Genome-wide association and gene-virus interaction study of liver disease in hepatitis C virus-infected patients

Background and Aims: Chronic hepatitis C (CHC) can progress to cirrhosis and hepatocellular carcinoma (HCC). This study aimed to identify genetic determinants and host-viral interactions that drive this progression to inform risk stratification and personalised treatment strategies. Methods: We performed a genome-wide association study (GWAS) of cirrhosis (2,829 cases and 1,515 CHC controls), followed by a GWAS of HCC (706 cases and 2,152 cirrhosis controls). We performed cis-eQTL mapping and deconvolution in liver tissue of HCV-infected (136 CHC and 54 cirrhosis) patients to investigate gene expression regulation and cellular heterogeneity. Additionally, ten polygenic risk scores (PRS) for non-viral liver diseases were tested in 3,406 infected individuals. Results: We identified the missense risk variant rs738409 in PNPLA3 and a protective variant (rs4386418) in XKR3 in genotype 1-infected patients that were significantly associated with cirrhosis but not HCC progression. HLA fine-mapping identified two amino acids in HLA-DQB1*03:01 and HLA-DRB1*13:01 associated with cirrhosis risk. No genome‑wide significant association was observed for HCC, and loci previously linked to non‑viral HCC did not replicate. The eQTL analysis revealed 2,060 genes under cis-regulatory control and 129 whose effects were modified by cirrhosis. An intronic eQTL lowered PNPLA3 expression, but was not linked to cirrhosis risk. Deconvolution revealed expansion of plasma cells and macrophages and depletion of hepatocytes in CHC, with further immune-stromal remodelling in cirrhosis. All PRS showed a significant association with cirrhosis risk but not HCC progression. Conclusion: Cirrhosis in CHC shares genetic architecture with non-viral liver diseases but also displays virus-specific risk variants. Cirrhosis risk involves genetic factors that differ from those underlying progression to HCC.