Hiroyuki Suto

Association between diversity in the Src homology 2 domain--containing tyrosine phosphatase binding site of Helicobacter pylori CagA protein and gastric atrophy and cancer.

We investigated the relationship between the diversity of Helicobacter pylori CagA protein and clinical outcome. The cagA gene was sequenced in 115 clinical isolates. The binding affinity of CagA to Src homology 2 domain-containing tyrosine phosphatase (SHP-2) was examined by in vitro infection. Two major CagA subtypes were observed--the East Asian and the Western type. The grades of inflammation, activity of gastritis, and atrophy were significantly higher in patients with gastritis infected with the East Asian CagA-positive strain than in patients with gastritis infected with cagA-negative or Western CagA-positive strains. All strains isolated from patients with gastric cancer were East Asian CagA positive. East Asian CagA exhibited stronger SHP-2-binding activity than did Western CagA. These findings suggest that infection with East Asian CagA-positive H. pylori is associated with atrophic gastritis and gastric cancer and that persistent active inflammation induced by the East Asian CagA-positive strain may play a role in the pathogenesis of disease.

Distinct Diversity of vacA, cagA, and cagE Genes of Helicobacter pylori Associated with Peptic Ulcer in Japan

ABSTRACT Colonization of the stomach mucosa by Helicobacter pylori is a major cause of acute and chronic gastric pathologies in humans. Several H. pylori virulence genes that may play a role in its pathogenicity have been identified. The most important determinants are vacA and cagA in the cag pathogenicity island (cagPAI) genes. In the present study, to consider the association of molecular genetics between vacA and the cagPAI regarding clinical outcome, we selected H. pylori strains with various genotypes of vacA in Japan and sequenced full-length vacA, cagA, and cagE genes. Sequencing of vacA and cagA genes revealed variable size, whereas the cagE gene was well conserved among strains. Each of the phylogenetic trees based on the deduced amino acid sequences of VacA, CagA, and CagE indicated that all three proteins were divided into two major groups, a Western group and an East Asian group, and the distributions of isolates exhibited similar patterns among the three proteins. The strains with s2 and s1a/m1a vacA genotypes and the Western-type 3′ region cagA genotype were classified into the Western group, and the strains with the s1c/m1b vacA genotype and the East Asian-type 3′ cagA genotype were included in the East Asian group. In addition, the prevalence of infection with the Western group strain was significantly higher in patients with peptic ulcer (90.0%, 9/10) than in patients with chronic gastritis (22.7%, 5/22) (χ2 = 12.64, P = 0.00057). These data suggest that the molecular genetics of vacA and cagPAI are associated and that the Western group with vacA and cagPAI genes is associated with peptic ulcer disease.

Distinct Diversity of the cag Pathogenicity Island among Helicobacter pylori Strains in Japan

ABSTRACT The severity of Helicobacter pylori-related disease is correlated with the presence of a cag pathogenicity island (PAI). Genetic diversity within the cag PAI may have a modifying effect on the pathogenic potential of the infecting strain. We analyzed the complete cag PAI sequences of 11 representative Japanese strains according to their vacA genotypes and clinical effects and examined the relationship between the diversity of the cag PAI and clinical features. The cag PAI genes were divided into two major groups, a Western and a Japanese group, by phylogenetic analysis based on the entire cag PAI sequences. The predominant Japanese strains formed a Japanese cluster which was different from the cluster formed by Western strains. The diversity of the cag PAI was associated with the vacA and cagA genotypes. All strains with the s1c vacA genotype were in the Japanese cluster. In addition, all strains with the East Asian-type cagA genotype were also in the Japanese cluster. Patients infected with the Japanese-cluster strain had high-grade gastric mucosal atrophy. These results suggest that a distinct diversity of the cag PAI of H. pylori is present among Japanese strains and that this diversity may be involved in the development of atrophic gastritis and may increase the risk for gastric cancer.

Helicobacter pylori infection occurs via close contact with infected individuals in early childhood

Background : The manner in which Helicobacter pylori is transmitted is of fundamental importance when considering strategies for its control, yet, to date, the exact mode of transmission remains uncertain.

Susceptibility of Helicobacter pylori isolates to metronidazole, clarithromycin and amoxycillin in vitro and in clinical treatment in Japan

Primary and acquired resistance to antibiotics is an important factor in determining the reason for treatment failure in Helicobacter pylori infection. We examined the relationship between the susceptibility of H. pylori isolates and the efficacy of chemotherapy.

