The functional cytotoxic T lymphocyte–associated Protein 4 49G‐to‐A genetic variant and risk of pancreatic cancer

BACKGROUND: Antitumor T lymphocytes play an essential part in immune surveillance of cancer cells. Cytotoxic T lymphocyte–associated Protein 4 (CTLA‐4) is a negative regulator of T cell activation and proliferation and therefore influences immune surveillance of carcinogenesis of pancreas. Thus, this study examined the association between functional CTLA‐4 49G‐to‐A (49G>A) single‐nucleotide polymorphism and pancreatic cancer risk. METHODS: Genotypes were determined in 368 patients with pancreatic cancer and 926 controls, and odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. RESULTS: A significant increased risk of pancreatic cancer was found to be associated with the CTLA‐4 49G>A single‐nucleotide polymorphism. Compared with noncarriers, the OR of developing pancreatic cancer for CTLA‐4 49 GA or AA carriers was 1.75 (95% CI = 1.34‐2.30, P = 4.83 × 10 −5 ) or 2.54 (95% CI = 1.67‐3.87, P = 1.36 × 10 −5 ), respectively. In stratified analyses, the association was more pronounced in GA and AA carriers aged ≤60 years (OR = 3.10, 95% CI = 2.15‐4.47, P interaction = .002), smokers with GA and AA genotypes (OR = 3.92, 95% CI = 2.39‐6.43, P interaction = .037), and drinkers with GA and AA genotypes (OR = 4.55, 95% CI = 2.65‐7.82, P interaction = .042), compared with GG carriers. Moreover, a supermultiplicative interaction between the CTLA‐4 49AA genotype and smoking plus drinking was also evident in intensifying risk of pancreatic cancer ( P interaction = 5.64 × 10 −12 ). CONCLUSIONS: These results suggest that CTLA‐4 49G>A polymorphism is involved in susceptibility to developing pancreatic cancer, alone and in a gene–environment interaction manner. Cancer 2012. © 2012 American Cancer Society.