柴田 知行

A comp I ex interaction of host genetic and environmental If actors maybe relevant in the development of Helicocobacter pylori-related gastric carcinogenesis. We investigated the effect of vascular endothelial growth factor (VEGF) gene polymorphisms on the risk of gastric cancer (GC) and peptic ulcer diseases in a Japanese population. The G1612A-(rs10434)and C936T(rs3025039) polymorph isms in the 3' untranslated region (3'-UTR) of VEGF gene were genotyped in a total of 844 subjects including 385 GC, 143 ulcer including 98 gastric ulcer (GU), 45 duodenal ulcer (DU), and 316 nonulcer subjects. The 1612A carrier held a significantly higher risk of GC when compared to both noncancer and nonulcer (overall noncancer vs. GC; OR=1.61, 95% CI=1.17-2.21, P=0.0038, nonulcer vs. GC; OR=1.54, 95% CI=1.07-2.22, P=0.0197). The 1612 A carrier was more closely associated with an increased risk of noncardiac cancer (OR = 1.64, 95% CI=0,17-2.21, P=0.0038), lower third cancer (OR=1.97, 95% CI=1.30-3.00, P=0.002), and Lauren's diffuse-type cancer (OR=1.75, 95% CI =1.24-2.46, P=0.001), while the same genotype was not associated with the progression of GC. The C936T genotype was not associated with a risk of GC and its progression. Both the G1612A and C936T genotypes were not associated with the risk of peptic ulcer diseases. Our data suggest that the G1612A, but not C936T polymorphisms in the 3 '-UTR of VEGF gene is associated with the susceptibility to GC in the Japanese population. (C) 2009 Wiley-Liss, Inc.

CpG island hyper-methylation (CIHM) is one of the major events in the gastric carcinogenesis and also occurs in non-neoplastic gastric mucosa. IL-17A, -17F and MIF have a crucial role in the gastric inflammation and carcinogenesis. The CIHM status in the non-cancerous gastric mucosa, in relation to IL-17A (-197G>A, rs2275913), -17F (7488T>C, rs763780) and MIF (-173G>C and -794 tetranucleotide repeats) polymorphisms was investigated. Gastric mucosa samples were obtained from 121 cancer free subjects. CIHM of p14, p16, DAP-kinase and CDH1 genes were determined by methylation-specific polymerase chain reaction (MSP). CIHM high was defined as three or all CpG islands methylated. We employed the PCR-SSCP (multiplex PCR for IL-17A and -17F) method to detect the gene polymorphisms. No association were found between CIHM status and L-17A (-197G>A), IL-17F (7488T>C) and MIF (-173G>C) polymorphisms. MIF 5-CATT repeat carrier (5/5+5/6+5/7) held a significantly higher risk of CIHM of DAP-kinase (OR=2.33, 95% CI=1.07-5.09, p=0.03) and CIHM high (OR=3.63, 95% CI=1.31-10.08, p=0.01). Weak association was also found between the same genotype and increased risk of CIHM of p 16 (OR=2.45, 95% CI=0.90-6.68, p=0.08) and CDH1 (OR=2.23, 95% CI=094-5.32, p=0.07). 6-CATT repeat carrier (5/6+6/6+6/7) was significantly associated with reduced risk of CIHM of p16 (OR=0.31, 95% CI=0.11-0.90, p=0.03), CDH1 (OR=0.40, 95% CI=0.17-0.98, p=0.045). DAP-kinase (OR=0.37, 95% CI=0.17-0.83, p=0.02) and CIHM high (OR=0.25, 95% CI=0.09-0.74, p=0.01). -7-CATT repeat carrier (6/7+7/7) was weakly associated with reduced risk of CIHM of p 16 (OR=0.34, 95% CI=0.10-1.13. p=0.08), DAP-kinase (OR=0.43, 95% CI=0.17-1.06, p=0.07) and CIHM high (OR=0.38, 95% CI=0.12-1.20, p=0.098). The present results provided the first evidence that the genetic polymorphisms MIF polymorphism is associated with CIHM status in the human gastric mucosa. Genetic polymorphisms of MIF-794-CATT repeat may be involved in methylation related carcinogenesis in the stomach.

Background: A complex interaction of genetic and environmental factors is relevant in gastric carcinogenesis. Previous studies reported that the expression of RANTES is enhanced in Helicobacter pylori-infected gastric mucosa. Elevated serum level of RANTES in gastric cancer patients was also reported. We aimed to clarify the effect of RANTES promoter polymorphism on the risk of gastric cancer (GC) in a Japanese population. Materials and Methods: A total of 191 GC and 335 non-cancer patients including H. pylori-positive gastritis (n=180) and H. pylori-negative healthy stomach (n=155) were genotyped for polymorphisms at -28 C/G in the RANTES gene promoter region. Results: RANTES promoter genotype distributions were not significantly different among GC, overall non-cancer patients, healthy stomach and gastritis. In the comparison of genotype frequency between GC and healthy stomach, only a weak correlation was found between -28G/G genotype and GC in individuals more than 70 years of age (odds ratio (OR)=7.65, 95% confidence interval (CI)=0.78-75.0, p=0.07), with advanced stage (OR=6.58, 95% CI=0.72-59.77, p=0.07), lymph node metastasis (OR=7.20, 95% CI=0.79-65.46, p=0.06) and peritoneal dissemination (OR=10.93, 95% CI=0.96-124.64, p=0.07). Conclusion: The effect of -28 C/G polymorphism in the RANTES gene promoter on GC development may not to be very strong. The role of RANTES promoter polymorphism in gastric carcinogenesis needs further evaluation.

Altered inflammatory immune responses have been shown to be associated with functional gastro intestinal disorder. We aimed to clarify the effect of functional promoter polymorphism of RANTES, which is a potent chemoattractant peptide for memory T lymphocytes and eosinophils, on the risk of functional dyspepsia in a Japanese population. RANTES promoter C-28G polymorphism was genotyped in 246 subjects including 134 FD patients according to Roma III criteria and 112 non-symptomatic healthy controls. Although frequency of RANTES promoter polymorphisms in overall dyspeptic patients and non-symptomatic healthy controls did not show any significant differences, a significant association was found between G carrier and reduced risk of PDS according to Roma III criteria (age, sex, H. pylori infection adjusted OR = 0.23, 95% Cl = 0.06-0.80). We also found that the same genotype held a lower risk of PDS in H. pylori positive PDS subjects (age, sex adjusted OR = 0.11, 95% Cl = 0.01-0.94). Our data suggest that RANTES promoter -28G carriers is associate with a reduced risk of PDS especially in H. pylori positive subjects.

Background: Magnifying narrow-band imaging (NBI) endoscopy clearly Visualizes superficial gastric mucosal patterns and capillary patterns. Objective: To investigate gastric mucosal patterns by using magnifying NBI endoscopy and identify any relationship between those patterns and Helicobacter pylori-induced gastritis. Design: Gastric mucosal patterns seen with magnifying NBI in uninvolved gastric corpus were divided into the following categories: normal-small, round pits with regular subepithelial capillary networks; type 1-slightly enlarged, round pits with unclear or irregular subepithelial capillary networks; type 2-obviously enlarged, oval or prolonged pits with increased density of irregular vessels; and type 3-well-demarcated oval or tubulo-villous pits with clearly visible coiled or wavy vessels. Setting: Department of Gastroenterology, Fujita Health University Patients: This study involved 106 participants undergoing upper endoscopy. Results: H pylori infection-positive ratios of normal and types 1, 2, and 3 patterns were 7.5%, 92.9%, 94.5%, and 66.7%, respectively Sensitivity and specificity for types 1 + 2 + 3 for detection of H pylori positivity and type 3 for detection of intestinal metaplasia were 95.2%, 82.2%, 73.3%, and 95.6%, respectively. Development of mucosal patterns from normal to types 1, 2, and 3 was correlated with all histological parameters (P <.0001), lower pepsinogen I/II ratios (P <.0001), and degree of endoscopic atrophy (P <.0001.). Sensitivity and specificity of type 3 for the prediction of severe histological atrophy was also better than those of serum pepsinogen level and standard endoscopy Limitations: Only I endoscopist performed endoscopic procedures, and interobserver agreement could not be assessed. Conclusions: Magnifying NBI endoscopy is useful for predicting H pylori infection and the histological severity of gastritis and is valuable for predicting gastric atrophy in the entire stomach. (Gastrointest Endosc 2009;70:246-53.)

