Genetic variations in cytotoxic T-lymphocyte antigen-4 and susceptibility to cervical cancer

Cytotoxic T-lymphocyte antigen-4 (CTLA-4), a molecule expressed predominantly on activated T cells, plays an important role in the down-regulation of T-cell activation. To evaluate the potential effects of CTLA-4 gene polymorphisms on susceptibility to cervical cancer, we genotyped polymorphisms in CTLA-4 (− 318 T/C, CT60 G/A, + 49 G/A, − 658 T/C, and − 1661 G/A) and calculated odds ratios for the genotype and allele distributions between patients and controls. We then examined the functional relevance of the polymorphisms using enzyme-linked immunosorbent assays (ELISAs), in vitro lymphocyte proliferation assay, and cytotoxic assay. The CTLA-4 − 318 CC, CT60 AA, and + 49 GG genotype frequencies were lower in patients than in controls (p < 0.05). The frequencies of CTLA-4 − 318 T allele and CT60G allele carriers were significantly higher in patients than in controls (p < 0.05). Upon stimulation, peripheral blood mononuclear cells (PBMCs) carrying the − 318TT and CT60GG genotypes exhibited significantly lower proliferation, IL-2, and IL-4 levels; fewer cytolytic activities; and higher TGF-β levels compared with PBMCs carrying the − 318 CC/CT or CT60 AA/AG genotypes. We also found that CTLA-4 − 318 T/C and CT60 G/A single nucleotide polymorphisms were associated with the severity of cervical cancer. These results indicate that CTLA-4 − 318 T/C and CT60 G/A can affect cervical cancer susceptibility by altering the immune status of an individual.