Multicenter epidemiological survey of pneumatosis intestinalis in Japan.

BACKGROUND: Pneumatosis intestinalis (PI) is a rare condition characterized by gas collection in the intestinal wall. We aimed to determine the etiology and affected segments associated with complications, treatment, and outcome. METHODS: We conducted a multicenter epidemiological survey using a standardized data collection sheet in Japan. Complicating PI was defined as strangulation or bowel necrosis, bowel obstruction, adynamic ileus, sepsis, shock, and massive gastrointestinal bleeding requiring blood transfusion. RESULTS: We enrolled 167 patients from 48 facilities. Multivariate analysis revealed that older age (adjusted OR, 1.05 and 95% confidence intervals [CI], 1.02-1.09, P = 0.0053) and chronic kidney disease (adjusted OR, 13.19 and 95% CI 1.04-167.62, P = 0.0468) were independent predictors of the small-bowel-involved type. Complicating PI was associated with the small-bowel-involved combined type (adjusted OR, 27.02 and 95% CI 4.80-152.01, P = 0.0002), the small-bowel-only type (adjusted OR, 3.94 and 95% CI 1.02-15.27, P = 0.0472), and symptomatic PI (adjusted OR, 16.24 and 95% CI 1.82-145.24, P = 0.0126). Oxygen therapy was performed in patients with a past history of bowel obstruction (adjusted OR, 13.77 and 95% CI 1.31-144.56, P = 0.0288) and surgery was performed in patients with complicating PI (adjusted OR, 8.93 and 95% CI 1.10-72.78, P = 0.0408). Antihypertensives (adjusted OR, 12.28 and 95% CI 1.07-140.79, P = 0.0439) and complicating PI (adjusted OR, 11.77 and 95% CI 1.053-131.526; P = 0.0453) were associated with exacerbation of PI. The complicating PI was the only indicator of death (adjusted OR, 14.40 and 95% CI 1.09-189.48, P = 0.0425). DISCUSSION: Small-bowel-involved type and symptomatic PI were associated with complications which were indicators of poor prognosis.

Validation study for development of the Japan NBI Expert Team classification of colorectal lesions.

BACKGROUND AND AIM: The Japan narrow-band imaging (NBI) Expert Team (JNET) was organized to unify four previous magnifying NBI classifications (the Sano, Hiroshima, Showa, and Jikei classifications). The JNET working group created criteria (referred to as the NBI scale) for evaluation of vessel pattern (VP) and surface pattern (SP). We conducted a multicenter validation study of the NBI scale to develop the JNET classification of colorectal lesions. METHODS: Twenty-five expert JNET colonoscopists read 100 still NBI images with and without magnification on the web to evaluate the NBI findings and necessity of the each criterion for the final diagnosis. RESULTS: Surface pattern in magnifying NBI images was necessary for diagnosis of polyps in more than 60% of cases, whereas VP was required in around 90%. Univariate/multivariate analysis of candidate findings in the NBI scale identified three for type 2B (variable caliber of vessels, irregular distribution of vessels, and irregular or obscure surface pattern), and three for type 3 (loose vessel area, interruption of thick vessel, and amorphous areas of surface pattern). Evaluation of the diagnostic performance for these three findings in combination showed that the sensitivity for types 2B and 3 was highest (44.9% and 54.7%, respectively), and that the specificity for type 3 was acceptable (97.4%) when any one of the three findings was evident. We found that the macroscopic type (polypoid or non-polypoid) had a minor influence on the key diagnostic performance for types 2B and 3. CONCLUSION: Based on the present data, we reached a consensus for developing the JNET classification.

Comparison of Targeted vs Random Biopsies for Surveillance of Ulcerative Colitis-Associated Colorectal Cancer.