Background: Heat-shock protein (HSP) 70 plays essential roles in cellular response to a variety of environmental stresses or unfavorable conditions. A to G transition at the 1267 position of the HSP70-2 gene confers different levels of HSP70 mRNA expression. We aimed to clarify the effect of HSP70-2 polymorphism on the risk of premalignant condition, on the degree of acute or chronic inflammation in the stomach. Patients and Methods: A total of 378 individuals participated in this study. Restriction fragment length polymorphism analysis was performed for polymorphisms at 1267 of HSP70-2 gene. Prevalence of intestinal metaplasia was investigated histologically and the degree of histological gastritis in the antrum was classified according to the updated Sydney System. Results: Although a direct association was not observed between HSP7 polymorphism and prevalence of intestinal metaplasia, a significant association was found between the BB genotype and lower metaplasia score in individuals who were Helicobacter pylori (H. pylori) positive and aged 60 years or older (BB vs. A carriers; 0.84 +/- 0.95 vs. 1.23 +/- 1.01, p=0.0197). When individuals were divided into 3 groups according to the severity of gastric mucosal atropy: non-atrophic gastritis (NA) group (atrophy score=0 and metaplasia score=0), severe atrophic gastritis (SA) group (atrophy score >= 2 or metaplasia score >= 2), and mild atrophic gastritis (MA) group (all others), the BB genotype was associated with a lower risk of severe atrophy in the SA subgroup (adjusted odds ratio=0.37, 95% confidence interval =0.16-0.84, p=0.0172). Conclusion: The BB genotype of HSP70-2 gene is associated with a reduced risk of gastric pre-malignant condition in H. pylori-infected older individuals.

Host genetic factors may play a key role in determining the long-term outcome of the Helicobacter pylori infection. Toll-like receptor 4 (TLR4) and CD14-mediated recognition of lipo-polysaccharide (LPS) is required for efficient recognition of Gram-negative bacterial infections. We investigated the effects of common polymorphisms of TLR4 Asp299Gly, Thr399Ile, and CD14 promoter-C159T on the risk of gastric cancer including its subtypes and clinicopathologic features. We also investigated the effects of these polymorphisms on histologic degree of H. pylori-induced gastritis. The study was performed in 149 gastric cancer (GC) cases [mean age 64.0 +/- A 12.4, M:F = 109:40] and 94 patients without evidence of GC (mean age 64.1 +/- A 12.3, M:F = 65:25, Peptic ulcer diseases = 43.6%, gastritis = 56.4%) as the control group. TLR4 Asp299Gly, Thr399Ile, and CD14 promoter-C159T were determined by PCR-RFLP in all the patients. Gastritis scores of non-cancerous gastric mucosa were assessed according to the updated Sydney system in H. pylori-positive subjects (n = 179). The frequencies of CD14-260 TT and T carrier were significantly lower in patents with intestinal-type gastric cancer than in controls (OR = 0.31; 95%CI = 0.12-0.78, OR = 0.38; 95%CI = 0.18-0.81, respectively). Compared to patients older than 61 years, the atrophy score in antrum was significantly lower in TT and CT patients. TLR4 Asp299Gly and Thr399Ile were not detected in all the patients. Our data suggests that CD14 promoter-159TT and T carrier were associated with a lower risk of developing gastric mucosal atrophy in H. pylori-infected patients of more than 61 years of age, and these genotypes may reduce the risk of intestinal-type gastric cancer.

Objective Mannan-binding lectin (MBL) is an important constituent of the innate immune system, and deficiency of MBL has been reported to increase the overall susceptibility of an individual to infectious disease. Codon 54 G/A variant of exon 1 (B allele) affects MBL2 gene and alters its activity. We investigated the influence of MBL2 variant on the risk of gastroduodenal diseases and on the severity of Helicobacter pylori-induced gastritis in a Japanese population. Methods One hundred and two gastric ulcers, 48 duodenal ulcers, 275 nonulcer participants were included in this study. B allele of the MBL2 gene was detected by polymerase chain reaction based restriction fragment length polymorphism. The severity of the histological chronic gastritis in antral biopsy specimens were classified according to the updated Sydney system. Results MBL2 B allele was significantly associated with severity of gastric mucosal atrophy and intestinal metaplasia (atrophy, G/G vs. G/A vs. A/A; P=0.02, A/A vs. others; P=0.009, intestinal metaplasia; G/G vs. G/A vs. A/A; P=0.03, A/A vs. others; P=0.004). When participants were divided into the following three groups according to the severity of gastric atrophy: the nonatrophic gastritis (NA) group, the severe atrophic gastritis (SA) group, and mild atrophic gastritis (MA) group, the frequency of A/A was significantly higher in the SA group than in others (SA vs. MA; odds ratio=8.42, 95% confidence interval = 1.05-67.45, SA vs. others; odds ratio = 10.06, 95% confidence interval = 1.26-80.45). Conclusion Our data suggest that the MBL2 codon 54 B allele is associated with a risk of developing more severe gastric mucosal atrophy in H. pylori-infected Japanese patients. Eur J Gastroenterol Hepatol 21:781-786 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Interleukin-17A (IL-17A) and IL-17F play a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. We investigated the associations between gastric cancer and polymorphisms of IL-17A (rs2275913, G-197A) and -17F (rs763780, 7488 T/C) genes. The study was performed in 811 Subjects (524 without gastric cancer and 287 with gastric cancer). We used the multiplex PCR-SSCP method to detect gene polymorphisms. Overall, the number of IL-17A/-197A allele was significantly correlated to the development of gastric cancer (OR, 1.42; 95% Cl, 1.09 -1.85; p = 0.010). The frequency of IL-17A/-197 A/A homozygote was also significantly higher in gastric cancer group than in non-cancer group (OR, 3.02; 95% Cl, 1.86-4.91: p < 0.0001). The IL-17A/G-197A polymorphism was more closely correlated to intestinal-type cancer than diffuse-type cancer. In addition, IL-17A/-197A allele carriers had an increased risk of the development of gastric mucosal atrophy (OR, 1.68; 95% CI, 1.06-2.65; p = 0.026), and a positive relationship between the inflammation score and the number of -197A allele was observed (p = 0.022). We concluded that G-197A polymorphism of IL-17A gene was significantly associated with the development of gastric cancer, especially intestinal-type cancer. (C) 2009 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics.

There have been reports showing a protective role of nonsteroidal anti-inflammatory drugs (NSAIDs) against gastrointestinal cancers. CpG island hyper methylation (CIHM) of tumor suppressor genes is a major event in carcinogenesis. We investigated the CIHM status of non-cancerous gastric mucosa in chronic NSAID users and non-users and assessed the effect of NSAIDs on CIHM. Gastric mucosa samples were obtained from 51 chronic NSAID users and 180 non-users. CIHM of p14(ARF), p16(INK4a), death-associated protein kinase (DAP-kinase), and E-cadherin (CDH1) genes were determined by methylation-specific PCR. CIHM high was defined as two or more CpG islands methylated. CIHM of p14, p16, CDH1, and CIHM high were lower in chronic NSAID users than in non-users (p14: non-users vs users = 32.2% vs 9.8%, P = 0.003; p16: non-users vs users = 35.0% vs 15.7%, P = 0.02; CDH1: non-users vs users = 36.1% vs 9.8%, P = 0.0009; CIHM high: non-users vs users = 44.4% vs 17.6%, P = 0.0009). NSAID use was also associated with decreased number of CIHM by anova (R = -0.32, P < 0.0001). Multivariate logistic regression analysis with adjustment for sex, age, Helicobacter pylori infection, and NSAID use revealed that NSAID use was inversely correlated with all four CIHM and CIHM high as an independent factor (p14: odds ratio [OR] = 0.17, 95% confidence interval [CI] = 0.06-0.48; p16: OR = 0.32, 95% CI = 0.14-0.75; DAP-kinase: OR = 0.45, 95% CI = 0.22-0.92; CDH1: OR = 0.18, 95% CI = 0.06-0.48; CIHM high: OR = 0.21, 95% CI = 0.09-0.49). No association was found between CIHM status and the duration or dose of NSAIDs. Chronic NSAID use suppresses CIHM in human gastric mucosa. NSAIDs may have a suppressive role against methylation-related gastric carcinogenesis. (Cancer Sci 2009; 100: 1192-1197)

DNA methylation is one of the major events in the early process of gastric carcinogenesis and also occurs in non-neoplastic gastric mucosa. Catechol-O-methyltransferase (COMT) catalyzes the methylation of various endobiotic and xenobiotic substances, and protects DNA from oxidative damage. The association between a common functional polymorphism of COMT Val158Met and DNA methylation status in the stomach was investigated. Patients and Methods: One hundred and sixty-nine gastric mucosa samples from non-cancer patients were obtained by endoscopy. The promoter methylation status of p14 and p16 was determined by methylation-specific PCR (MSP). The COMT Val158Met polymorphism was detected by PCR-restriction fragment length polymorphism (RFLP). Results: CpG island methylation was observed in 32.5% of the p14, and 37.9% of the p16. The methylation status of both p14 and p16 was not associated with gender or age, while p16 methylation was strongly associated with Helicobacter pylori infection (OR=4.71, 95% CI=2.35-9.46, p<0.0001). The Val/Val genotype held a significantly higher risk of p16 methylation (OR=3.27, 95% CI=1.05-10.25, p=0.0418). Conclusion: The COMT polymorphism may influence the susceptibility to gene methylation in the gastric mucosa. The promoter CpG island of p16 gene, but not of p14 may be one of the specific regions whose methylation is closely influenced by the COMT polymorphism.

