Our aim was to evaluate the association of genetic polymorphisms of immunoregulatory molecules with susceptibility to hepatocellular carcinoma (HCC). The polymorphisms in CTLA-4 (-318 T/C, CT60 G/A), TNF (-238 G/A, -308 G/A) and IL10 (-592 C/A, -819 C/T) were genotyped by PCR and DNA sequencing. The functional relevance of the polymorphisms was examined by ELISAs, in vitro lymphocyte proliferation assay and cytotoxic assay. The CTLA-4 -318 TC/TT, CTLA-4 CT60 GG, IL10 -592 CA and -819 CT/TT variants, CTLA-4 -318 T and IL 10 -819 T alleles were positively associated with HCC risk (P < .05). While TNF -238 AA variant, TNF -238 A allele were associated with decreased risk of HCC (P < .05). Furthermore, combinations of CTLA-4 -318 TC/TT and TNF -238 GG/GA; CTLA-4 -318 TC/TT and IL 10 -819 CC; CTLA-4 -318 CC and IL 10 -819 CT/TT in patients with HCC were statistically significant (P < .05). Peripheral blood mononuclear cells (PBMCs) carrying -318 TC/TT genotypes exhibited significantly lower proliferation rates, decreased IL-2, IL-4 levels, fewer cytolytic activities and elevated TGF-β levels. For IL 10 -819 C/T, the CC genotype was significantly associated with higher proliferation rate, decreased TGF-β, IL-10 levels and higher cytolytic activities (P < .05). For TNF -238 G/A, the AA genotype only had association with serum IL-2, IL-4 (P < .05). In addition, we also found that CTLA-4 -318 T/C, IL-10 -819 T/C variants, combinations of CTLA-4 -318 CC with IL 10 -819 CT or TT, CTLA-4 -318 TC or TT with IL 10 -819 CT or TT were associated with the severity of HCC. These findings suggest that CTLA-4 -318 TC/TT and IL 10 -819 CT/TT could promote the pathogenesis of HCC, which might be related with down-regulation of Th1/Th2-type cytokines and/or up-regulation of Th3-type cytokines.
Keywords: CTLA-4; cytokines; genetic polymorphisms; hepatocellular carcinoma.
© 2019 The Scandinavian Foundation for Immunology.