Toll-Like Receptor 4+3725 G/C Polymorphism, Helicobacter pylori Seropositivity, and the Risk of Gastric Atrophy and Gastric Cancer in Japanese

Toll-like receptor 4 (TLR4) Asp299Gly and Thr399Ile polymorphisms were reported to be a risk factor of gastric carcinoma or its precursors in Caucasian and Indian population, but these polymorphisms are absent in Japanese. We investigated the associations of TLR4 +3725 G/C polymorphism, another functional polymorphism of TLR4, with risk of gastric cancer and gastric atrophy in Japanese. Study subjects were 583 histologically diagnosed gastric cancer patients and age- and sex-matched 1592 control outpatients, who visited Aichi Cancer Center Hospital from 2001 to 2005. Serum anti-H. pylori IgG antibody and pepsinogens were measured to evaluate H. pylori infection and gastric atrophy, respectively. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by a logistic model. Among the seropositive subjects, the age- and sex-adjusted OR of gastric atrophy was 1.17 (95%CI: 0.91-1.50) for G/C, 1.20 (95%CI: 0.76-1.89) for C/C, and 1.18 (95%CI: 0.93-1.49) for G/C+C/C relative to G/G genotype. The age- and sex-adjusted OR of severe gastric atrophy among H. pylori seropositive subjects was 1.43 (95%CI: 0.99-2.06) for G/C, 1.47 (95%CI: 0.76-2.88) for C/C, and 1.43 (95%CI: 1.01-2.04) for G/C+C/C. The OR of gastric cancer compared with gastric atrophy controls was not statistically significant. Our study found that TLR4 +3725 G/C polymorphism was a risk factor of severe gastric atrophy in H. pylori seropositive Japanese. Our results underscored the significance of the variations in host innate immunity due to TLR4 polymorphism as genetic predispositions to gastric precancerous lesions in Eastern Asian populations with the same backgrounds.