Helicobacter pylori infection introduces DNA double-strand breaks in host cells.

Gastric cancer is an inflammation-related malignancy related to long-standing acute and chronic inflammation caused by infection with the human bacterial pathogen Helicobacter pylori. Inflammation can result in genomic instability. However, there are considerable data that H. pylori itself can also produce genomic instability both directly and through epigenetic pathways. Overall, the mechanisms of H. pylori-induced host genomic instabilities remain poorly understood. We used microarray screening of H. pylori-infected human gastric biopsy specimens to identify candidate genes involved in H. pylori-induced host genomic instabilities. We found upregulation of ATM expression in vivo in gastric mucosal cells infected with H. pylori. Using gastric cancer cell lines, we confirmed that the H. pylori-related activation of ATM was due to the accumulation of DNA double-strand breaks (DSBs). DSBs were observed following infection with both cag pathogenicity island (PAI)-positive and -negative strains, but the effect was more robust with cag PAI-positive strains. These results are consistent with the fact that infections with both cag PAI-positive and -negative strains are associated with gastric carcinogenesis, but the risk is higher in individuals infected with cag PAI-positive strains.

Intact long-type dupA as a marker for gastroduodenal diseases in Okinawan subpopulation, Japan.

BACKGROUND: Helicobacter pylori dupA can be divided into two types according to the presence or absence of the mutation. In addition, full-sequenced data revealed that dupA has two types with different lengths depend on the presence of approximately 600 bp in the putative 5' region (presence; long-type and absence; short-type), which has not been taken into account in previous studies. METHODS: A total of 319 strains isolated from Okinawa, the south islands of Japan, were included. The status of dupA and cagA was determined by polymerase chain reaction. The presence of mutations in long-type dupA was determined by DNA sequencing. RESULTS: The prevalence of long-type dupA was 26.3% (84/319). Sequence analysis showed that there were only six cases (7.1%) with point mutations lead to stop codon among 84 long-type dupA strains studied. Interestingly, intact long-type dupA without frameshift mutation, but not short-type dupA, was significantly associated with gastric ulcer and gastric cancer than gastritis (p = .001 and p = .019, respectively). After adjustment by age, gender, and cagA, the presence of intact long-type dupA was significantly associated with gastric ulcer and gastric cancer compared with gastritis (odds ratio [OR] = 3.35, 95% confidence interval [CI] = 1.55-7.24 and OR = 4.14, 95% CI = 1.23-13.94, respectively). CONCLUSIONS: Intact long-type dupA is a real virulence marker for severe outcomes in Okinawa, Japan. The previous information gained from PCR-based methods without taking long-type dupA into account must be interpreted with caution.

Helicobacter pylori cagA 12-bp insertion can be a marker for duodenal ulcer in Okinawa, Japan.

BACKGROUND AND AIM: Helicobacter pylori cagA can be classified into mainly two types (East-Asian-type and Western-type cagA) according to the repeat regions located in the 3' region. Recent studies showed that the Western-type cagA in strains from Okinawa, Japan formed a different cluster (J-Western-type cagA subtype). It has also been reported that J-Western-type cagA possesses a 12-bp insertion located in the 5' region of cagA sequence. METHODS: The prevalence of 12-bp insertion in cagA in Okinawa and the United States (U.S.) was examined by DNA sequencing. The primer pair that can detect the 12-bp insertion only by polymerase chain reaction was then designed. The prevalence of strains with 12-bp insertion was examined in 336 strains isolated from Okinawa by polymerase chain reaction. RESULTS: In case of Western-type cagA/vacA s1m2 strains, the prevalence of 12-bp insertion was significantly higher in strains isolated from Okinawa than that from the U.S. (P = 0.002). Phylogenetic tree showed that strains with 12-bp insertion formed two individual clusters within J-Western-type cagA subtype; one is from Okinawa and another is from the U.S. The designed primer set showed high sensitivity (100%) and specificity (90.8%) in Okinawa. The 12-bp insertion was found in 23.7%, 14.3%, 4.2%, and 4.0% of strains with duodenal ulcer (DU), gastritis, gastric cancer, and gastric ulcer (GU), respectively (P < 0.001 for DU vs GU) in Okinawa. CONCLUSIONS: Although the mechanisms are unknown, the presence of 12-bp insertion was associated with the presence of DU and might have a suppressive action on GU and gastric cancer.