Background/Aims: A complex interaction of genetic and environmental factors is relevant in gastric carcinogenesis. Cyclin D1 (CCND1) is known to regulate function in G1 arrest and therefore, may play an important role in carcinogenesis. The present study aimed to clarify the effect of G870A polymorphism of the CCND1 gene on the risk of gastric cancer (GC) in a Japanese population. Methodology: Restriction fragment length polymorphism analysis was performed for polymorphisms at 870GA in the CCND1 gene in 392 GC and 359 cancer-free subjects including 203 H. pylori positive gastritis and 156 H. pylori negative healthy stomach Results: Non significant association was found between CCND1 G870A genotypes and risk of GC when compared to that of all non-cancer subjects (AA vs. GG+GA: OR=1.13, 95%CI=0.81-1.58, A carrier vs. GG: OR=1.13, 95%CI=0.81-1.56), healthy stomach(AA vs. GG+GA: OR=1.27, 95%CI=0.81-2.00, A carrier vs. GG: OR=1.13, 95%CI=0.8-1.84) and gastritis. (AA vs. GG+GA: OR=1.03, 95%CI=0.7-1.53, p=0.92, A carrier vs. GG: 1.06, 95%CI=0.72-1.56, p=0.77)No association was found between CCND1 genotypes and any of clinico-pathological features of GC. Conclusion: It appears that the G870 polymorphism of CCND1 is not associated with the risk of GC in the Japanese population.

Background/Aims: The role of genetics in the susceptibility to functional dyspepsia (FD) is not well established. Cholecystokinin (CCK) is released from enteroendocrine cells in the duodenal mucosa after food ingestion and signals satiation through peripheral or central actions. A common polymorphisms of CCK and it's receptor gene has been shown to be associated with panic disorder and schizophrenia. It was investigated the prevalence of CCK polymorphism in dyspeptic patients in a Japanese population. Methodology: A total of 124 dyspeptic patients, 119 non-symptomatic healthy controls participated in this study. Dyspeptic patients were also classified by Rome III criteria. T779C of Cholecystokinin (CCK)-1 intron 1, by polymerase chain reaction-restriction fragment length polymorphism. H.pylori infection status was examined by histology or antibody against H.pylori. Results: Although frequency of CCK-1 polymorphisms in overall dyspeptic patients, subgroups by Roma III criteria and non-symptomatic healthy controls did not show any significant differences, 779 T carriers significantly increased the risk of postprandial syndrome (PDS) in male subjects (53.5%vs, 84.2; OR=4.63, 95%CI=1.24-17.31, p=0.018). This significant association was also remained after logistic regression analysis with adjustment for age and H.pylori infection status (OR=4.99, 95%CI=1.31-18.95, p=0.018). In female and different H. pylori infection status, no significant association was observed between CCK-1 polymorphisms and dyspepsia. Conclusion: Our data suggest that the 779 T carriers of CCK-1 intron 1 is associated with an increased risk of PDS in Japanese male subjects.

Background A complex interaction of host genetic and environmental factors may be relevant in the development of Helicobacter pylori (H. pylori)-related gastro-duodenal diseases. RANTES is a potent chemoattractant peptide for memory T lymphocytes and eosinophils, and has been shown to be enhanced in H. pylori-infected gastric mucosa. We aimed to clarify the effect of RANTES functional promoter polymorphism on the risk of gastro-duodenal diseases in a Japanese population. Methods Four hundred and eighty-three subjects, comprising 106 gastric ulcer, 52 duodenal ulcer, and 325 non-ulcer subjects, were included in this study. Restriction fragment length polymorphism (RFLP) analysis was performed for polymorphisms at -28 C/G in the RANTES gene promoter region. Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system. Results There were no significant differences in the RANTES promoter genotype distributions among non-ulcer subjects, ulcer patients, and gastric and duodenal ulcers. However, the degree of intestinal metaplasia was significantly lower among G carriers in H. pylori-infected subjects aged 60 years or older (C/C vs. G carriers; 1.28 +/- A 1.02 vs. 0.83 +/- A 0.89, P = 0.0357). In addition, we also found that the same genotype held a lower risk of more severe intestinal metaplasia in H. pylori-infected female subjects (C/C vs. G carriers; 0.91 +/- A 1.03 vs. 0.41 +/- A 0.73, P = 0.0443). Conclusion The polymorphism of RANTES promoter is not associated with the susceptibility to peptic ulcer diseases, but the -28 G carrier is associated with a reduced risk of developing more severe intestinal metaplasia in H. pylori-positive subjects aged 60 years and older and in female subjects.

Tryptase acting at protease-activated receptor 2 (PAR2) contributes to the pathogenesis of Inflammatory bowel diseases (IBDs). DNA methylation has been shown to be an important mechanism in gene silencing. We attempted to clarify the relationship between the promoter methylation of PAR2 and ulcerative colitis (UC). 84 UC patients enrolled in the study. UC patients were classified by disease behavior, severity and extent of disease. For rectal inflammatory mucosal specimens from all the patients, and normal terminal ileum from 23 patients, promoter methylation of PAR2 gene was quantified by digital densitographic analysis following to methylation-specific polymerase chain reaction (MSP). The mean methylation levels of the PAR2 gene in all 84 subjects was 38.4 +/- A 19.6%. Although mean methylation levels in rectal inflammatory mucosa, and paired normal terminal ileum did not vary, methylation levels of PAR2 gene was significantly higher in total colitis than rectal colitis (total colitis vs. rectal colitis; 42.9 +/- A 19.6% vs. 34.5 +/- A 18.9%, P = 0.046). The higher methylation levels were also associated with Steroid-dependent (P = 0.002) and refractory (P = 0.007) UC. Our data suggest that PAR2 methylation status in rectal mucosa correlates with more severe disease phenotypes of UC.

Background Promoter hypermethylation of tumor suppressor genes is one of the major events in gastric carcinogenesis. Promoter hypermethylation is also present in non-neoplastic gastric epithelium as age-related phenomenon and some reports suggest the potential association between promoter hypermethylation and Helicobacter pylori infection. Here, we examined whether methylation of multiple promoter CpG islands would occur by H. pylori infection and correlate with histological or serological severity of chronic gastritis. Methods One hundred and ninety-one gastric mucosa samples were obtained by endoscopy. The promoter methylation status of the p14, p16, DAP-kinase and CDH1 genes were determined by methylation-specific-polymerase chain reaction. The degree of gastritis in the antrum was assessed according to the updated Sydney system in 150 participants. The pepsinogen (PG) I/II ratio was calculated based on the data of serum PG I and PG II levels measured by radioimmunoassay in 54 selected cases. Results CpG island methylation was found in 32.5% for p14, 35.1% for p16, 43.5% for DAP-kinase and 36.1% for CDH1, whereas non, 1, 2, 3, and all methylation of four promoter CpG sites were present in 46 (24.1%), 59 (30.9%), 46 (24.1%), 30 (15.7%), and 10 (5.2%) participants, respectively. A strong association between the increased number of methylated CpG islands and H. pylori infection was observed (P<0.0001). An increased number of methylated CpG islands was also associated with severity of neutrophil infiltration (P<0.0001), mononuclear cell infiltration (P<0.0001) and atrophy (P=0.0021) in all, and severity of neutrophil infiltration (P=0.0177) and mononuclear cell infiltration (P=0.0004) in H. pylori-positive participants. An increased number of methylated CpG islands correlated with lower PG I/II ratio in all (P=0.0105) and H. pylori-infected participants (P=0.074). Conclusion Multiple promoter CpG islands would be methylated by H. pylori infection, and an increased number of methylated CpG sites correlate with histological and serological severity of chronic gastritis. Eur J Gastroenterol Hepatol 21:613-619 (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Altered MDR1 expression and/or function contribute to the pathogenesis of inflammatory bowel disease (IBD). DNA methylation was shown as an important mechanism in gene silencing. We investigated DNA methylation of the MDR1 gene in ulcerative colitis (UC) and its relation to MDR1 C3435T genotypes. Eighty-three UC patients were enrolled, Methylation of MDR1 promoter was determined by methylation specific polymerase (MSP) for rectal inflammatory mucosa from all patients and normal terminal ileum from 17 patients. Promoter methylation of MDR1 gene was also quantified by digital densitographic analysis following MSP. MDR1 methylation was detected in 51 (61.4%) out of 83 patients in rectal inflammatory mucosa. Mean methylation level of MDR1 gene in rectal inflammatory mucosa was significantly higher than in normal terminal ileum (p = 0.021). MDR1 methylation occurred more frequently in total colitis, and total + left side colitis, compared to rectal colitis (p = 0.001, 0.013, respectively). Higher methylation levels were also associated with chronic continuous type (p = 0.034) and earlier onset of disease (p = 0.038). The 3435 CC+CT genotype of MDR1 was associated with more than 6-fold increased risk of MDR1 methylation, especially in UC patients with 9 years and shorter duration. Both frequency and level of MDR1 methylation were higher in UC onset at younger or in middle age with the same genotype. MDR1 methylation frequently occurred in inflammatory rectal mucosa from UC patients and was influenced by MDR1 C3435T polymorphism, especially in patients with shorter duration and younger onset.

