Integrating CTLA-4 Genetics and Soluble Isoforms for the Stratification of HCV-Related Hepatocellular Carcinoma Risk and Aggressiveness

Host genetic factors influencing immune regulation are believed to modulate susceptibility to hepatitis C virus (HCV) and related hepatocellular carcinoma (HCC). This study aimed to investigate the association of Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) genetic variants with HCV-related HCC risk, soluble CTLA-4 (sCTLA-4) levels, and disease severity. 225 age- and sex-matched participants (75 controls, 75 HCV, and 75 HCV-HCC) were enrolled. TaqMan allelic discrimination assays were used for genotyping three CTLA-4 SNPs, and sCTLA-4 was quantified by ELISA. Our results demonstrated that the rs231726 TT genotype and T-allele were significantly associated with HCC. The rs11571317 CC genotype and C-allele, alongside the rs13384548 GG genotype and G-allele, conferred increased risk for both HCV and HCC. Clinically, these high-risk genotypes correlated with worse liver function (Child-Pugh C), higher MELD/Na scores, and larger tumors. Moreover, sCTLA-4 levels showed a stepwise elevation from controls to HCV to HCC patients, peaking in carriers of the rs231726 TT and rs13384548 GG genotypes. In conclusion, this study identifies rs231726, rs11571317, and rs13384548 as robust genetic markers for HCV-related HCC susceptibility and cancer aggressiveness. Our findings provide novel evidence of their role in immune evasion through sCTLA-4 upregulation, offering new perspectives into genotype-based risk stratification and tailored immunotherapeutic strategies.