Role of Helicobacter pylori plasticity region genes in development of gastroduodenal diseases.

The plasticity region of Helicobacter pylori is a large chromosomal segment including isolate-specific open reading frames with characteristics of pathogenicity islands. It remains unclear whether genes in the plasticity region play a role in the pathogenesis of gastric mucosal inflammation and gastroduodenal disease. Our aim was to assess the role of selected genes in the plasticity region in relation to risk of H. pylori-related disease and the severity of gastric mucosal damage. We used PCR to study the relation of disease outcome and mucosal damage with four genes in the H. pylori plasticity region (jhp0940, jhp0945, jhp0947, and jhp0949) from isolates obtained from both Western (n = 296) and East Asian (n = 217) patients. The prevalence of jhp0945, jhp0947, and jhp0949 differed significantly between Western and East Asian isolates. In Western isolates, the presence of jhp0945 was significantly associated with gastric ulcer, duodenal ulcer, and gastric cancer (odds ratios [95% confidence intervals]: 2.27 [1.04 to 4.98], 1.86 [1.03 to 3.34], and 1.92 [1.03 to 3.56], respectively). jhp0940-positive Western isolates were significantly associated with absence of gastric ulcer or duodenal ulcer (0.21 [0.05 to 0.94] and 0.31 [0.12 to 0.78], respectively). No significant difference was observed between inflammatory cell infiltration or atrophy and the presence or absence of plasticity region genes. The outcome of H. pylori infections varies widely geographically. These data suggest a possible role for difference in the prevalence of plasticity region genes in the geographic variation in H. pylori-related diseases.

Association between Helicobacter pylori virulence factors and gastroduodenal diseases in Okinawa, Japan.

The incidence of gastric cancer in Okinawa is lowest in Japan. Some previous reports using small number of strains suggested that the high prevalence of Helicobacter pylori with Western-type cagA in Okinawa compared to other areas in Japan might contribute to the low incidence of gastric cancer. It has still not been confirmed why the prevalence of Western-type cagA strains is high in Okinawa. We examined the association between the virulence factors of H. pylori and gastroduodenal diseases in Okinawa. The genotypes of cagA and vacA of 337 H. pylori strains were determined by PCR and gene sequencing. The genealogy of these Western-type cagA strains in Okinawa was analyzed by multilocus sequence typing (MLST). Overall, 86.4% of the strains possessed cagA: 70.3% were East-Asian type and 16.0% were Western type. After adjustment by age and sex, the presence of East-Asian-type cagA/vacA s1m1 genotypes was significantly associated with gastric cancer compared to gastritis (odds ratio = 6.68, 95% confidence interval = 1.73 to 25.8). The structure of Western-type CagA in Okinawa was different from that of typical Western-type CagA found in Western countries. Intriguingly, MLST analysis revealed that the majority of Western-type cagA strains formed individual clusters but not hpEurope. Overall, low prevalence of gastric cancer in Okinawa may result from the high prevalence of non-East-Asian-type cagA strains. The origin of Western-type cagA strains in Okinawa may be different from those of Western countries.

Association between Helicobacter pylori cagA-related genes and clinical outcomes in Colombia and Japan.

BACKGROUND: Specific genotypes of several virulence factors of Helicobacter pylori (eg, cagA-positive, vacA s1, oipA "on" and babA-positive) have been reported to be predictors of severe clinical outcomes. Importantly, the presence of these genotypes correlates with each other. We hypothesized that novel virulence genes correlate with the presence of cagA. Therefore, we aimed to find novel candidate virulence genes that correlate with cagA and examined the association of these genes with clinical outcomes in Colombian and Japanese populations. METHODS: cagA-associated genes were selected based on previous H. pylori genome microarray data. A total of 343 strains (174 from Colombia and 169 from Japan) were examined for the status of cagA, vacA, and candidate genes by polymerase chain reaction and dot blot. RESULTS: Microarray data showed that 9 genes were significantly correlated with the presence of cagA. Among the 9 genes, the functions of 4 were known, and we selected these 4 genes as candidate genes (hp0967, jhp0045, jhp0046, and jhp0951). The prevalences of cagA, vacA s1/m1 genotype, and hp0967 were significantly higher in Japan than Colombia, whereas those of jhp0045 and jhp0046 were more prevalent in Colombia than Japan. The prevalences of jhp0045 and jhp0046 in cagA-positive cases of gastric cancer were significantly higher than those from gastritis in Colombia (P = 0.015 and 0.047, respectively). In contrast, the prevalence of 4 candidate genes was independent of clinical outcomes in Japan. CONCLUSIONS: jhp0045 and jhp0046 might be novel markers for predicting gastric cancer in cagA-positive cases in Colombia, but not in Japan.