BACKGROUND & AIMS: A random biopsy is recommended for surveillance of ulcerative colitis (UC)-associated colorectal cancer. However, a targeted biopsy might be more effective. We conducted a randomized controlled trial to compare rates of neoplasia detection by targeted vs random biopsies in patients with UC. METHODS: We performed a study of 246 patients with UC for 7 years or more, seen at 52 institutions in Japan from October 1, 2008 through December 31, 2010. Patients were randomly assigned to the random group (4 random biopsies collected every 10 cm in addition to targeted biopsies, n = 122) or the target group (biopsies collected from locations of suspected neoplasia, n = 124). The primary end point was the number of neoplastic lesions detected in a single surveillance colonoscopy. We estimated the ratio and difference in the mean number of neoplastic lesions between the groups. We also evaluated the non-inferiority between the groups as an exploratory study. A non-inferiority margin of 0.65 (0.13 of 0.20) was considered for the ratio of the mean number of neoplastic lesions between groups. RESULTS: The mean number of biopsies found to contain neoplastic tissue per colonoscopy was 0.211 (24 of 114) in the target group and 0.168 (18 of 107) in the random group (ratio of 1.251; 95% confidence interval, 0.679-2.306). The lower limit was above the non-inferiority margin of 0.65. Neoplasias were detected in 11.4% of patients in the target group and 9.3% of patients in the random group (P = .617). Larger numbers of biopsy samples per colonoscopy were collected in the random group (34.8 vs 3.1 in the target group; P < .001), and the total examination time was longer (41.7 vs 26.6 minutes in the target group; P < .001). In the random group, all neoplastic tissues found in random biopsies were collected from areas of the mucosa with a history or presence of inflammation. CONCLUSIONS: In a randomized controlled trial, we found that targeted and random biopsies detect similar proportions of neoplasias. However, a targeted biopsy appears to be a more cost-effective method. Random biopsies from areas without any signs of present or past inflammation were not found to contain neoplastic tissues. Clinical Trial Registry: UMIN000001608.

Narrow-band imaging (NBI) magnifying endoscopic classification of colorectal tumors proposed by the Japan NBI Expert Team.

Many clinical studies on narrow-band imaging (NBI) magnifying endoscopy classifications advocated so far in Japan (Sano, Hiroshima, Showa, and Jikei classifications) have reported the usefulness of NBI magnifying endoscopy for qualitative and quantitative diagnosis of colorectal lesions. However, discussions at professional meetings have raised issues such as: (i) the presence of multiple terms for the same or similar findings; (ii) the necessity of including surface patterns in magnifying endoscopic classifications; and (iii) differences in the NBI findings in elevated and superficial lesions. To resolve these problems, the Japan NBI Expert Team (JNET) was constituted with the aim of establishing a universal NBI magnifying endoscopic classification for colorectal tumors (JNET classification) in 2011. Consensus was reached on this classification using the modified Delphi method, and this classification was proposed in June 2014. The JNET classification consists of four categories of vessel and surface pattern (i.e. Types 1, 2A, 2B, and 3). Types 1, 2A, 2B, and 3 are correlated with the histopathological findings of hyperplastic polyp/sessile serrated polyp (SSP), low-grade intramucosal neoplasia, high-grade intramucosal neoplasia/shallow submucosal invasive cancer, and deep submucosal invasive cancer, respectively.

Fusobacterium detected in colonic biopsy and clinicopathological features of ulcerative colitis in Japan.

BACKGROUND AND AIMS: Fusobacterium species are part of the gut microbiome in humans, but some species have been recognized as opportunistic pathogens implicated in inflammatory diseases including inflammatory bowel diseases. Here, we performed prevalence screening of Fusobacterium in ulcerative colitis (UC) in Japanese patients. METHODS: We examined Fusobacterium nucleatum (F. nucleatum) and whole Fusobacterium species (Pan-fusobacterium) by quantitative real-time PCR in 163 inflamed mucosae from 152 UC patients. Data were correlated with clinical subtypes of UC. RESULTS: In an initial prevalence screen, F. nucleatum and Pan-fusobacterium were detected in 6.3 % (4/64) and 53.1 % (34/64). For all 163 mucosae, the prevalence of Pan-fusobacterium was 54.6 % (89/163). Pan-fusobacterium status was concordant in inflamed and normal adjacent samples, and the matched cases during 1-year follow-up colonoscopy. The higher amount of Pan-fusobacterium was observed in chronic continuous type compared to one attack and relapse/remitting type (p = 0.039). The higher amount of Pan-fusobacterium was also associated with rather mild clinical course of disease, such as non-steroid dependency (p = 0.015), non-refractory phenotype (p = 0.013), and non-severe phenotype (p = 0.04). Based on the distribution of Pan-fusobacterium measurable cases, we identified 10 cases as having a high amount of Pan-fusobacterium (FB-high). The clinicopathological features of FB-high UC cases were also highlighted by chronic continuous type and mild phenotypes of disease. CONCLUSION: Whole Fusobacterium species, but not F. nucleatum, are common in UC patients and have a role in persistence of colonic inflammation in UC. However, Fusobacterium infection is associated with rather mild clinical phenotypes of UC.

