A2 exerted partial protection via CD14+CD16+ monocytes (4.7% mediation). DISCUSSION: This study suggests a protective role for BTN3A2 in PSC pathogenesis, supported by reliable DNA methylation regulation. Although CD14+CD16+ monocytes had a minor impact, they provide new insights into the immune mechanisms of PSC. However, these findings require cautious interpretation pending experimental validation. CONCLUSION: These findings identify BTN3A2 as a causal protective factor in PSC, mediated by DNA methylation and CD14+CD16+ monocyte-driven immunity, highlighting its therapeutic potential for precision medicine.