Mendelian randomization analysis of druggable gene expression in liver cancer risk and autoimmune hepatitis.

BACKGROUND

Liver cancer remains one of the most prevalent and lethal malignancies worldwide, while autoimmune hepatitis is an immune-mediated inflammatory liver disease characterized by circulating autoantibodies and distinctive histopathological features. Mendelian Randomization (MR), as an innovative epidemiological research method, providing a reliable approach for exploring causal relationships between gene expression and liver disease risk.

METHODS

This study employed a comprehensive two-sample Mendelian randomization analytical approach to systematically evaluate the causal relationships between druggable gene expression levels and liver disease risk, including both liver cancer and autoimmune hepatitis. The study incorporated expression quantitative trait loci (eQTL) data from 4,479 druggable genes as exposure variables, with liver cancer genome-wide association study (GWAS) data and autoimmune hepatitis GWAS data serving as outcome variables.

RESULTS

Mendelian randomization analysis revealed significantly different impacts of multiple gene expression levels on liver disease outcomes. For liver cancer, high expression of CCL7 and CCL11 genes demonstrated protective effects, with CCL11 gene showing statistical significance (HR = 0.600, 95%CI: 0.409-0.953, p = 0.027), suggesting these genes may exert protective functions through immune response regulation mechanisms. Conversely, high expression of CASP8, CD5, and FGF21 genes significantly increased patient mortality risk.

CONCLUSIONS

This study provides sufficient and reliable scientific evidence for liver disease risk-related genes through multidimensional Mendelian randomization validation analysis.