Light blue crest and ridge/villous patterns in the uninvolved gastric antrum by magnifying NBI endoscopy correlate with serum pepsinogen and gastric cancer occurrence.

BACKGROUND/AIMS: Combining the magnifying endoscopy and the narrow-band imaging (NBI) system is an endoscopic imaging technique for the enhanced visualization of mucosal microscopic structure and capillaries of the superficial mucosal layer. Light blue crest (LBC) and, ridge/villous pattern have been thought to be suggestive signs for gastric intestinal metaplasia (IM) of magnifying NBI endoscopy. Since the IM is related to gastric cancer risk (GC), the prevalence of LBC and ridge/villous pattern in the nonneoplastic gastric antrum was examined in relation to gastric cancer (GC) risk and serological severity of gastritis. METHODOLOGY: In 100 subjects including 13 GC patients, gastric mucosal pattern were examined using magnifying NBI. The mucosal patterns in the antrum were classified according to the presence of LBC or ridge/villous pattern. Serum pepsinogen (PG) levels were also examined. RESULTS: The sensitivity and specificity for predicting IM was the best when LBC and ridge/villous patterns were combined (sensitivity 95.2%, specificity 98.7%). Both LBC and ridge/villous pattern showed lower serum PGI and PGI/II ratio than those without (P = 0.046, 0.0005, respectively.) In particular, PGI/II ratio was lowest in ridge/villous pattern. The LBC and ridge/villous pattern showed higher incidence of all GC and diffuse GC compared to those without (P = 0.002, 0.002, respectively). CONCLUSIONS: LBC and ridge/villous pattern in uninvolved gastric antrum by magnifying NBI endoscopy are useful signs for predicting gastric atrophy in the entire stomach and GC risk.

Correlation between magnifying narrow band imaging and histopathology in gastric protruding/or polypoid lesions: a pilot feasibility trial.

BACKGROUND: Several study showed usefulness of microscopic capillaries, seen by magnifying narrow band imaging (NBI) endoscopy for predicting histopathology among superficial depressed or flat elevated gastric neoplasia (GN). Here we assessed the diagnostic efficacy of magnifying NBI for predicting histopathology among gastric protruding/or polypoid lesions. METHODS: Using endoscopic pictures of magnifying NBI from 95 protruding/or polypoid lesions (19 fundic gland polyps: FGP, 47 hyperplastic polyps: HP, and 29 GN), fine mucosal patterns were classified into four categories: small round, prolonged, villous or ridge, and unclear patterns, and micro vascular patterns were classified into five categories: honey comb, dense vascular, fine net work, core vascular, and unclear patterns. RESULTS: Most suggestive micro vascular patterns for predicting FGP, and HP were honeycomb (sensitivity 94.7%, specificity 97.4%), and dense vascular patterns (sensitivity 93.6%, specificity 91.6%), respectively. Fine net work, core vascular, and unclear patterns presented higher specificity (97%, 100%, and 100%) for predicting GN, and diagnostic efficacy of combined of those patterns was favorable (sensitivity 86.2%, specificity 97.0%). CONCLUSION: Micro vascular patterns by using magnifying NBI provides meaningful information for predicting the histopathology of gastric protruding/or polypoid lesions.

Presence of minimal change esophagitis closely correlates with pathological conditions in the stomach.

