Endoscopic features of lymphoid follicles in the colonic mucosa using the image enhanced endoscopy and its association with colorectal adenoma.

BACKGROUND/AIM: Lymphoid follicles hyperplasia (LH) is sometimes observed in the normal colon as small, round, yellowish-white nodules. LH is associated with food hypersensitivity and bowel symptoms and histologically characterized as intense infiltration of lymphocytes or plasmacytes. It is suggested that LH represents inflammatory immune response in the colonic mucosa. We investigated the presence of LH in the normal colonic mucosa and its association with incidence of colorectal lesions including colorectal cancer, adenoma and hyperplastic polyp. PATIENTS/METHODS: 605 participants undergoing colonoscopy for various indications were enrolled. Presence of LH in the proximal colon (appendix, cecum and the ascending colon) was observed using the blue laser imaging (BLI) endoscopy, a new generation image enhanced endoscopy (IEE) system. LH was defined as well demarcated white nodules. Elevated LH with erythema was distinguished as LH severe. Association between presence of LH and occurrence of colorectal lesions was investigated. RESULTS: Prevalence of all colorectal lesions and adenoma were significantly lower in LH severe group compared to the LH negative group (P = 0.0008, 0.0009, respectively). Mean number of all colorectal lesions and adenoma were also lower in LH severe group compared to the LH negative group (P = 0.005, 0.003 respectively). The logistic regression with adjustment for gender and age demonstrated that presence of LH severe held significantly lower risk of all colorectal lesions (OR = 0.48, 95%CI = 0.27-0.86) and adenoma (OR = 0.47, 95%CI = 0.26-0.86). CONCLUSION: LH in the colonic mucosa visualized by IEE is useful endoscopic finding to predict risk of colorectal adenoma.

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.

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.

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.

COMT gene Val158Met polymorphism influences the severity of intestinal metaplasia in H. pylori infected older subjects.

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 vs. Met/Met; 0.59 +/- 0.93 vs. 0.13 +/- 0.52, p = 0.052). Among H. pylori infected subjects, the degree of intestinal metaplasia was significantly lower among 158Met carriers in 50 years or older age (Val/Val vs. 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.

Oral spherical adsorptive carbon for the treatment of intractable anal fistulas in Crohn's disease: a multicenter, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Anal fistulas are common in individuals with Crohn's disease (CD). We sought to evaluate the efficacy of oral spherical adsorptive carbon (AST-120) (Kremezin; Kureha Corporation, Tokyo, Japan) for the treatment of intractable anal fistulas in patients with CD. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, patients with CD and at least one active anal fistula under treatment were assigned to receive either AST-120 or placebo for 8 wk. Improvement was defined as a reduction of 50% or more from baseline in the number of draining fistulas observed at both 4 and 8 wk. Remission was defined by closure of all draining fistulas at both 4 and 8 wk. The Perianal Disease Activity Index (PDAI) and Crohn's Disease Activity Index (CDAI) were also assessed. RESULTS: In total, 62 patients were randomized, of whom 57 received AST-120 (N = 27) or placebo (N = 30). The improvement rate in the AST-120 group (37.0%) was significantly greater than that in the placebo group (10.0%) (P= 0.025). The corresponding remission rates were 29.6% and 6.7%, respectively (P= 0.035). PDAI significantly improved at both 4 and 8 wk with AST-120, compared to placebo (P= 0.004 and P= 0.005, respectively). CDAI was also significantly improved at both 4 and 8 wk in the AST-120 group, compared to the placebo group (P= 0.007 and P= 0.001, respectively). AST-120 treatment was well tolerated and no life-threatening adverse events were observed. CONCLUSION: AST-120 is useful for the control of intractable anal fistulas in CD patients.

Aberrant DNA methylation in ulcerative colitis without neoplasia.

