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

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Hassan M.; El-Maadawy W.H.; Fahim S.A.; Youssef S.M.; Badran O.M.; Balata M.

Journal: International Journal of Molecular Sciences

Publisher: Multidisciplinary Digital Publishing Institute (MDPI)

Publication Date: 15 November 2025

Volume / Issue: Volume 26 / Issue 22

Article No.: 11067

ISSN: 16616596

DOI: 10.3390/ijms262211067

Scopus: View on Scopus

PubMed: 41303553

Document Type: Article

Access: All Open Access; Gold Open Access

Authors and Affiliations

Hassan M., Immunology Department, Theodor Bilharz Research Institute, Giza, 12411, Egypt; El-Maadawy W.H., Pharmacology Department, Theodor Bilharz Research Institute, Giza, 12411, Egypt; Fahim S.A., Biochemistry Department, School of Pharmacy, NewGiza University, Giza, 12577, Egypt; Youssef S.M., Pharmacy Practice Department, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; Badran O.M., Hepatogastoenterology Department, Theodor Bilharz Research Institute, Giza, 12411, Egypt; Balata M., University Hospital Rostock, Ernst-Heydemann-Straße 6, Rostock, 18057, Germany, University Hospital Bonn, Venusberg-Campus 1, Bonn, 53127, Germany

Abstract

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. © 2025 by the authors.

Keywords

biomarker; CTLA-4; gene polymorphism; hepatitis C virus; hepatocellular carcinoma; Immune checkpoint; rs11571317; rs13384548; rs231726; Aged; Alleles; Carcinoma, Hepatocellular; Case-Control Studies; CTLA-4 Antigen; Female; Genetic Predisposition to Disease; Genotype; Hepacivirus; Hepatitis C; Humans; Liver Neoplasms; Male; Middle Aged; Polymorphism, Single Nucleotide; Protein Isoforms; Risk Factors; cytotoxic T lymphocyte antigen 4; CTLA4 protein, human; isoprotein; adult; allele; Article; blood level; cancer risk; case control study; clinical study; cohort analysis; comorbidity; controlled study; disease predisposition; DNA polymorphism; gene frequency; genetic marker; genetic variation; heredity; human; immune evasion; immune response; immunoregulation; immunosuppressive treatment; immunosurveillance; liver cell carcinoma; major clinical study; protein protein interaction; upregulation; blood; complication; etiology; genetic predisposition; genetics; liver tumor; pathology; risk factor; single nucleotide polymorphism; virology

Citation Information

Scopus Citations: 1

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