INTRODUCTION: It is suggested that minimal change (grade M) esophagitis is a spectrum of gastric acid reflux disease. We evaluated the clinical significance of grade M esophagitis, including its subtypes (reddish change: MR and whitish change: MW), especially with attempt to pathological conditions in the stomach that relates to gastric acid secretion. MATERIALS AND METHODS: Using 241 subjects undergoing esophagogastroduodenoscopy for various indications, we investigated the association between grade M esophagitis with histological and serological severity of gastritis and endoscopic degree of atrophy. We also examined its association with ulcer diseases and various symptoms. RESULTS: When grade M cases were divided into MR and MW, all MR cases had MW in considerable degrees. Dyspeptic symptoms were more likely to be associated with H. pylori negative grade M cases, while presence of duodenal ulcer and its scar were associated with Helicobacter pylori-positive grade M cases. In all subjects, histological parameters, especially in the corpus, were lower in grade M cases compared to normal appearance. In grade M cases, degree of acute and chronic inflammation, and atrophy in corpus were lowest in cases that have grade MR. Grade M cases were also associated with higher pepsinogen I/II ratio and lower endoscopic atrophy. CONCLUSIONS: Pathological conditions of the stomach relate to higher gastric acid secretion correlates with grade M esophagitis. In grade M cases, appearance of MR may reflect higher gastric acid secretion or severe acid reflux than cases that have grade MW only.

Role of heat-shock protein (HSP) 70-2 genotype in peptic ulcer in Japanese population.

BACKGROUND/AIMS: There have been reports showing the protective role of inducible heat-shock protein (HSP) 70 in gastric epithelial cells. An A to G transition at the 1267 position HSP70-2 gene has been shown to be associated with a different level of HSP70 mRNA expression. We aimed to clarify the effect of HSP70-2 polymorphism on the risk of peptic ulcer diseases in a Japanese population. METHODOLOGY: A total of 519 subjects participated in this study. All subjects underwent upper gastroscopy. Restriction fragment length polymorphism analysis was performed for polymorphisms at 1267 of HSP70-2 gene in all the subjects. RESULTS: After gastroscopy, 109, 53 and 357 subjects were diagnosed as gastric ulcer, duodenal ulcer and non-ulcer subjects, respectively. Although, there were no significant differences of HSP70-2 genotype distributions among nonulcer subjects, overall ulcer, gastric and duodenal ulcers when the subjects were divided into two groups according to age distribution, logistic regression analysis showed that the BB genotype increased the risk of duodenal ulcer in subjects 60 years and older. (Gender, status of H. pylori infection and NSAID use adjusted OR=3.12, 95%CI=1.33-7.35, p=0.009). CONCLUSIONS: It appears that polymorphism of HSP70-2 gene is not directly associated with the susceptibility to peptic ulcer diseases but BB genotype is associated with an increased risk of duodenal ulcer in older subjects in the Japanese population.

Examination of serum pepsinogen in functional dyspepsia.

BACKGROUND/AIMS: Although serum pepsinogen (PG) is considered as a marker of gastric atrophy, it also reflects gastric acid secretion, which closely influences dyspeptic symptoms. We investigated serum PG levels and PGI/PGII ratios in dyspeptic patients, in relation to various different subtypes of symptoms including Rome III classifications. METHODOLOGY: Serum PGs were measured in 75 subjects with dyspeptic symptoms and 42 asymptomatic healthy subjects. RESULTS: PG II level was significantly higher (p=0.0001) and PG I/II ratio was significantly lower (p<0.0001) in subjects with H. pylori infection than those without, while no associations were found between PG levels and usage of H2 receptor antagonists or proton-pump inhibitors. In all subjects with pain in stomach, abdominal bloating and PDS-like symptoms according to Rome III criteria, presented significantly higher levels of PGI, compared to subjects without symptoms (p=0.043, 0.015 and 0.037, respectively). In addition, burning sensation and abdominal pain presented significantly higher PGI/II ratios (p=0.0005 and 0.003, respectively), and higher PGI/II ratio was also positively correlated with a number of symptoms (p=0.04). When subjects were divided according to H. pylori infection status, higher PGI/II ratio was significantly associated with abdominal pain in H. pylori negative subjects (p=0.03), while higher PGI level was significantly associated with functional esophageal disorders (FEG) according to Rome III criteria, and higher number of dyspeptic symptoms in H. pylori positive subjects (p=0.016). CONCLUSIONS: Our data suggest that subjects with higher PGI level, and PG I/II ratio are more likely to develop several dyspeptic symptoms.

Synergistic effect of IL-1ß and TNF-α polymorphisms on the H. pylori-related gastric pre-malignant condition.