Background/Aims: A complex interaction of host genetic and environmental factors may be relevant in the development of Helocobacter pylori (H. pylori)-related gastroduodenal diseases. Catechol-O-methyltransferase (COMT) is expressed catalyzes the methylation of various endobiotic and xenobiotic substances and thus might protect DNA from oxidative damage. We aimed to clarify the effect of COMT functional polymorphism on the severity of histological gastritis in a Japanese population. Methodology: 203 subjects were included in this study. Restriction fragment length polymorphism analysis was performed for polymorphisms at codon 158 in the COMT gene. Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system. Results: COMT genotype distribution in the study subjects was 158Val/Val (51.2%), 84Val/Met (41.4%), and 15Met/Met (7.4%). It was within the Hardy -Weinberg equilibrium (p=0.73). In over all subjects, the degree of intestinal metaplasia tended to be lower among 158Met/Met when compared to Val/Val (Val/Val us. Met/Met; 0.59 +/- 0.93 vs. 0.13 +/- 0.52, p=0.052). Among Hpylori infected subjects, the degree of intestinal metaplasia was significantly lower among 158Met carriers in 50 years or older age (Val/Val us. Met carriers; 1.20 +/- 1.06 vs. 0.75 +/- 1.08, p=0.0436). No significant association was found between COMT genotypes and the degree of gastritis in different gender Conclusion: Our data suggest that COMT gene 158Met polymorphism is associate with a reduced risk of developing more severe intestinal metaplasia in H.pylori infected older subjects.

Background: A complex interaction of host genetic and environmental factors may be relevant in Helicocobacter pylori-related gastric carcinogenesis. We investigated the effect of VEGF gene polymorphisms on the risk of gastric pre-malignant condition. Patients and Methods: The G1612A and C936T polymorphisms in the 3'-untranslated region (3'-UTR) of the VEGF gene were genotyped in 337 cancer-free individuals. The presence of intestinal metaplasia in the gastric antrum was assesed in all. Gastritis scores were also assessed according to the updated Sydney system. Results: The 1612 GA genotype held a significantly higher incidence of intestinal metaplasia in H. pylori-positive individuals more than 65 years of age (OR=4.05, 95% CI=1.08-15.15, p=0.038). The degree of intestinal metaplasia was also higher among individuals with 1612 GA in the same generation (GG vs. GA; 0.98+/-0.87 vs. 1.55+/-0.96, p=0.026). Conclusion: The G1612A but not the C936T polymorphism of the VEGF gene is associated with gastric pre-malignant condition in older individuals.

Background Heat shock protein 70-2 (HSP70-2) has a cytoprotective role in various conditions and also protects the gastric mucosa. Recently, polymorphism of HSP70-2 at position 1267 was suggested to be associated with carcinogenesis. We investigated the association of this polymorphism with the risk of gastric cancer in the present study. Methods We examined 223 patients (159 men and 64 women, mean age 64.8 years) with gastric cancer who underwent gastrointestinal endoscopy at our department. The controls were 200 age-matched patients (140 men and 60 women) without gastric cancer diagnosed by gastrointestinal endoscopy. Genotyping was done by PCR-based restriction fragment length polymorphism analysis, and the PCR products were digested with PstI. The two allelic forms, corresponding to the presence or absence of the PstI site, were designated as the P1 allele and P2 allele, respectively. Logistic regression analysis was performed to calculate an odds ratios (ORs) for differences of HSP70-2 polymorphism between the two groups. Results Among the 223 patients with gastric cancer, 46 (20.6%) had P1/P1, 177 (79.4%) were P1 carriers, and 6 (2.7%) were P2/P2. In the control group, 33 (16.5%) patients had P1/P1 polymorphism, 167 (83.5%) were P1 carriers, and 12 (6.0%) were P2/P2. The OR for gastric cancer of subjects with P2/P2 polymorphism relative to P1 carriers was 0.43 (95% CI = 0.16-1.17) (P = 0.097). Among females, the OR for gastric cancer of subjects with P2/P2 polymorphism relative to P1 carriers was 0.10 (95% CI = 0.012-0.838) (P = 0.014). This polymorphism was also associated with a lower risk of middle third cancer (OR = 0.13; 95% CI = 0.02-1.00). Conclusions P2/P2 polymorphism of HSP70-2 at position 1267 was associated with a lower risk of gastric cancer in females.

Objective. Superoxide has been implicated in the pathogenesis of Helicobacter pylori-related diseases through inflammation. NADPH oxidase, a major source of superoxide generation, plays a critical role in H. pylori-related gastric inflammation. The aim of this study was to clarify the effect of the p22PHOX C242T polymorphism, an essential component of NADPH oxidase in the risk of gastroduodenal diseases, on the severity of H. pylori-induced gastritis in a Japanese population. Material and methods. The study comprised 436 patients attending the Endoscopy Center of Fujita Health University Hospital. The p22PHOX C242T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system. Results. The 436 patients represented 106 gastric ulcers (24.3%), 48 duodenal ulcers (11.0%), and 282 non-ulcer subjects (64.7%). No association was found between p22PHOX polymorphism and the risk of ulcer diseases compared to non-ulcer subjects. However, among H. pylori-positive subjects, the degree of intestinal metaplasia tended to be lower in 242T carriers aged more than 60 years (p=0.0488). The same allele also decreased the risk of developing a more severe intestinal metaplasia in H. pylori-positive female subjects (p=0.0441). Conclusions. Our data suggest that the p22PHOX 242T allele is associated with a reduced risk of developing a more severe intestinal metaplasia in subjects older than 60 years of age and in female subjects with H. pylori infection.

Background: Inflammation is a key factor in the process of carcinogenesis from chronic gastritis induced by Helicobacter pylori. Selenoprotein S (SEPSI) is involved in the control of the inflammatory response in the endoplasmic reticulum (ER). Recently the -105G> A polymorphism in the promoter of SEPSI was shown to increase pro-inflammatory cytokine expression. We examined the association between this polymorphism and the risk of gastric cancer. Methods: We took stomach biopsies during endoscopies of 268 Japanese gastric cancer patients (193 males and 75 females, average age 65.3), and 306 control patients (184 males and 122 females, average age 62.7) and extracted the DNA from the biopsy specimens. All subjects provided written informed consent. For the genotyping of the SEPSI promoter polymorphism at position -105G> A, PCR-RFLP methods were used and the PCR products were digested with PspGI. Logistic-regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusting for age, sex, and H. pylori infection status. Results: Among cases, the distribution of genotypes was as follows: 88.4% were GG, 11.2% were GA, and 0.4% were AA. Among controls, the distribution was as follows: 92.5% were GG, 7.2% were GA, and 0.3% were AA. Among males, carrying the A allele was associated with an increased odds of gastric cancer, compared with the GG genotype (OR: 2.0, 95% CI 1.0-4.1, p = 0.07). Compared with the GG genotype, carrying the A allele was significantly associated with increased risks of intestinal type gastric cancer (OR: 2.0, 95% CI 1.0-3.9, p < 0.05) as well as of gastric cancer located in the middle third of the stomach (OR: 2.0, 95% CI 1.0-3.9, p < 0.05). Conclusion: The -105G> A promoter polymorphism of SEPSI was associated with the intestinal type of gastric cancer. This polymorphism may influence the inflammatory conditions of gastric mucosa. Larger population-based studies are needed for clarifying the relation between inflammatory responses and SEPSI polymorphism.