Obscure gastrointestinal bleeding: diagnosis and treatment.

Small-bowel bleeding comprises a majority of obscure gastrointestinal bleeding, but is caused by various kinds of diseases. For its diagnosis, history-taking and physical examination is requisite, leading to a suspicion of what diseases are involved. Next, cross-sectional imaging such as computed tomography should be done, followed by the latest enteroscopy, videocapsule endoscopy and deep enteroscopy according to the severity of hemorrhage and patient conditions. After comprehensive diagnosis, medical, enteroscopic, or surgical treatment should be selected.

Relationship between expression of onco-related miRNAs and the endoscopic appearance of colorectal tumors.

Accumulating data indicates that certain microRNAs (miRNAs or miRs) are differently expressed in samples of tumors and paired non-tumorous samples taken from the same patients with colorectal tumors. We examined the expression of onco-related miRNAs in 131 sporadic exophytic adenomas or early cancers and in 52 sporadic flat elevated adenomas or early cancers to clarify the relationship between the expression of the miRNAs and the endoscopic morphological appearance of the colorectal tumors. The expression levels of miR-143, -145, and -34a were significantly reduced in most of the exophytic tumors compared with those in the flat elevated ones. In type 2 cancers, the miRNA expression profile was very similar to that of the exophytic tumors. The expression levels of miR-7 and -21 were significantly up-regulated in some flat elevated adenomas compared with those in exophytic adenomas. In contrast, in most of the miR-143 and -145 down-regulated cases of the adenoma-carcinoma sequence and in some of the de novo types of carcinoma, the up-regulation of oncogenic miR-7 and/or -21 contributed to the triggering mechanism leading to the carcinogenetic process. These findings indicated that the expression of onco-related miRNA was associated with the morphological appearance of colorectal tumors.

Classification of intestinal lymphangiectasia with protein-losing enteropathy: white villi type and non-white villi type.

BACKGROUND/AIMS: We classified intestinal lymphangiectasia (IL) into two categories, the white and non-white villi types, and evaluated their clinical characteristics and therapeutic responses. METHODS: Of the 988 patients who underwent double-balloon enteroscopy, 14 consecutive patients (7 men and 7 women, median age at onset 34 years) were enrolled with immunohistochemically confirmed IL with protein-losing enteropathy. RESULTS: Enteroscopically the white villi type (n = 8) showed white plaques and white-tipped villi were scattered in the small bowel, while non-white villi type (n = 6) showed that apparently normal but under more detailed observation, low and round villi with a normal color were diffused. The serum albumin levels and fecal α1-antitrypsin clearance before treatment were significantly worse in the non-white villi type (p = 0.017 and 0.039, respectively), whereas the serum immunoglobulin A and M levels were significantly lower in the white villi type (p = 0.010 and 0.046, respectively). At gastroscopy, a non-cirrhotic snakeskin appearance was significantly observed in the non-white villi type (p = 0.015). The corticosteroid response was better in the non-white villi type (p = 0.015). CONCLUSION: Two distinct subgroups were found in IL. This classification was useful in pathophysiological clustering and in predicting the therapeutic response.

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.

Digestive disease management in Japan: a report on the 6th diagnostic pathology summer fest in 2012.

The 6th Diagnostic Pathology Summer Fest, held in Tokyo on August 25-26, 2012, opened its gates for everyone in the medical profession. Basic pathology training can contribute to the improvement of algorithms for diagnosis and treatment. The 6th Summer Fest with the theme 'Pathology and Clinical Treatment of Gastrointestinal Diseases' was held at the Ito International Research Center, The University of Tokyo. On August 25, 'Treatment of Early Gastrointestinal Cancer and New Guidelines' was discussed in the first session, followed by 'Biopsy Diagnosis of Digestive Tract: Key Points of Pathological Diagnosis for Inflammation and Their Clinical Significance' in the second session. On August 26, cases were discussed in the third session, and issues on pathological diagnosis and classification of neuroendorcrine tumor in the fourth session. The summaries of speeches and discussions are introduced along with the statements of each speaker. This meeting was not a formal evidence-based consensus conference, and 20 experts gave talks on their areas of specialty. Discussion was focused on how the management strategy should be standardized on the algorithm of patient care.

Downregulation of anti-oncomirs miR-143/145 cluster occurs before APC gene aberration in the development of colorectal tumors.