BACKGROUND/AIMS: We investigated the effect of IL-1ß and TNF-α polymorphisms, and its synergistic effect with age, gender and H. pylori status on the gastric pre-malignant condition. METHODOLOGY: IL-1ß-31(T>C) and -511(C>T) and TNF-α-857 (C>T) polymorphisms were genotyped in 123 cancer free subjects. Degree of histological gastritis in both antrum and corpus, and extension of endoscopic gastric atrophy were also evaluated. RESULTS: Significant associations were found between degrees of mononuclear cell infiltration (p=0.007) and atrophy (p=0.01) in the antrum with IL-1ß-31(T>C) polymorphism, and degree of endoscopic gastric atrophy with both IL-1ß-31(T>C), -511(C>T) polymorphisms (p=0.03, 0.04, respectively). When subjects were divided into the 3 groups according to the histological severity of gastric mucosal atrophy: the non-atrophic gastritis (NA) group (atrophy score=0 and metaplasia score=0), the severe atrophic gastritis (SA) group (atrophy score>=2 or metaplasia score>=2), and the mild atrophic gastritis (MA) group (all others), synergistic effect was found between numbers of IL-1ß-31C, IL-1ß-511T variant alleles with co-factors on the development of gastric atrophy in the antrum (gender + H. pylori + number of IL-1ß-31C allele: p=0.001, age + gender + H. pylori + number of IL-1ß-31C allele: p=0.0008, gender + H. pylori + number of IL-1ß-511T allele: p=0.016, age + gender + H. pylori + number of IL-1ß-511T allele: p=0.013), while such association was found for TNF-α-857 T allele in the antrum and all genotypes in the corpus. CONCLUSIONS: IL-1ß-31C, IL-1ß-511T variant alleles may accelerate gastric mucosal inflammation and atrophy, not only by themselves, but also through the interaction with co-factors.

Association study of common genetic variants in pre-microRNAs in patients with ulcerative colitis.

BACKGROUND: Common single-nucleotide polymorphisms (SNPs) in microRNAs (miRNA) have been shown to be associated with susceptibility to several human diseases. We evaluated the associations of three SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (miR-196a2, miR-146a, and miR-499) with the risk of ulcerative colitis (UC) in a Japanese population. METHODS: The rs11614913 (T > C), rs2910164 (C > G), and rs3746444 (A > G) SNPs were genotyped in 170 UC and 403 control subjects. RESULTS: The rs3746444 AG genotype was significantly higher among the UC group (odds ratio (OR) = 1.51, 95% CI = 1.03-2.21, p = 0.037). The rs3746444 AG genotype was associated with onset at an older age (OR = 1.70, 95% CI = 1.04-2.78, p = 0.035), left-sided colitis and pancolitis (left-sided colitis, OR = 2.10, 95% CI = 1.12-3.94, p = 0.024; pancolitis, OR = 1.81, 95% CI = 1.09-3.01, p = 0.028, left-sided colitis + pancolitis, OR = 1.91, 95% CI = 1.26-2.92, p = 0.003), higher number of times hospitalized (OR = 2.63, 95% CI = 1.22-5.69, p = 0.017), steroid dependence (OR = 2.63, 95% CI = 1.27-5.44, p = 0.014), and refractory phenotypes (OR = 2.76, 95% CI = 1.46-5.21, p = 0.002) while the rs3746444 AA genotype was inversely associated with the number of times hospitalized (2∼, OR = 0.36, 95% CI = 0.17-0.79, p = 0.012), steroid dependence (OR = 0.42, 95% CI = 0.21-0.88, p = 0.021), and refractory phenotypes (OR = 0.38, 95% CI = 0.20-0.72, p = 0.003). The rs1161913 TT genotype also held a significantly higher risk of refractory phenotype (T/T vs. T/C + C/C, OR = 2.21, 95% CI = 1.17-4.18, p = 0.016). CONCLUSIONS: Our results provided the first evidence that rs3746444 SNP may influence the susceptibility to UC, and both rs3746444 and rs11614913 SNPs may influence the pathophysiological features of UC.