Full-Length Sequence Analysis of the vacA Gene from Cytotoxic and Noncytotoxic Helicobacter pylori

Some clinical isolates of Helicobacter pylori fail to express vacuolating cytotoxin, despite possessing a copy of the vacA gene on the chromosome. To gain insight into the differences between vacA from cytotoxic and noncytotoxic strains, the vacA open-reading frames from 16 cytotoxic and 22 noncytotoxic strains were sequenced. Mutations that cause truncation of VacA in 11 of 22 noncytotoxic strains were identified, including internal duplication, large deletion, 1-bp insertion, and non-sense mutations. In contrast, none of the 16 cytotoxic strains had any truncation of VacA. Four cytotoxic strains had inserted sequences downstream of vacA. Three were mini-IS605, and the other was a putative rfaJ gene that encodes lipopolysaccharide glucosyltransferase. The rfaJ gene identified in this study had a poly(C) tract, resulting in premature termination of the gene product. The phylogenetic tree based on the vacA open-reading frame indicated that two different H. pylori lineages are circulating in Japan and the West.

Relationship between the diversity of the cagA gene of Helicobacter pylori and gastric cancer in Okinawa, Japan.

BackgroundHelicobacter pylori CagA protein is considered to be one of the virulence factors associated with gastric cancer. CagA is injected into gastric epithelial cells, undergoes tyrosine phosphorylation, and binds to Src homology 2 domain-containing protein-tyrosine phosphatase (SHP-2). Two major subtypes of CagA have been observed in the SHP-2-binding site, the Western and East Asian types. The East Asian-type CagA binds to SHP-2 more strongly than the Western-type CagA. The diversity of CagA, which collectively determines the binding affinity of CagA to SHP-2, may be an important variable in determining the clinical outcome of infection by different H. pylori strains.MethodsWe investigated the relationship between the diversity of CagA and clinical outcome in Okinawa, Japan. A total 24 strains, 13 gastric cancer strains and 11 duodenal ulcer strains, were studied. We sequenced full-length cagA genes and analyzed the phylogenetic relationships between Okinawa isolates and previously characterized Western H. pylori strains.ResultsAll isolates examined were cagA positive. The prevalence of East Asian CagA-positive strains was significantly higher in patients with gastric cancer (84.6%) than in patients with duodenal ulcer (27.3%) (χ-squared = 8.06, P = 0.011). The phylogenetic analysis showed that all gastric cancer strains with East Asian-type CagA were in the East Asian cluster, and that most duodenal ulcer strains were in the Western cluster.ConclusionsThe origins of H. pylori isolates are different between gastric cancer strains and duodenal ulcer strains, and East Asian CagA-positive H. pylori infection is associated with gastric cancer. The strain diversity observed in Okinawa may affect the difference in the prevalence of disease associated with H. pylori infection in Japan.

Eradication of Helicobacter pylori infection induces an increase in body mass index.

The relationship between H. pylori infection and body mass indices is controversial.

Association between interleukin-1β-511C/T polymorphism and reflux esophagitis in Japan

BackgroundInterleukin-1β (IL-1β) gene polymorphisms are related to hypochlorhydria and increase the risk of gastric cancer in the presence of Helicobacter pylori infection. However, little information is available about the genetic risk factors of reflux esophagitis. In this study we investigated its association with the IL-1β polymorphisms.MethodsWe examined 48 patients with reflux esophagitis and 96 control subjects, 89 with gastric cancer. IL-1β-511C/T genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.ResultsThe frequency of IL-1β-511T alleles was significantly higher in reflux esophagitis patients (57.3%) than in controls (41.1%) (P = 0.0215, χ2 = 5.289). The frequency of IL-1β-511T/T genotypes was also significantly higher in reflux esophagitis patients (31.3%) than in controls (15.6%). The odds ratio and the 95% confidence interval were 4.000 and 1.393–11.486, respectively. The frequency of IL-1β-511T/T genotypes was significantly higher in reflux esophagitis patients (31.3%) than in gastric cancer patients (21.4%). The odds ratio and the 95% confidence interval were 2.961 and 1.054–8.316, respectively.ConclusionsIL-1β-511T was associated with reflux esophagitis having hyperacidity. Differences of genetic background regarding gastric acid secretion may exist between Japanese and Caucasians.

The effect of Helicobacter pylori eradication therapy on dyspepsia symptoms in industrial workers in Japan

The relationship between Helicobacter pylori infection and non‐ulcer dyspepsia is still controversial. The potential benefits and risks of the treatment could depend on local conditions, such as the prevalence of the infection and the local rates of gastric cancer.