Background: The altered expression of multidrug resistance 1 (MDR1) contributes to various types of carcinogenesis and their disease progression. Hypermethylation of CpG islands located in the promoter regions is involved in gene silencing at the transcriptional level. The methylation status of MDR1 gene promoter was investigated in gastric cancer in relation to various clinicopathological features. Patients and Methods: The methylation of the MDR1 promoter was estimated in both antral non-neoplastic mucosa and cancer lesions in 83 patients with gastric cancer using a methylation-specific PCR method. Results: The methylation ratio (MR) of the cancer lesions (31.3+/-20.5) was significantly, higher than that of non non-neoplastic mucosa (20.9+/-31.3, p=0.0004). The MR was especially high in Lauren's intestinal cancer (p<0.0001). A higher MR was also observed in more advanced stage (p=0.005) and lymph vessel invasion-positive cases (p=0.002). Conclusion: The promoter methylation of MDR1 seems to have a significant role in carcinogenesis and tumor progression in the stomach.

Background: Cyclin D1 (CCND1) is known to regulate function in G1 arrest and therefore may play an important role in carcinogenesis. The aim of this study was to investigate the effect of G870A polymorphism of the CCND1 gene on gastric precancerous condition, on histological chronic gastritis, and on the risk of peptic ulcer diseases. Methods: Restriction fragment length polymorphism analysis was performed for polymorphisms at 870GA in the CCND1 gene in 524 cancer-free subjects, including 111 gastric and 54 duodenal ulcers, and 359 non-ulcer subjects. Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system in 384 subjects. Results: CCND1 genotype was significantly associated with the severity of intestinal metaplasia by the Kruskal-Wallis test, and this tendency was especially stronger among older subjects of 61 years or older (overall subjects: p=0.035, 61 years similar to: p=0.007). We also found that the 870AA genotype held a significant high risk of intestinal metaplasia [Helicobacter pylori infection adjusted odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.03-3.15, p=0.04]. The same genotype was more closely associated with the risk of intestinal metaplasia in older subjects of 61 years or older (H. pylori infection adjusted OR = 3.45, 95% CI = 1.48-8.08, p = 0.004). A non-significant association was found between CCND1 G870A genotypes and the risk of peptic ulcer diseases as well as histological severity of acute or chronic inflammation. Conclusions: It appears that the G870A polymorphism of CCND1 is associated with gastric premalignant condition especially in older subjects. Clin Chem Lab Med 2008; 46: 1696-701.

Background Mannan-binding lectin (MBL) is believed to be an important constituent of the innate immune system. It has been reported that the codon 54 G/A polymorphism of exon-1 affects the MBL2 gene and alters its activity. Aims We investigated the association between polymorphism of the MBL2 gene and gastric cancer risk as well as Helicobacter pylori infection in a Japanese population. Methods The study cohort comprised 388 gastric cancer patients and 144 healthy volunteers. Polymorphism at codon 54 of exon 1 of the MBL2 gene was investigated by PCR-based restriction fragment length polymorphism analysis. Results There was no significant difference in the distribution of the MBL2 genotype among the gastric cancer patients and healthy controls. However, the carrier of the A allele was more prevalent among patients with a more advanced stage gastric cancer [odds ratio (OR) 1.68, 95% confidence interval (CI) 1.05-2.67; P = 0.03] and also had an increased risk of gastric cancer among patients 65 years of age or younger (OR = 1.6, 95%CI = 1.01-2.52, < 0.05). Conclusion The codon 54 polymorphism of the MBL2 gene is associated with more advanced phenotypes of gastric cancer and the risk of gastric cancer in Japanese patients 65 years of age or younger.

Background/Aims: Reactive oxygen species has been implicated in the development of gastric cancer. NADPH oxidase, a major source of superoxide generation play a critical role in H. pylori related gastric inflammation. We aimed to clarify the effect of C242T polymorphism of p22PHOX, an essential component of NADPH oxidase on the risk of gastric cancer, gastric ulcer and duodenal ulcer in a Japanese population. Materials and Method: 376 gastric cancer patients and 436 cancer-free subjects participated in this study. The p22PHOX C242T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism. Results: In the non-cancer subjects, the p22PHOX genotype distribution was 365CC (83.7%), 63CT (15.4%), and 4TT (0.9%). Meanwhile, the p22PHOX genotype distribution in gastric cancer was 311CC (82.7%), 63CT (16.8%), and 2TT (0.5%). There was no significant difference between two groups in the distribution of T carrier frequency (OR=1.04, 95% CI=0.71-1.53). No association was also observed between p22PHOX genotypes and Lauren's classification, tumor stage and anatomical locations. Conclusion: It appears that the C242T polymorphism of p22PHOX is not associated with the incidence of gastric cancer in the Japanese population.

Decay rates of bacteriophage P22 and Staphylococcus aureus on six types of common household inanimate surfaces were evaluated based on cultivation and quantitative PCR. A much higher level of inactivation was observed using the plate assay, suggesting that detection of the pathogen genome in samples from fomites does not necessarily imply a health risk to humans.

Background/Aims: Reactvie oxygen species as been implicated in the development of. ulcerative colitis (UC). NADPH oxidase, a major source of superoxide generation play A critical role in H. pylori related gastric inflammation. We aimed to clarify the effect of C242T polymorphism of p22PHOX, an essential component of NADPH oxidase on the risk of UC in a Japanese population. Methodology: 123 UC patients and 456 healthy control (HQ subjects participated in this study. The p22PHOX C242T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism. Results: In the HG group, the p22 PHOX genotype distribution was 379C/C (82.6%), 79C/T (1.7.2%), and 5T/T (1.2%). Meanwhile, the p22 1 PHOX genotype distribution in UC group was 96C/C (78.0%), 26C/T (21.1%), and IT/T (0.9%): No significant difference of the p22 PHOX genotype distribution was observed between HC and UC group. (C/C vs. T/T; OR=0.80, 95%CI=0.09-'6.84, C/C vs. C/T; OR=1.37 95%CI=0.83-2.25, C/C vs. T carriers; OR=1.33, 95%CI=0.82-2.18, T/T vs. others; OR=0.74, 95%CI =0.09-6.43): No association was also found between p22PHOX gene polymorphism and different clinicopathological features of UC such as gender, age, age of onset, clinical type, extension of colitis and response to treatment. Conclusions: It appears that the C242T polymorphism of p22 PHOX is not assocaited with the incidence of gastric cancer in the Japanese population.

Background/Aims: The role of genetics in the susceptibility to functional dyspepsia (FD) is unclear. Serotonin (5-HT) is expressed in gastro-intestinal tract and modulates the sensory-motor functions in the digestive tract. Genetic association has been reported between C102T polymorphism in the gene encoding 5-HT 2A receptor (5HTR2A) and various diseases. We aimed to clarify the association between 5HTR2A C102T polymorphism and dyspeptic symptom in a Japanese population. Methodology: 91 dyspeptics and 93 non-dyspeptic subjects enrolled in this study. Dyspeptic symptoms were divided into 9 categories. 5HTR2A gene T102C polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism. Results: In the non-dyspeptics, the 5HTR2A geno type distribution was 21TT (22.6%) 50TC (53.8%), and 22CC (23.6%). Meanwhile, the 5HTR2A genotype distribution in dyspeptics was 30 TT (33.0%), 40 TC (43.9%), and 21 CC (23.1%). There was no significant difference between the two groups in the genotype distribution. We did not find any association between 5HTR2A genotypes and dyspeptic patients in different gender and H. pylori infection Also, no correlation was found between 5HTR2A polymorphism and any of the 9 different dyspeptic symptoms. Conclusions: Our results suggest that 5HTR2A polymorphism is unlikely to be associated with susceptibility of dyspeptic symptoms. The role of genetics to the development of dyspepsia needs further evaluation.