Effect of polymorphisms of IL-1ß and TNF-α genes on CpG island hyper methylation (CIHM) in the nonneoplastic gastric mucosa.

CpG island hyper methylation (CIHM) is one of the major events in gastric carcinogenesis. To evaluate the influence of host genetic factors in CIHM related carcinogenesis, we investigated the association between common polymorphisms in IL-1ß and TNF-α genes, with CIHM status in the nonneoplastic gastric mucosa. Polymorphisms in the IL-1ß gene (-31T>C and -511C>T) and the TNF-α gene (-857C>T) were genotyped in 385 cancer-free subjects. CIHM of four candidate genes: p16 (INK4a), p14 (ARF), E-cadherin (CDH1), and death-associated protein kinase (DAP-kinase), were determined by methylation-specific-polymerase chain reaction (MSP). CIHM high was defined as two or more CpG islands methylated. CIHM of all four genes and CIHM high were significantly associated with Helicobacter pylori infection status. In over all, significant marginal association was found between IL-1ß-511 TT genotype and reduced susceptibility to CIHM of DAP-kinase (adjusted OR = 0.48, 95% CI = 0.29-0.78) and CIHM high (adjusted OR = 0.53, 95% CI = 0.32-0.86). This association was more enhanced in subjects 65 yr or younger age. We also found positive association between TNF-α-857T carrier and increased susceptibility to CIHM of CDH (adjusted OR = 1.78, 95% CI = 1.01-3.16), and CIHM high (adjusted OR = 1.86, 95% CI = 1.04-3.33) in the same generation. The mean number of CIHM was lower in subjects with IL-1ß-511TT genotype, while the mean number was higher in subjects with TNF-α-857 T carrier especially in subjects 65 yr and younger patients. IL-1ß-511 TT genotype is associated with reduced susceptibility to CIHM especially in younger generation. Furthermore, the TNF-α-857T carrier is associated with increased susceptibility of CIHM in the same generation.

Usefulness of magnifying narrow-band imaging endoscopy in the Helicobacter pylori-related chronic gastritis.

Combining the narrow-band imaging (NBI) system and magnifying endoscopy allows simple and clear visualization of microscopic structures of the superficial mucosa and its capillary patterns, which may be useful for precise endoscopic diagnosis in the gastrointestinal tract, being more closely to histopathological diagnosis. In the non-neoplastic gastric mucosa, there have been reports showing a potential usefulness of magnifying NBI for the diagnosis of Helicobacter pylori infection, degree of histological gastritis, and intestinal metaplasia. We have shown that magnifying NBI appearances in the non-neoplastic gastric mucosa also predicts pepsinogen levels, which indicates extension of gastric atrophy in the entire stomach, and gastric cancer occurrence. Furthermore, we have shown that magnifying NBI appearances predicts the result of H. pylori treatment. Clear visualization of fine mucosal and capillary patterns, obtained by magnifying NBI, allows prediction of the histological condition, more in detail without biopsy, and it may also be useful for less invasive, and cost-effective endoscopic gastric cancer surveillance, and prediction of H. pylori eradication.

Increased number of CpG island hypermethylation in tumor suppressor genes of non-neoplastic gastric mucosa correlates with higher risk of gastric cancer.

