Associations of a PTPN11 G/A polymorphism at intron 3 with Helicobactor pylori seropositivity, gastric atrophy and gastric cancer in Japanese

Background: Previous studies have revealed the significance of Helicobacter pylori (H. pylori) infection as a risk factor of gastric cancer. Cytotoxin-associated gene A (cagA) positivity has been demonstrated to determine the clinical outcome of H. pylori infection in the presence of SHP-2 (src homology 2 domain-containing protein tyrosine phosphatase-2). This study aimed to examine the formerly reported association of G/A PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) polymorphism (rs2301756) with gastric atrophy, as well as the association with gastric cancer in a Japanese population using a large sample size. Methods: Study subjects were 583 histologically diagnosed patients with gastric cancer (429 males and 154 females) and age-and sex-frequency-matched 1,636 non-cancer outpatients (1,203 males and 433 females), who visited Aichi Cancer Center Hospital between 2001-2005. 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. Results: Among H. pylori seropositive non-cancer outpatients, the age-and sex-adjusted OR of gastric atrophy was 0.82 (95% CI 0.62-1.10, P = 0.194) for G/A, 0.84 (95% CI 0.39-1.81, P = 0.650) for A/A, and 0.83 (95% CI 0.62-1.09, P = 0.182) for G/A+A/A, relative to G/G genotype, and that of severe gastric atrophy was 0.70 (95% CI 0.47-1.04, P = 0.079), 0.56 (95% CI 0.17-1.91, P = 0.356), and 0.68 (95% CI 0.46-1.01, P = 0.057), respectively. Among H. pylori infected subjects (H. pylori seropositive subjects and seronegative subjects with gastric atrophy), the adjusted OR of severe gastric atrophy was further reduced; 0.62 (95% CI 0.42-0.90, P = 0.012) for G/A+A/A. The distribution of the genotype in patients with gastric cancer was not significantly different from that for H. pylori infected subjects without gastric atrophy. Conclusion: Our study results revealed that those with the A/A genotype of PTPN11 rs2301756 polymorphism are at lower risk of severe gastric atrophy, but are not associated with a decreased risk of gastric cancer, which partially supported our previous finding that the polymorphism in the PTPN11 gene encoding SHP-2 was associated with the gastric atrophy risk in H. pylori infected Japanese. The biological roles of this PTPN11 polymorphism require further investigation.