Accumulating data indicate that some microRNAs (miRNAs or miRs) can function as tumor suppressors or oncogenes and as such are important in cancer development. We previously reported that miR-143 and -145 are frequently downregulated in colon adenomas and cancers, acting as tumor suppressors. In this present study, we investigated the relationship between the downregulation of the miR-143/145 cluster and genetic aberrations of adenomatous polyposis coli (APC), which are early genetic events in the development of colorectal tumors. The expression levels of both miRs were determined by performing real-time PCR on tissue samples of familial adenomatous polyposis (FAP), colorectal adenoma, colorectal cancer, and paired non-tumorous tissues. Also, the expression of C- or N-terminus of the APC protein and that of the p53 protein in these tissues were examined immunohistochemically. Our data clearly indicated that the decreased expression of miR-143 and -145 frequently occurred before APC gene aberrations. The downregulation of miR-143 and -145 is thus an important genetic event for the initiation step in colorectal tumor development.

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.

Usefulness of magnifying narrow-band imaging endoscopy for the diagnosis of gastric and colorectal lesions.

A series of studies about the potential usefulness of magnifying endoscopy with narrow-band imaging (NBI) for the diagnosis of gastric and colonic lesion is reviewed. Concerning the magnifying NBI appearances of gastric lesions, a light blue crest is a highly accurate sign of the presence of histological intestinal metaplasia. Also, the degree of irregularity of the mucosal and vascular pattern is correlated with the histological severity of Helicobacter pylori-associated chronic gastritis. According to the 'VS classification', an irregular microvascular pattern and/or an irregular microsurface pattern together with a clear demarcation line are characteristic for early gastric carcinoma, and a multicenter prospective randomized controlled trial demonstrated that magnifying endoscopy with NBI is superior to ordinary white light endoscopy for making a differential diagnosis of a small depressed lesion between carcinoma and non-carcinoma. Concerning the magnifying NBI appearances of colonic tumor, the vague or invisible microvascular pattern is mostly observed in hyperplastic polyp. The regular meshed microvascular pattern is mostly observed in adenoma. The irregular meshed microvascular pattern is mostly observed in intramucosal or shallow submucosal-invasive carcinoma. The decreased or loose microvasucular pattern is mostly observed in deep submucosal-invasive carcinoma. Thus, magnifying NBI endoscopy is useful for the differentiation of colorectal non-adenomatous lesions from adenoma, the differentiation of adenoma from carcinoma, and the assessment of invasion depth of early colorectal carcinoma. At present, several magnifying NBI classifications for the diagnosis of early colorectal neoplasia have been proposed in Japan. Recently, the NICE classification based on NBI findings with/without magnification for colorectal tumor was established by an international group.

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.

Polymorphisms of DNA repair and xenobiotic genes predispose to CpG island methylation in non-neoplastic gastric mucosa.

BACKGROUND: Genetic factors, related to DNA repair or xenobiotic pathways might confer different degrees of susceptibility to gastric carcinogenesis. CpG island hyper methylation (CIHM) is a major event in gastric carcinogenesis. We evaluated the association between XRCC1, GSTP1, GSTT1 and GSTM1 polymorphisms with CIHM status in non-neoplastic gastric mucosa. METHODS: XRCC1 Arg399Gln, and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms were genotyped in 415 cancer free subjects, in relation to four candidate CpG (p14, p16, DAP-kinase and CDH1) loci, assessed by Methylation-Specific-Polymerase Chain Reaction (MSP). CIHM high was defined as two or more CpG islands methylated. RESULTS: Significant association between XRCC1 codon 399 Gln/Gln genotype and reduced susceptibility to CIHM of DAP-kinase (adjusted OR = 0.30, 95%CI = 0.13-0.71, p = .0055) and CIHM high (OR = 0.42, 95%CI = 0.19-0.97, p = .04). XRCC1 codon 399 Gin/Gln genotype also presented lower number of CIHM when compared with both Arg/Gln, and Arg/Arg + Arg/Gln genotypes (p = .02, .046, respectively) When subjects were divided according to age (>50 and <50), an association was found between GSTM1 null genotype and increased susceptibility to CIHM high in the 50 years and older generations (OR = 1.63, 95%CI = 1.01-2.62, p = .045). CONCLUSION: XRCC1 codon 399 Gln/Gln genotype is associated with reduced susceptibility to CIHM especially DAP-kinase. GSTM1 null genotype may increase the susceptibility to CIHM especially in older patients. Genetic factors, related to DNA repair or xenobiotic pathways may have a role in CIHM-related gastric carcinogenesis.