BACKGROUND/AIM: We investigated the relationship of gastric cancer (GC) and CpG island hypermethylation (CIHM) in tumor suppressor genes of non-neoplastic gastric mucosa. METHODS: Gastric mucosa samples were obtained from 125 GC and 180 non-GC subjects. CIHM of p14, p16, DAP-kinase and CDH1 genes were determined by methylation-specific polymerase chain reaction. High CIHM was defined as three or all methylated CpG islands. RESULTS: Rates of CIHM of p14, CDH1, DAP-kinase, and high CIHM were significantly higher in all GC samples than non-GC samples (p14: 32.2 vs. 50.4%; OR = 1.70, 95% CI = 1.03-2.80, p = 0.04, CDH1: 36.1 vs. 84.0%; OR = 8.65, 95% CI = 14.74-15.77, p < 0.0001, DAP-kinase: 42.2 vs. 83.2%; OR = 5.98, 95% CI = 3.37-10.62, p < 0.0001, and high CIHM: 44.4 vs. 80.8%; OR = 4.40, 95% CI = 2.51-7.72, p < 0.0001). CIHM in CDH1 and DAP-kinase were associated with a greater risk of GC including all of its different subtypes. An increased number of CIHM was associated with an increased risk of all GC (1 CIHM; OR = 2.33, 95% CI = 0.82-6.64, p = 0.11, 2 CIHM; OR = 4.89, 95% CI = 1.79-13.37, p = 0.002, 3 CIHM; OR = 9.43, 95% CI = 3.20-27.78, p < 0.0001, and all CIHM OR = 24.71, 95% CI = 6.70-91.18, p < 0.0001). Three and all CIHM were closely associated with a higher risk of intestinal-type GC, Helicobacter pylori-positive infection status, male gender, and middle and older GC while 3 CIHM was closely associated with a higher risk of diffuse-type GC, H. pylori-negative infection status and younger GC. CONCLUSIONS: CIHM of CDH1 and DAP-kinase in non-neoplastic gastric mucosa corresponded to a risk of GC regardless of histological subtype, H. pylori infection status, gender and generation. An increased number of CIHM correlates with a higher GC risk including its various clinico-pathological subtypes.

Chronic aspirin use suppresses CDH1 methylation in human gastric mucosa.

There have been reports showing a protective role of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) against gastrointestinal cancers. E-cadherin (CDH1) is an adhesion molecule involved in tumour invasion/metastasis. Silencing of CDH1 by promoter CpG island methylation was shown in gastric cancer, precancerous lesion, and Helicobacter pylori-infected chronic gastritis. We investigated the methylation status of CDH1 in noncancerous gastric mucosa in chronic aspirin user, and assessed its effect on methylation-associated carcinogenesis. Gastric mucosa samples from antrum were obtained from 217 cancer-free subjects, including 37 chronic aspirin users and 180 subjects with no history of chronic or occasional intake of aspirin. Methylation-specific polymerase chain reaction (PCR), i.e., MSP, was performed for CDH1 gene promoter. In all 217 subjects, CDH1 methylation was detected for 69 subjects (31.7%). CDH1 methylation more frequently occurred in H. pylori-infection-positive subjects (P < 0.0001), while chronic aspirin users had a significantly lower risk of CDH1 methylation [nonuser versus user 36.1% versus 10.8%; odds ratio (OR) = 0.21, 95% confidence interval (CI) = 0.07-0.63, P = 0.005]. Logistic regression analysis showed that chronic aspirin use was the independent factor for lower risk of CDH1 methylation (adjusted OR = 0.21, 95%CI = 0.07-0.66, P = 0.008). Chronic aspirin use was associated with lower risk of CDH1 methylation in H. pylori-positive subjects (nonuser versus user 49.5% versus 19.0%; OR = 0.24, 95%CI = 0.08-0.76, P = 0.01). Similar trend was also found in H. pylori-negative subjects (P = 0.07). No association was found between CDH1 methylation status, and duration and dose of aspirin. Our data suggest that chronic aspirin use is associated with reduced risk of CDH1 methylation in human gastric mucosa. Aspirin may have suppressive role against methylation-related gastric carcinogenesis.

Association between cyclin D1 polymorphism with CpG island promoter methylation status of tumor suppressor genes in gastric cancer.