Prevalence of two homologous genes encoding glycosyltransferases of Helicobacter pylori in the United States and Japan.

BACKGROUND AND AIM: jhp0562 and ß-(1,3)galT (jhp0563) of Helicobacter pylori have been suggested as novel virulent factors; however, the clinical associations and functions of these genes remain unclear. We examined the prevalence of jhp0562, ß-(1,3)galT, and cagA in the United States (US) and Japanese populations. METHODS: A total of 308 strains (171 from the US and 137 from Japan) were examined for the status of jhp0562, ß-(1,3)galT, and cagA by polymerase chain reaction. RESULTS: There were significant differences in the status of jhp0562, ß-(1,3)galT and cagA between the US and Japanese populations (P < 0.001). In the US, the prevalence of ß-(1,3)galT was significantly lower in strains isolated from patients with duodenal ulcer (DU) or gastric ulcer (GU) than those with gastritis (47.8% and 32.1% vs 72.0%, P < 0.01), and the absence of ß-(1,3)galT was an independent factor discriminating DU and GU from gastritis (adjusted odds ratios, 4.21 and 8.52; 95% confidence intervals, 1.75 to 10.12 and 2.76 to 26.33, respectively). In the US, the prevalence of the jhp0562-positive/ß-(1,3)galT-negative genotype was significantly higher in strains from DU and GU patients than in those from gastritis patients (50.0%, 67.9%, and 24.4%, P < 0.01) and the cagA status was significantly correlated with that of jhp0562 and inversely correlated with that of ß-(1,3)galT. In contrast, the prevalence of these three genes was not significantly different in Japan. CONCLUSIONS: jhp0562 or ß-(1,3)galT can be used to discriminate peptic ulcers from gastritis in the US, but not in Japan.

Helicobacter pylori and NSAID-induced gastric ulcer in a Japanese population.

A recent meta-analysis by Huang et al. clarified that Helicobacter pylori infection and nonsteroidal antiinflammatory drugs (NSAIDs) are important factors for peptic ulcer. The results showed that the risk for ulcer in NSAID(+)/H. pylori(+) patients was 61.1 fold higher when compared with NSAID(-)/H. pylori(-) patients. Some gastric ulcers detected in patients on NSAID therapy may actually be caused by H. pylori, but it is difficult to differentiate NSAID-induced gastric ulcer from H. pylori-induced gastric ulcer. Several studies have investigated the effects of H. pylori eradication on ulcer healing. One study reported that H. pylori eradication actually lowered the healing rate of gastric ulcers. Because there have been no studies finding that H. pylori eradication facilitates healing, H. pylori eradication is not recommended for NSAID users. Concerning the efficacy of H. pylori eradication in the prevention of NSAID-induced gastric ulcer, a meta-analysis concluded that among all patients on NSAID therapy, H. pylori eradication lowered the prevalence of ulcer, which was particularly marked in NSAID-naïve patients. When compared with those of proton pump inhibitors (PPIs), the preventative effects of H. pylori eradication were inferior. In Japan, national health insurance does not cover procedures that prevent or lower the risk for NSAID-induced ulcer. When administering NSAID to patients with risk factors, it is desirable to administer antiulcer agents.

Helicobacter pylori iceA, clinical outcomes, and correlation with cagA: a meta-analysis.