BACKGROUND/AIMS: DNA methylation has been reported to correlate with the development of colitis associated cancer. We detected the promoter methylation of estrogen receptor gene (ER), TP53, p14, p16, p21 and hMLH1 in ulcerative colitis without neoplasia. METHODOLOGY: A total of 49 specimens from 36 patients, including 36 at rectal inflammatory mucosa and 13 at terminal ileum were obtained by colonoscopic biopsies. Methylation specific polymerase chain reaction were performed to detect the methylation in promoters of the above six genes. RESULTS: Methylation rate of ER promoter was significantly higher in the rectal mucosa than that in the ileum (76.3% vs. 46.2%, P=0.044). Moreover, ER methylation in rectal mucosa was significantly higher in relapse-remitting type compared to one attack only type cases (P=0.008), and also increased in cases longer than 7 years (P=0.036). Methylation rates of p14 or p16 were higher in rectal mucosa than those in the ileum, but the differences were not of statistic significance. Meanwhile, methylation in TP53 promoter was found in only one case, while p21 and hMLH1 methylation were negative in all cases. CONCLUSIONS: Methylation in promoters of ER, p14 and p16 occurs in rectal inflammatory mucosa without neoplasia. Examination of ER methylation in rectal mucosa may be useful for predicting cases at high risk of neoplasia.

Polymorphism of peroxisome proliferator-activated receptor gamma is not associated to Japanese ulcerative colitis.

BACKGROUND/AIMS: Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) has been reported to be impaired in patients with ulcerative colitis (UC), and activation of PPARgamma is proved to inhibit the intestinal inflammation. As Plo12Ala polymorphism in codon 12 of the PPARgamma gene may decrease the promoter activity, we investigated the influences of PPARgamma polymorphism on the risk of UC in Japanese population. METHODOLOGY: The study recruited 118 patients with UC and 142 health controls. Plo12Ala polymorphisms of PPARgamma were detected by polymerase chain reaction based restricted fragment length polymorphism. RESULTS: The frequency of Pro/Alo heterozygotes of PPARgamma gene in UC and control group was 4.2% and 4.9%, respectively. No significant difference was found between UC and control group (P=1.00, Fisher's exact test). Plo12Ala genotype of PPARgamma did not show significant association with UC risk (OR=0.85, 95%CI=0.26-2.76). CONCLUSIONS: Our research suggests that Plo12Ala polymorphism of PPARgamma may not be associated with the risk of developing ulcerative colitis in Japanese population.

No association between a genetic variant of the p22PHOX component of NADPH oxidase C242T and ulcerative colitis.

BACKGROUND/AIMS: Reactive oxygen species has 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 459 healthy control (HC) subjects participated in this study. The p22PHOX C242T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: In the HC group, the p22 PHOX genotype distribution was 379C/C (82.6%), 79C/T (17.2%), and 5T/T (1.2%). Meanwhile, the p22 PHOX geno type distribution in UC group was 96C/C (78.0%), 26C/T (21.1%), and 1T/T (0.9%). No significant difference of the p22 PHOX genotype distribution was observed between HC and UC groups. (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 associated with the incidence of gastric cancer in the Japanese population.

Genetic variant of the p22PHOX component of NADPH oxidase C242T and the incidence of gastric cancer in Japan.

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.

A Genetic Variant of the CD14 C-159T in Patients with Functional Dyspepsia (FD) in Japanese Subjects.

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.

Risk prediction of gastric cancer by analysis of aberrant DNA methylation in non-neoplastic gastric epithelium.