BACKGROUND: CpG island hypermethylation of tumor suppressor genes is highly involved in gastric carcinogenesis, and enhanced cell proliferation could accelerate this process. Cyclin D1 regulates cell cycle function and may play a role in methylation-related carcinogenesis. AIMS: We investigated the association between Cyclin D1 gene G870A polymorphism and the methylation status of tumor suppressor genes in gastric cancer. METHODS: Polymorphisms at G870A in the Cyclin D1 gene were genotyped, and methylation status of the p14, p16, DAP-kinase, and CDH1 genes were determined by methylation-specific-polymerase chain reaction in 139 gastric cancer tissues. CIHM high was defined as three or more methylated CpG islands. RESULTS: Although no association was found between methylation status and different stages and Lauren's subtypes, patients with CIHM of DAP-kinase showed significantly worse survival than those without (p = 0.017). In addition, the number of methylated sites was also associated with survival curves (p = 0.0397). The 870G carrier a significantly lower prevalence of CIHM high compared to the AA genotype in advanced-stage gastric cancer (adjusted OR = 0.32, p = 0.047). A weak correlation between the same genotypes and CIHM of p14 were found in the same subtype (adjusted OR = 0.32, p = 0.052). The mean methylation number was significantly lower in G carriers than in AA genotypes in advanced-stage gastric cancer (p = 0.017). CONCLUSIONS: Genetic polymorphism of CCND1 is associated with CIHM status in gastric cancer, especially in the advanced stage, but is independent of clinico-pathological features.

Selenoprotein S (SEPS1) gene -105G>A promoter polymorphism influences the susceptibility to gastric cancer in the Japanese population.

BACKGROUND: Inflammation is a key factor in the process of carcinogenesis from chronic gastritis induced by Helicobacter pylori. Selenoprotein S (SEPS1) is involved in the control of the inflammatory response in the endoplasmic reticulum (ER). Recently the -105G>A polymorphism in the promoter of SEPS1 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 SEPS1 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 SEPS1 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 SEPS1 polymorphism.

Effect of MDR1 gene promoter methylation in patients with ulcerative colitis.

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.

Effect of polymorphisms in the 3'-untranslated region (3'-UTR) of VEGF gene on gastric pre-malignant condition.

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 assessed 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.

Promoter methylation of protease-activated receptor (PAR2) is associated with severe clinical phenotypes of ulcerative colitis (UC).

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 +/- 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 +/- 19.6% vs. 34.5 +/- 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.

Protective role of genetic polymorphism of heat shock protein 70-2 for gastric cancer risk.

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.

Effect of RANTES promoter genotype on the severity of intestinal metaplasia in Helicobacter pylori-infected Japanese 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 +/- 1.02 vs. 0.83 +/- 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 +/- 1.03 vs. 0.41 +/- 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.

MTHFR 677T carrier influences the methylation status of H. pylori-infected gastric mucosa in older subjects.

DNA methylation is one of the major events in the early process of gastric carcinogenesis and it also occurs in non-neoplastic gastric mucosa. MTHFR plays a central role in biotransformation of folate to form S-adenosylmethionine, the universal methyl donor in cells and affects DNA methylation status. We investigated the association between common functional polymorphism of MTHFR C677T and DNA methylation status in H. pylori-infected non-neoplastic gastric mucosa. For 99 gastric mucosa samples from H. pylori positive non-cancer subjects, we assessed the association between MTHFR C677T genetic polymorphism and promoter methylation status of the four candidate promoters (p14, p16, DAP-kinase, and CDH1). In most all of the subjects, weak correlation was found between the p16 promoter methylation and MTHFR 677T carriers (age, sex-adjusted OR = 2.57, P = 0.053). When subjects were divided into two groups according to age, the MTHFR T carrier held a significantly higher risk of p16 promoter methylation, especially in 66 years or older generation (sex-adjusted OR = 14.28, P = 0.02). In addition, mean number of methylated CpG cites were significantly higher in T carrier than CC genotype in the same generation (P = 0.0418). Our data suggest that MTHFR 677T carrier influences the risk of DNA methylation in gastric mucosa in the long-term outcome of the H. pylori infection.

779 TC of CCK-1 intron 1 is associated with postprandial syndrome (PDS) in Japanese male subjects.

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.