Association of CTLA-4, TNF alpha and IL 10 polymorphisms with susceptibility to hepatocellular carcinoma.

Abstract

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.