Polymorphisms in genes involved in Th1-type cell-mediated response and the risk of gastric cancer

Purpose Helicobacter pylori infection is a major known risk factor for gastric cancer. The pathogenesis of H. pylori infection is in part mediated by the immunologic reaction, which tend to polarize to a T helper type 1 cells (Th1) cell-mediated response, characterized by high IFN-γ, TNF-a, and IL-2 production. These Th1 prominent cytokines have been demonstrated to activate macrophages to produce proinflammatory cytokines, increase gastrin release, inhibit acid secretion and promote cell apoptosis and proliferation. We evaluated the association of gastric cancer risk with several genetic variants in Th1 related genes, including TNFα (A308G), IL2 (T330G), and IFNGR2 (Q64R, T58R, and 128C>T) in a Polish population. Methods We conducted a population-based study of 305 gastric cancer cases and 427 controls in Warsaw, Poland, between 1994 and 1996. Controls were randomly selected and frequency matched to cases by sex and age in 5-year groups. Genomic DNA from peripheral blood lymphocytes was used for genotyping, using TaqMan™ assays. Unconditional logistic regression was used to calculate ORs and 95% CIs, adjusting for sex, age, education, and smoking status. Results Carriers of the TNFa-308 AA genotype were at increased risk of gastric cancer (OR = 2.56, 95% CI 1.6–4.1, p-trend <0.001) relative to GG carriers. Of the three polymorphisms that we examined in IFNGR2, only T128C variants were significantly associated with gastric cancer risk (OR = 1.79, 95% CI: 1.15–2.78, p-trend = 0.009 for CC carriers relative to TT carriers). No clear association was seen for the IL2 (T330G) variant. Subjects carrying both IFNGR2-128 C allele and TNFa-308 AA genotype had the highest risk when compared to carriers of both IFNGR2-128 T allele and TNFa-308 GG genotype (OR = 5.11, 95% CI = 2.59–10.0, and p < 0.001). Conclusions Our results suggest that variants in genes involved in Th1 cell-mediated immunologic response may contribute, at least in part, to the etiology of gastric cancer.