Association between the Cytotoxic T-Lymphocyte Antigen 4 +49G > A polymorphism and cancer risk: a meta-analysis

Background: As a key gene in the immunosurveillance of cell malignancy, Cytotoxic T-lymphocyte antigen 4 (CTLA-4 is an important negative regulator of T cell activation and proliferation. The CTLA-4 +49G > A polymorphism is one of the most commonly studied polymorphisms in this gene due to its association with cancer risks, but previous results have been conflicting. Methods: We preformed a meta-analysis using 22 eligible case-control studies (including 32 datasets) with a total of 11,273 patients and 13,179 controls to summarize the existing data on the association between the CTLA-4 +49G > A polymorphism and cancer risk. Results: Compared with the common CTLA-4 +49G > A GG genotype, the carriers of variant genotypes (CTLA-4 +49 GC/CC) had a 1.24-fold elevated risk of cancer (95% CI = 1.18-1.32, P < 0.05) under the dominant genetic model, as estimated using a fixed effect model. The effect of the CTLA-4 +49G > A polymorphism was further evaluated using stratification analysis. In four breast cancer studies, patients with the variant genotypes had a significantly increased risk of breast cancer (OR = 1.31, 95% CI = 1.17-1.48, P < 0.00001). A similar result was found in three skin cancer studies (OR = 1.30, 95% CI = 1.10-1.52, P = 0.001). In 26 solid tumor studies, subjects with the variant genotypes had a significantly higher risk of developing solid tumors (OR = 1.25, 95% CI = 1.18-1.33, P < 0.00001) compared with the 6 non-solid tumor studies (OR = 1.08, 95% CI = 0.79-1.48, P = 0.62). Patients with variant genotypes had significantly increased risk of non-epithelial tumors and epithelial tumors, with ORs of 1.23 (95% CI = 1.14-1.32, P < 0.00001) and 1.29 (95% CI = 1.17-1.41, P < 0.00001), respectively. It was also demonstrated that the increased risk of cancer associated with CTLA-4 +49G > A variant genotypes was more pronounced in Caucasians (OR = 1.29, 95% CI = 1.13-1.47, P = 0.0002), Asians (OR = 1.23, 95% CI = 1.16-1.32, P < 0.00001) and Chinese (OR = 1.23, 95% CI = 1.15-1.31, P < 0.00001). Conclusion: Our meta-analysis suggests that the CTLA-4 +49G > A polymorphism genotypes (GA + AA) might be associated with an increased risk of cancer, especially in Caucasians and Chinese.