Immune and genetic landscapes of biliary atresia: a pathway to precision medicine.

BACKGROUND

Biliary atresia (BA) is a rare pediatric cholestatic disorder characterized by progressive bile duct inflammation and fibrosis. The underlying molecular mechanisms of BA remain poorly defined. This study aimed to identify susceptibility genes causally associated with BA by integrating genome-wide association study (GWAS) and transcriptomic data, and to explore their potential immunopathological roles.

METHODS

Two independent BA transcriptomic datasets from the Gene Expression Omnibus (GEO) were analyzed, and Mendelian randomization (MR) was applied to assess causal associations between differentially expressed genes (DEGs) and BA. Co-expressed genes were further evaluated for biological pathway enrichment and immune cell infiltration patterns. Expression levels of candidate genes were validated using quantitative real-time PCR (qRT-PCR) in liver tissues from 20 BA patients and 10 normal controls. Representative liver histopathology was also examined.

RESULTS

We identified 816 DEGs, including 458 upregulated and 358 downregulated genes. MR analysis highlighted seven co-expressed genes with potential causal relevance to BA, including C12orf75, PSD3, CRIM1, CHIT1 (upregulated), and SEC14L4, MAPRE3, TCEA3 (downregulated). qRT-PCR validation confirmed significantly elevated expression of C12orf75, PSD3, and CHIT1, and reduced expression of TCEA3 in BA liver tissues compared to controls (P < 0.05), consistent with MR predictions. Histopathological analysis revealed severe portal fibrosis, bile duct proliferation, and pseudolobule formation in BA samples, whereas normal controls exhibited preserved hepatic architecture with minimal fibrotic changes.

CONCLUSION

This study identifies a panel of immune- and transcription-related genes with potential causal roles in BA and validates their expression in human liver tissue. These findings offer new insights into the genetic and molecular basis of BA, supporting future efforts in subtype classification and immunomodulatory therapeutic development.