BACKGROUND: Although the iceA (induced by contact with epithelium) allelic types of Helicobacter pylori have been reported to be associated with peptic ulcer, the importance of iceA on clinical outcomes based on subsequent studies is controversial. The aim of this study was to estimate the magnitude of the risk for clinical outcomes associated with iceA. METHODS: A literature search was performed using the PubMed and EMBASE databases for articles published through April 2011. Published case-control studies examining the relationship between iceA and clinical outcomes (gastritis, peptic ulcer, including gastric ulcer and duodenal ulcer, and gastric cancer) were included. RESULTS: Fifty studies with a total of 5,357 patients were identified in the search. Infection with iceA1-positive H. pylori increased the overall risk for peptic ulcer by 1.26-fold (95% confidence interval [CI], 1.09-1.45). However, the test for heterogeneity was significant among these studies. Sensitivity analysis showed that the presence of iceA1 was significantly associated with peptic ulcer (odds ratio [OR] = 1.25, 95% CI = 1.08-1.44). The presence of iceA2 was inversely associated with peptic ulcer (OR = 0.76, 95% CI = 0.65-0.89). The presence of iceA was not associated with gastric cancer. Most studies examined the cagA status; however, only 15 studies examined the correlation and only 2 showed a positive correlation between the presence of cagA and iceA1. CONCLUSION: Our meta-analysis confirmed the importance of the presence of iceA for peptic ulcer, although the significance was marginal.

Serum Helicobacter pylori CagA antibody as a biomarker for gastric cancer in east-Asian countries.

AIMS: In east-Asian countries, while almost all Helicobacter pylori strains possess the cytotokine-associated gene A (CagA) gene, serum CagA antibody is not detected in some infected subjects. We aimed to clarify the association between anti-CagA antibody and gastric cancer in east-Asian countries. MATERIALS AND METHODS: We performed a meta-analysis of case-control studies with age- and sex-matched controls, which provided raw data in east-Asian countries. RESULTS: Ten studies with a total of 4325 patients were identified in the search. Some reports from Japan, Korea and China showed a positive association between the presence of anti-CagA antibody and gastric cancer; however, the results differed in their various backgrounds. The disparate findings appeared to result from the use of different methods or from variations in the antigens used to detect the anti-CagA antibody. CagA seropositivity was associated with an increased risk of developing gastric cancer. CONCLUSION: Anti-CagA antibody can be used as a biomarker for gastric cancer even in east-Asian countries.

Systematic review and meta-analysis: the relationship between the Helicobacter pylori dupA gene and clinical outcomes.

BACKGROUND: In 2005, the first disease-specific Helicobacter pylori virulence factor that induced duodenal ulcer and had a suppressive action on gastric cancer has been identified, and was named duodenal ulcer promoting gene (dupA). However, the importance of the dupA gene on clinical outcomes is conflicting in subsequent studies. The aim of this study was to estimate the magnitude of the risk for clinical outcomes associated with dupA gene. METHODS: A meta-analysis of case-control studies which provided raw data on the infection rates with the dupA-positive H. pylori detected by polymerase chain reaction was performed. RESULTS: Seventeen studies with a total of 2,466 patients were identified in the search. Infection with the dupA-positive H. pylori increased the risk for duodenal ulcer by 1.41-fold (95% confidence interval [CI], 1.12-1.76) overall. Subgroup analysis showed that the summary odds ratio (OR) was 1.57 (95% CI, 1.19-2.06) in Asian countries and 1.09 (95% CI, 0.73-1.62) in Western countries. There was no association between the presence of the dupA gene and gastric cancer and gastric ulcer. Publication bias did not exist. CONCLUSION: Our meta-analysis confirmed the importance of the presence of the dupA gene for duodenal ulcer, especially in Asian countries.

Cap polyposis (CP) which relapsed after remission by avoiding straining at defecation, and was cured by Helicobacter pylori eradication therapy.

A 52-year-old woman was diagnosed with cap polyposis (CP) with characteristic clinical, endoscopic, and histological features. By avoiding straining at defecation, her symptoms improved temporarily, however recrudesced. She was diagnosed with Helicobacter pylori (H. pylori) infection, and received eradication therapy successfully. After this eradication therapy, her symptoms and colonoscopic findings recovered completely. Only two reports in the English language literature have discussed the relationship between CP and eradication therapy for H. pylori, all patients achieved complete recovery. We recommend H. pylori testing for all cases of CP and H. pylori eradication therapy if necessary.