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

Abstract

BackgroundPrevious 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.MethodsStudy 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.ResultsAmong 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.ConclusionOur 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.

Finding the Smoking Gun: Protein Tyrosine Phosphatases as Tools and Targets of Unicellular Microorganisms and Viruses

“…Biological role of this polymorphism is unclear, but it may be responsible for alternative splicing of the C-terminal SH2 domain. More detailed examination of patients with differing ethnicity is needed, as the follow-up studies either did not confirm the above mentioned relationship (the Uzbek cohort [28]), or confirmed only the association with severe gastric atrophy [29].…”

“…(4)), and NF290 (25)) were reported to inhibit YopH in low µM range, while being >20-fold selective over PTP1B, CD45, Cdc25A, VHR, PTPα, and LAR [152]. Among the other inhibitors are also p-nitrocatechol sulfate (26) [140], hexapeptide mimetic Ac-DADE-F 2 Pmp-L-NH 2 (27) of the YopH's natural substrate (F 2 Pmp = difluoro-substituted phosphonomethylphenylalanine, a phosphotyrosine analogue) [153], aurintricarboxylic acid (28) [154], furanyl salicylate compounds (29)(30)(31)(32) [155], α-ketocarboxylic acids and squaric acids [156].…”

Genetic Factors Involved in the Genesis of Helicobacter Pylori-Induced Gastric Cancer

“…Among H. pylori seropositive subjects, we found a significant association between RUNX3 rs760805 T/A polymorphism and the risk of gastric atrophy with the age-and sex-adjusted OR of 1.51 (95% CI 1.11-2.05, P=0.008) in TA, 1.59 (95% CI 1.08-2.33, P=0.019) in AA, and 1.53 (95% CI 1.14-2.05, P=0.004) in TA+AA, compared with TT genotype (Hishida et al, 2009b). This finding was in accordance with the recent biological report that RUNX3 expression correlated with chief cell differentiation in human gastric cancers (Ogasawara et al, 2009 OR and/or GA% IL-1B C-31T 5'UTR rs1143627 253 Japanese (Atsuta, 2006) CC (54%),CT (52%),TT (56%) " 455 Jpn.Brazil.…”

“…PTPN11 G/A at intron3 intron rs2301756 248 Japanese (Goto, 2006a) GG ,GA :0.70,AA :0.09 *GG (59%),GA (49%),AA (11%) " 979 Japanese (Hishida, 2009a) GG ,GA+AA :0.62 ‡ *GG (22%),GA+AA (15%) ‡ NOD1 G796A Non-synonimous (Glu266Lys) rs2075820 150 Turks (Kara, 2010) GG ,GA : 13.35*,AA :34.2* TLR4 A+896G Non-synonimous (Asp299Gly) rs4986790 103 Caucasians (Hold, 2007) AA ,AG :11.0* AA (36%),AG (87%) § " 717 Venezuelan (Kato, 2007) GlyGly/ AspGly,AspAsp : 1.53 TLR4 G+3725C 3'UTR rs11536889 980 Japanese (Hishida, 2009b) GG,GC+CC:1.33 GG(18%),GC+CC(22%) ‡ CD14 C-159T(C-260T) 5'UTR rs2569190 717 Venezuelan (Kato, 2007) CC,CT+TT :1.06…”

No association between AICDA 7888 C/T polymorphism, Helicobacter pylori seropositivity, and the risk of atrophic gastritis and gastric cancer in Japanese

“…Severe atrophic gastritis and corpus-predominant gastritis, together with intestinal metaplasia, are well established as predominant predispositions to gastric cancer [2]. Host genetic factors, along with bacterial virulence factors such as CagA, have been shown to determine the severity of gastric damage and the eventual clinical outcome of H. pylori infection [3][4][5][6]. The risk of gastric cancer increases several fold if both host genetic factors and certain bacterial virulence factors are present [7,8].…”