Background: Prostaglandins (PGs), catalyzed from arachidonic acid by cyclooxygenase (COX), are involved in a variety of physiological processes in the stomach. COX-1 has been regarded as a constitutively expressed enzyme that generates prostaglandins for gastrointestinal integrity. We investigated the association between the potentially functional polymorphism T-1676C in the COX-1 gene promoter and functional dyspepsia (FD) in the Japanese population. Methods: The study was performed in 272 subjects (185 with no upper abdominal symptoms and 87 with FD). We employed the PCR-SSCP method to detect the gene polymorphism. Results: Overall, female sex had a 2-2.5- fold risk for the development of FD compared with male sex, whereas the COX-1 gene polymorphism and Helicobacter pylori infection were not associated with susceptibility to FD. However, in female subjects, -1676T allele carriers had a significantly increased risk for the development of FD (OR 2.70, 95%CI 1.04-6.99, p = 0.041), especially the epigastric pain syndrome (EPS) subgroup (OR 4.07, 95% CI 1.15-14.4, p = 0.029). Conclusions: Our results provide the first evidence that the COX-1 gene polymorphism is significantly associated with the development of the EPS subgroup of FD in female subjects.

A polymorphism within the 3'-UTR 8473T -> C of the cyclooxygenase-2 (COX-2) gene, which plays a role in gastrointestinal cancer development, has been associated with susceptibility to malignant disease. Here, we report on the interaction between the COX-2 3'-UTR T-C polymorphism and gastric cancer development. DNA from 121 Japanese patients with gastric cancer and 126 age-matched control patients was examined for the COX-2 polymorphism by PCR-RFLP. Odds ratios and the 95% confidence interval (CI) were calculated. Homozygous carriage of the COX-2 8473C allele tended to be associated with an increased risk of gastric cancer compared to the T allele homozygotes of the subjects (OR=3.70; 95% CI, 0.96-14.25). The CC allele was associated with a significant increased risk of diffuse-type gastric cancer (OR=5.29; 95% CI, 1.18-23.70). These findings suggest that the COX-2 3'-UTR 8473T -> C polymorphism could be used as a marker for genetic susceptibility to gastric cancer in Japanese populations.

Background/Aims: The role of genetics in the susceptibility to functional dyspepsia (FD) is unclear. Catechol-O-methyltransferase (COMT) has been an important enzyme in brain gut axis and pain sensitivity. Polymorphism in codon 158 of the COMT gene influences its activity. This study aimed to clarify the association between COMT polymorphism and dyspepsia in a Japanese population. Methodology: 91 dyspeptics and 97 non-dyspeptic subjects enrolled in this study. Dyspeptic symptoms were divided into 9 categories. COMT gene val158met polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism. Results: The frequency of Met carriers was lower in over all dyspeptics than healthy control but the difference was not significant (Or = 0.79, 95% CI=0.44-1.41). However, when the interaction between age, gender, H. pylori infection status and the number of COMT 158Met alleles was assessed using ANOVA, a slight interaction with gender + age + COMT polymorphism was found in relation to overall dyspeptics (p=0.0476) No correlation was found between COMT polymorphism and any of 9 symptoms. Conclusions: The data suggest that the COMT genotype seems to influence the susceptibility of dyspepsia when it influence the susceptibility of dyspepsia when it interacts with gender and age. The role of genetics in the development of dyspepesia needs to further evaluation.

Background/Aims: Non-steroidal anti-inflammatory drugs (NSAIDs) aggravate or ameliorate clinical disease activity in patients with ulcerative colitis (UC). UC is associated with increased local production of prostanoids. This study attempted to clarify the relationship between cyclooxygenase-1 (COX1) gene polymorphisms (T-1676C and A-842G/C50T) and ulcerative colitis in a Japanese population. Methodology: The study was performed on 108 patients with UC (mean age: 39.1 years, M:F=56:52) and 293 healthy controls (mean age: 49.0 years, M:F=161:132). The PCR-SSCP method was employed to detect COX1 polymorphisms using DNA extracted from peripheral blood cells. Results: No A-842G/C50T polymorphism was detected in all 401 Japanese subjects. The frequency of -1676C allele of COX1 gene in HC group and UC group was 48.8% and 48.1%, respectively. T-1676C genotypes of COX1 did not show significant association with UC risk. In addition, these genotypes were not also associated with the clinicopathological parameters of UC, Conclusions: This research suggests that COX1 promoter polymorphisms (T-1676C and A-842G/C507) may not be associated with the risk of developing ulcerative colitis in a Japanese population.

Toll-like receptors (TLRs) play important roles in the signaling of many pathogen-related molecules and endogenous proteins associated with immune activation. -196 to -174del polymorphism affects the TLR2 gene and alters its promoter activity. We investigated the influence of TLR2 -196 to -174del polymorphism on the risk of gastro-duodenal diseases, on the severity of Helicobacter pylori-induced gastritis in a Japanesepopulation. The study was performed on 309 patients with abdominal discomfort and 146 healthy controls. -196 to -174del polymorphism of TLR2 was investigated by allele-specific polymerase chain reaction method in all of the subjects. Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system in H. pylori-positive subjects (n = 156). Patients with abdominal discomfort was consisted of 80 gastric ulcers (25.9%), 38 duodenal ulcers (12.3%), five gastric + duodenal ulcers (1.6%), 105 patients with gastritis (34.0%) and 81 normal healthy stomachs (26.2%). We did not find any association between TLR2 polymorphism and risk of gastric ulcer, duodenal ulcer, gastric and duodenal ulcer and gastritis compared to healthy controls. However, the TLR2-196 to -174ins allele was associated with severity of intestinal metaplasia in more than 60 years of ages (P = 0.02). The same allele also increased the risks of developing more severe gastric mucosal atrophy and intestinal metaplasia in female subjects (P < 0.05, P = 0.07 respectively). No association was observed between TLR2 polymorphism and severity of neutrophil and mononuclear cell infiltration. Our data suggest that the TLR2-196 to -174ins allele was associated with more severe intestinal metaplasia in patients older than was correlated with severity of gastric mucosal atrophy and intestinal metaplasia in female subjects.

The role of genetics in the susceptibility to functional dyspepsia (FD) is not well established. Recently, two different associations were reported between FD and G-protein beta3 (GNB3) subunit gene polymorphism. We aim to clarify the association between GNB3 protein C825T polymorphism and dyspepsia in the Japanese population. Eight-nine dyspeptics and 94 nondyspeptic subjects enrolled in this study. All subjects underwent gastroscopy and patients with significant upper gastrointestinal findings were excluded. Other diseases were also excluded by face-to-face history and physical examination. GNB3 protein C825T polymorphisms were determined by polymerase chain reaction-restriction fragment-length polymorphism. H. pylori infection status was examined by histology or antibody against H. pylori. Nonsignificant correlation was found between GNB3 protein homozygous 825T and unexplained dyspepsia (OR = 1.65, 95% CI: 0.87-3.13). However, among H. pylori-negative subjects, homozygous GNB3 protein 825T significantly increased the risk of dyspepsia (16.7% versus 40.5%; CC versus TT; OR = 5.10, 95% CI: 1.21-21.43, CC versus others; OR = 3.40, 95% CI: 1.16-9.93, respectively). This significant association remained after logistic regression analysis with adjustment for sex and age (CC versus TT; OR = 5.73, 95% CI: 1.27-25.82, CC versus others; OR = 3.08, 95% CI: 1.02-9.25). No significant correlation was found between GNB3 polymorphism and any dyspeptic symptoms. Our data suggest that the homozygous 825T allele of GNB3 protein is associated with dyspepsia in the H. pylori-negative Japanese population. The role of genetics in the development of dyspepsia needs further evaluation.

Activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to inhibit the proliferation of gastric cancer cells. A common polymorphism at codon 12 of this gene (Pro12Ala) has been shown to confer protection against diabetes and colorectal cancer. We investigated the influence of PPAR gamma gene Plo12Ala polymorphism on the risk of gastric cancer and on the severity of Helicobacter pylori-induced gastritis as well as impaired fasting glucose (IFG) in Japanese. About 215 patients with gastric cancer (GC) and 201 patients without GC enrolled in this study. Plo12Ala polymorphism of PPAR gamma was investigated by PCR-RFLP in all of the subjects. The gastritis score of noncancerous antral mucosa was calculated by the updated Sydney system. The diagnosis of IFG was based on repeated evidence of serum fasting glucose (SFG) concentration of greater than or equal to 110 mg/dl. The Plo12Ala genotype of PPAR gamma showed a significantly higher frequency in GC patients than in controls (OR = 2.43; 95%CI = 1.04-5.67). In contrast, the Plo12Ala genotype held a lower risk of IFG (OR = 0.33; 95%CI = 0.13-0.83). The same genotype was associated with an increased risk of non-cardiac gastric cancer (OR = 2.39; 95%CI = 1.02-5.65), lower third gastric cancer (OR = 3.56; 95%CI = 1.31-9.71), advanced cancer (OR = 2.93; 95%CI = 1.13-7.58), and Lauren's intestinal cancer (OR = 2.94; 95%CI = 1.13-7.66). Among 151 gastric cancer subjects, the atrophy and metaplasia scores of the antral mucosa adjacent to cancer showed a tendency to be higher in those with the12Ala allele. Our study suggests that the PPAR gamma Pro12Ala polymorphism may be a shared risk marker of both IFG and gastric cancer in Japanese.