BACKGROUND: Aberrant DNA methylation is one of the major events in carcinogenesis. Promoter DNA methylation is also present in various non-neoplastic tissues including gastric epithelium as age-related phenomenon, suggesting that it occurs early in the process of tumorigenesis. AIM: We aimed to clarify the relationship of aberrant DNA methylation in non-neoplastic gastric epithelia with the risk of gastric cancer, Helicobactor pylori infection, and the degree of H. pylori-induced gastritis. METHODS: 89 patients enrolled in this study. The status of aberrant DNA methylation was compared in two groups of patients: 43 cases with gastric cancer (mean age 65.9 years [29-91], F:M = 0.30, intestinal type [n = 25], diffuse type [n = 18]) and 46 age- and sex-matched patients without gastric cancer (peptic ulcer diseases [n = 11], gastritis [n = 35]) as a control group. Genomic DNA was extracted directly from non-neoplastic epithelia of antral biopsies obtained by endoscopy. The promoter methylation status of the p14 and p21 genes was determined by methylation-specific-polymerase chain reaction (MSP). The promoter methylation status of the p16 gene was quantified by digital densitographic analysis following MSP. The degree of gastritis in the antrum was assessed according to the updated Sydney system. The PG I/II ratio was calculated based on the data of serum PG I and PG II levels measured by radioimmunoassay. RESULTS: In all 89 subjects, CpG island methylation was found in 25.8% for p14, 52.8% for p16, 1.1% for p21. Among non-cancer patients, the methylation frequency of the p14 gene was significantly higher in H. pylori-positive than in H. pylori-negative patients (38.5 vs. 10.0%, p = 0.03). The mean (+/- SD) methylation levels of the p16 gene in non-neoplastic gastric epithelium was significantly higher in gastric cancer cases both in all patients and in H. pylori-positive patients (0.45 +/- 0.31 vs. 0.20 +/- 0.17; p = 0.019, 0.45 +/- 0.31 vs. 0.20 +/- 0.17; p = 0.016, respectively). The methylation level of the p16 gene was also associated with the presence of intestinal-type gastric cancer (p = 0.017). The methylation level of the p16 gene was significantly higher in patients with intestinal metaplasia (IM) than those without (p = 0.04). Furthermore, the methylation level of the p16 gene was correlated with lower PG l/ll ratio (p = 0.04). The methylation of the p21gene was found in only 1 patient with gastric cancer. CONCLUSIONS: Our data suggest that promoter of the p14 gene may be one of the specific regions whose methylation is closely associated with H. pylori infection. Methylation levels of the p16 gene seem to be accumulated in the progression of gastric mucosal atrophy and IM, and thus may be associated with the presence of gastric cancer especially for intestinal-type histopathology.

Endoscopic features of lymphoid follicles using blue laser imaging (BLI) endoscopy in the colorectum and its association with chronic bowel symptoms.

BACKGROUND/AIM: In the colorectum, lymphoid follicles hyperplasia (LH) is sometimes observed as small, round, yellowish-white nodules. The novel image-enhanced endoscopy system named blue laser imaging (BLI) provides enhanced the contrast of surface vessels using lasers for light illumination. We investigated the endoscopic features of LH observed by using BLI endoscopy and its association with chronic bowel symptoms. PATIENTS/METHODS: 300 participants undergoing colonoscopy for various indications were enrolled. Entire colorectum was observed by using BLI-bright mode with non-magnification view. LH was defined as well demarcated white nodules. Elevated LH with erythema was distinguished as LH severe. RESULTS: LHs were observed more clearly by using BLI-bright mode compared to conventional white light colonoscopy and were also histologically confirmed as intense infiltration of lymphocytes or plasmacytes. LH was observed in 134 subjects (44.6%) and 67 (22.3%) were LH severe. LH was associated younger age (Odds ratio (OR) = 1.05, 95%Confidence Interval (95%CI) = 1.03-1.07, P<0.0001) and chronic bowel symptoms including constipation, hard stools, diarrhea and loose stools (all LH: OR = 4.03, 95%CI = 2.36-6.89, P<0.0001, LH severe: OR = 5.31, 95%CI = 2.64-10.71, P<0.0001). LH severe was closely associated with both constipation associated symptoms (OR = 3.94, 95%CI = 1.79-8.66, P = 0.0007) and diarrhea associated symptoms (OR = 5.22, 95%CI = 2.09-13.05, P = 0.0004). In particular, LH severe in the ascending colon was strongly associated with bowel symptoms (P<0.0001). CONCLUSION: LH, visualized by using BLI endoscopy was associated with bowel symptom, raising the possibility of pathogenic role of this endoscopic finding in the functional lower gastrointestinal disorders.