Background. The relationship between endoscopic appearances such as endoscopic gastritis and duodenitis and dyspeptic symptoms has not been clearly demonstrated. We aimed to clarify the association of endoscopic appearances with Helicobacter pylori infection, histological severity of gastritis, and dyspeptic symptoms in a Japanese population. Methods. We enrolled 87 dyspeptic and 93 nondyspeptic subjects in this study. All subjects underwent gastroscopy, and patients with active peptic ulcer disease, reflex esophagitis with erosion, polyps > 1 cm, or cancer were excluded. Endoscopic appearances in patients with dyspeptic symptoms and in those without were assessed retrospectively on the basis of endoscopic images. The degree of atrophy by the Kimura-Takemoto classification system was also assessed. Helicobacter pylori infection status was examined by histology or antibody against H. pylori. Histological severity of inflammation and glandular atrophy in the antrum were assessed according to the updated Sydney System. The odds ratio (OR) and 95% confidence interval (CI) were calculated by logistic regression using the variables age, sex, H. pylori infection status, and all endoscopic appearances. Results. The degree of atrophy tended to be lower among dyspeptic patients (P = 0.06). Among all endoscopic appearances, the liner redness (friability) in the antrum (OR = 3.90, 95% CI = 1.20-12.64) and duodenal ulcer (DU) scarring (OR = 3.41, 95% CI = 1.08-10.79) were independently associated with dyspepsia. Histological severity of inflammation and glandular atrophy were not associated with dyspeptic symptoms. Also, no correlation was found between endoscopic appearances and any of the different subgroups of dyspeptic symptoms. Patients with friability in the antrum and DU scar, which correlated with dyspeptic symptom showed some of communal symptoms such as epigastric pain, epigastric discomfort, hypochondriac pain, early satiation/postprandial fullness, and belching, but they differed considerably with respect to H. pylori positivity and the histological severity of gastritis. Conclusions. Some endoscopic appearances such as friability in the antrum and DU scarring may be associated with dyspeptic symptoms, and endoscopic appearances may be useful markers to perform clinical implementation reflecting an individual's pathophysiology of dyspeptic symptoms.

Inflammatory changes in the gastric mucosa are commonly observed in Japanese patients with functional dyspepsia (FD). However, detailed data regarding the relationship between the genetic regulatory factors of inflammation and FD are not available. CD14 is an important mediator of the inflammatory response in the first line of host defense by recognition of Lipopolysaccharide (LPS). We aimed to investigate the association between CD14 promoter C-159T polymorphism and FD in a Japanese population. 108 patients with FD and 99 non-dyspeptic subjects enrolled in this study. Dyspeptic symptoms were divided according to Rome III criteria. CD14 gene C-159T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism. In the non-dyspeptics, the CD14 genotype distribution was 28CC (28.3%), 51CT (51.5%), 21TT (21.2%). Meanwhile, the CD14 genotype distribution in FD was 31CC (28.4%), 56CT (51.4%), 22TT (20.2%). The genotype distribution was not significantly different. There was no significant difference between two groups in the genotype distribution. We did not found any association between CD14 genotypes and dyspeptic patients in different gender and Helicobacter pylori infection status. No significant association was also found between CD14 polymorphism and any of different subtypes of FD according to Rome III while there was a weak correlation between TT genotype and PDS in male subjects (TT vs others, OR = 3.18, 95% CI = 0.98-10.26, p = 0.06). In conclusion, our results suggest that CD14 polymorphism is unlikely to associate with susceptibility of dyspeptic symptoms. The role of inflammation related-gene polymorphisms to the development of dyspepsia needs to further evaluation.

Background/Aims: Transcription factor Nrf2 regulates the expression of detoxifying and antioxidant genes. Three promoter polymorphisms of this gene have been identified. This study attempted to clarify the relationship between Nrf2 gene polymorphism and ulcerative colitis in a Japanese population. Methodology: The study was performed in 89 patients with ulcerative colitis (mean age: 40.2 years, M:F=47:42) and 141 healthy volunteers (mean age: 38.7 years, M:F=75:66). The PCR-SSCP method was employed to detect Nrf2 polymorphisms using DNA extracted from peripheral blood cells. Results: Comparison of genotype frequency, -686 . -684 A . G/A . G genotype was significantly lower in the UC group than those in the HC group (OR=0.45, 95%CI:0.22-0.93, p=0.029) and G.G carrier was higher in the UC group, especially in female subjects. Furthermore, -686 . -684 G-G carrier was more closely associated with chronic continuous phenotype (OR=2.57, 95%CI:1.01-6.60, p=0.043). On the other hand, no association between -650 genotype and ulcerative colitis was found. Conclusions: The -686 . -684 genotype of Nrf2 gene may be associated with the development of ulcerative colitis.

Background/Aims: Three gene polymorphisms of Nrf2, which regulate the expression of detoxifying and antioxidant genes, have been identified. We attempted to clarify the relationship of these polymorphisms with the carcinogenesis in the stomach. Methodology: The study was performed in 209 patients with gastric cancer and 198 patients with no evidence of gastric malignancies on upper gastroduodenal endoscopy. We employed PCR-SSCP method to detect gene polymorphisms. Results: Overall, both polymorphisms at position of -686/-684 and -650 were not significant risk factors of carcinogenesis in the stomach. However, the -686/-684 A/G allele carrier had a significantly reduced risk for gastric carcinogenesis (p=0.022), especially of diffuse type (p=0.020), in H. pylori-negative cases. The activity and inflammation scores in Nrf2 -686/-684 A/G carriers were significantly lower than those in the non-A/G carriers (p=0.038 and p=0.019, respectively). Conclusions: The -686/-684 haplotype of Nrf2 gene may be associated with the development of gastric inflammation and with gastric carcinogenesis without the influence of H. pylori infection, although overall association with gastric carcinogenesis seems to be none.

We investigated the association between ulcerative colitis (UC) and polymorphisms of IL-17A (rs2275913, G-197A) and IL-17F (rs763780, 7488T/C) genes. We employed the multiplex PCR-SSCP method to detect gene polymorphisms. Both the numbers of -197A (IL-17A) and 7488T (IL-17F) alleles were significantly correlated to the development of UC. The frequencies of -197A/A and 7488T/T genotypes in the UC group were significantly higher than those in the non-UC group. An adjusted analysis revealed that -197A and 7488T alleles were independent risk factors for the developing UC. In addition, both polymorphisms were significantly associated with the pancolitis phenotype. Furthermore, -197A allele was significantly correlated to the chronic relapsing phenotype and -197A/A homozygote was more frequent in steroid-dependent cases, whereas 7488T allele was correlated with the chronic continuous phenotype. Our results provided the first evidence that -197A (IL-17A) and 7488T (IL-17F) alleles may influence the susceptibility to and pathophysiological features of UC independently.

Aberrant promoter methylation is an important mechanism for gene silencing. Inflammation-related reactive oxygens contribute to this CpG island methylation. The nuclear factor-erythroid 2-related factor 2 gene (Nrf2) is known to regulate the expression of detoxifying and antioxidant genes. We investigated the relationship between promoter polymorphisms of Nrf2 gene and the CpG island methylation in non-cancerous gastric mucosa. The study was performed in 85 subjects (46 without gastric malignancies, non-GC group, and 39 with gastric cancer, GC group). The promoter methylation status of p14(ARF), p16(INK4a) and p21(Wafl) genes was determined by methylation-specific-polymerase chain reaction. The Nrf2 gene genotypes were determined by the PCR-SSCP method. In the 85 subjects, CpG island methylation was found in 25.9% for p14, 15.3% for p16, none for p21. The frequency of the methylated genes was significantly higher in GC group than non-GC group (OR, 2.67; 95% CI, 1.10-6.49; p=0.029). In particular, the frequency of p16 gene methylation was much higher in GC group (p=0.0023). The Nrf2 -686/-684 G/G haplotype was positively associated and A/G haplotype was inversely associated with the development of CpG island methylation, especially p14 gene methylation (OR, 3.28; 95% Cl, 1.26-8.59; p=0.015, and OR, 0.38; 95% CI, 0.15-0.96; p=0.040, respectively). In Helicobacter pylori (H. pylori) infected subjects, the number of -686/-684 G/G allele was positively correlated and that of A/G allele was inversely correlated to the methylation status, especially p14 methylation, by the adjusted analysis (OR, 2.90; 95% CI,

The macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator. Two functional polymorphisms have been identified in the promoter region of the MIF gene. We attempted to clarify the associations of these polymorphisms with the development of gastric cancer. The study was performed in 229 patients with gastric cancer and 428 subjects with no evidence of gastric malignancies on the upper gastro-duodenal endoscopy. The severity of histological chronic gastritis was classified according to the updated Sydney system. Overall, the 5-CATT carriers had a reduced risk of developing gastric cancer (OR, 0.67; 96% CI, 0.480.93; p=0.015), especially the diffuse type cancer. In subjects >60 years, the adjusted risk for gastric cancer among individuals who were -173C carriers was 1.71 (range, 1.03-2.84; p=0.038) compared to the G/G homozygous genotype. The number of 7-CATT alleles was also positively correlated with the development of intestinal type gastric cancer (adjusted OR, 1.70; 95% CI, 1.02-2.58; p=0.043). In subjects <60 years, the 7/7-CATT homozygous genotype was linked with a risk for the progression of atrophic gastritis (adjusted OR, 8.74; 95% CI, 1.31-58.6; p=0.026). In addition, the number of 7-CATT alleles was significantly correlated with the activity and inflammation scores (p=0.010 and 0.030, respectively). Our results suggested that functional promoter polymorphisms of the MIF gene are associated with the progression of gastric mucosal inflammation and the development of mucosal atrophy at an early stage in life and these genotypes

Transcription factor Nrf2 regulates the expression of detoxifying and antioxidant genes. Three promoter polymorphisms of this gene have been identified. We attempted to clarify the association of these polymorphisms with the development of peptic ulcer diseases. The study was performed with 384 stocked DNAs obtained from subjects with no evidence of gastric malignancy. In all 384 DNAs, 77 and 48 were obtained from gastric and duodenal ulcer patients, respectively. By an unadjusted analysis, infection with Helicobacter pylori (H. pylori), male gender and the -686/ -684 G/G carrier (OR, 2.52; 95% CI, 1.19-5.45; p=0.016) were associated with a significantly increased risk for developing gastric ulcer, whereas the -686/-684 A/G homozygote was linked to a significantly reduced risk for developing gastric ulcer (OR, 0.26; 95% CI, 0.099-0.67; p=0.0055). On the other hand, infection with H. pylori and male gender were significantly associated with the development of duodenal ulcer, whereas Nrf2 promoter polymorphisms were not. By the analysis, after adjustment for age, gender, non-steroidal anti-inflammatory drug/aspirin use and H. pylori infection status, the -686/-684 A/G homozygote was associated with a significantly reduced risk for gastric ulcer (OR, 0.25; 95% CI, 0.088-0.73; p=0.01 1). Our results suggest that promoter polymorphisms of the Nrf2 gene are associated with the susceptibility to gastric ulcer.

Toll like receptors (TLR) play important roles in the signaling of many pathogen-related molecules and endogenous proteins associated with immune activation. The -196 to -174del polymorphism affects the TLR2 gene and alters its promoter activity. We investigated the influence of the TLR2-196 to -174del polymorphism on the occurrence of non-cardiac gastric cancer (NCGC) in a Japanese population. The study was carried out with 289 patients with NCGC, 309 non-cancer patients with abdominal discomfort and 146 healthy controls. The -196 to -174del TLR2 polymorphism was investigated using the allele-specific polymerase chain reaction method in all of the subjects. The -196 to -174del/del genotype of TLR2 showed a significantly higher frequency in NCGC patients than in healthy controls (adjusted odds ratio [OR] = 6.06; 95% confidence interval [CI] = 1.86-19.72). Similarly, the frequency of the -196 to -174del/del genotype was significantly higher among NCGC patients than in non-cancer patients (adjusted OR = 2.02; 95% CI = 1.22-3.34). The same genotype was associated with an increased risk of both intestinal (OR = 2.00, 95% CI = 1.12-3.60) and diffuse-type (OR = 2.05; 95% CI = 1.11-3.79) histopathology. There were no significant associations between TLR2 genotypes and tumor stage and anatomical location. Our data suggest that the -196 to -174del/del genotype of TLR2 may increase the risk of gastric cancer in the Japanese population.

Inflammatory changes in the gastric mucosa are commonly observed in Japanese patients with functional dyspepsia (FD). However, detailed data regarding the relationship between the genetic regulatory factors of inflammation and FD are not available. We investigated the associations between FD and genetic polymorphisms. of molecules associated with inflammation or immune response (IL-17A, -17F and MIF). The study was performed with 278 subjects (188 with no upper abdominal symptoms and 90 with FD according to the Roma III criteria). We employed the PCR-SSCP (multiplex PCR for IL-17A and -17F) method to detect the gene polymorphisms. Overall, the polymorphisms of the IL- 17A, - 17F and MIF genes were not correlated with the susceptibility to FD. However, the MIF -173C allele carrier had a significantly increased risk for the development of epigastric pain syndrome (EPS) of FD (OR, 2.12; 95% CI, 1.00-4.49; p=0.0497). In Helicobacter pylori (H. pylori)infected cases, the number of IL-17F 7488T alleles was positively correlated with the development of EPS (OR, 11.3; 95% Cl, 1.23-103.2; p=0.032), while the IL-17F T/T homozygote and the MIF -173C carrier had an increased risk for EPS (OR, 10.4; 95% Cl, 1.17-92.3; p=0.036 and OR, 3.66; 95% Cl, 1.19-11.3; p=0.024, respectively). In addition, a significant interaction between the IL-17F 7488 polymorphism and H. pylori infection was shown to increase the activity and inflammation scores (p=0.043 and 0.042, respectively). There were no significant associations between the IL-17A polymorphism and FD. Our results provide the first evidence that the IL-17F and MIF gene polymorphisms are significantly associated with the development of FD, particularly EPS, a subgroup of FD, in H. pylori-infected subjects. The genetic polymorphisms of inflammation or immune response-related molecules are involved in the development of one of the FD subgroups via H. pylori-induced gastric inflammation.

Background and Aims: Host genetic factors play a key role in gastric carcinogenesis, but the mechanism has not been clarified. The multi-drug resistance 1 (MDR1) gene mediates the expression of P-glycoprotein, which has a role in active transport of various substrates, including xenobiotics, and thus has a protective function in various tissues and organs like gastrointestinal epithelial cells. C3435T polymorphism in exon 26 of the MDR1 gene influences P-glycoprotein expression and activity in the gastrointestinal tract. We investigated the influences of MDR1 gene polymorphism on the risk of gastric cancer. Method: The study was performed on 157 patients with gastric cancer (GC) and 104 patients without GC as the control group. C3435T polymorphism of MDR1 was investigated by PCR-RFLP in all of the patients. Results: The MDR1 3435 TT genotype showed a significantly higher frequency in controls than in GC patients (OR = 0.43; 95% CI = 0.23-0.79). There were no significant differences of the CT and CC genotype frequencies between GC patients and controls. We also found that the 3435TT genotype of MDR1 was associated with a lower risk of non-cardiac cancer (OR = 0.42; 95% CI = 0.23-0.79), middle-third cancer (OR = 0.36; 95% CI = 0.17-0.77), advanced cancer (OR = 0.31; 95% CI = 0.13-0.73), venous invasion (OR = 0.30; 95% CI = 0.10-0.91), and lymph node metastasis (OR = 0.28; 95% CI = 0.13-0.65). Conclusion: Our data suggest that 3435T/T polymorphism of MDR1 is associated with a reduced risk of gastric cancer in the Japanese population.

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator, which plays a pivotal role in inflammatory and immune diseases. We attempted to clarify associations of the functional polymorphisms of the MIF gene promoter with the development of chronic gastritis. The study was performed with 290 stocked DNAs from subjects with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. The severity of histological chronic gastritis in antral biopsy specimens was classified according to the updated Sydney system. Both the 7/7-CATT repeat at position -794 and the -173 C/C genotypes were significantly associated with a risk of developing severe gastric mucosal atrophy (OR, 9.69; 95% CI, 1.29-72.5; and OR, 4.60; 95% CI, 1.05-20.2, respectively). In subjects younger than 60 years old, the number of 7-CATT alleles was significantly correlated with both the activity and inflammation scores (p=0.0079 and 0.0080, respectively). Our results suggested that functional promoter polymorphisms of the MIF gene might be associated with the severity of gastric mucosal inflammation in younger subjects and with the subsequent development of mucosal atrophy.