Role of Deletion Located between the Intermediate and Middle Regions of the Helicobacter pylori vacA Gene in Cases of Gastroduodenal Diseases

Abstract

Gastric cancer arises through steps related to the presence of a chronic Helicobacter pylori infection, which leads to the precursor lesion, atrophic gastritis. The progression of gastric mucosal atrophy varies within and between different populations; and the differences relate to differences in H. pylori virulence, host genetic factors, and/or environmental factors. The important H. pylori virulence factors and host genetic factors are related to an increased inflammatory response and include the presence of the cag pathogenicity island, polymorphisms of host inflammationrelated cytokines (5, 6), drug metabolism-related enzymes (19,22), and growth factors (5,6,12,19,22,30).The vacuolating cytotoxin (VacA) was one of the first putative virulence factors discovered in H. pylori (4). Virtually all H. pylori strains possess a vacA gene; however, the in vitro vacuolating activities for cell lines vary considerably among strains; and the differences in the vacuolating activities are related to differences in the vacA structures at the signal (s) region (s1 and s2) and the middle (m) region (m1 and m2) (1). The s region encodes part of the signal peptide and the N terminus of the mature protein, whereas the m region encodes part of the 55,000-Da (55K) C-terminal subunit. The amount of toxin produced also varies according to the vacA m-region genotypes: vacA s1-m1 strains induce greater vacuolating activity than vacA s1-m2 strains (1, 11).Recently, a third polymorphic determinant of vacuolating activity was described as being located between the s and m regions and was termed the intermediate (i) region (16). Two i-region subtypes were described: the i1 and i2 subtypes. Among Western strains, vacA s1-m2 strains were noted to vary in their i-region genotypes; vacA s1-m1 and s2-m2 strains were exclusively i1 and i2, respectively. The vacA s1-i1-m2 strains induced vacuolation in rabbit kidney RK13 cells, whereas s1-i2-m2 strains did not. Clinically, the prevalence of the vacA i1 genotype in patients with gastric cancer was 80%, which was significantly higher than that in patients in an Iranian population with nonulcer dyspepsia (37%) (16). Subsequent studies showed that infection with vacA i1 strains was associated with gastric cancer in patients in Iranian and Italian populations and gastric ulcer in patients in Iraqi and Italian populations (2,8,16). This allowed the conclusion that the vacA i-region genotype might be a better predictor of the carcinogenic potential of H. pylori than the previously used vacA s-and mregion genotypes. However, our recent study shows that determination of the vacA genotypes for the combination of three regions (the s, m, and i regions) did not provide any advantage as a disease determinant marker over determination of s-and

Helicobacter pylori vacA d1 Genotype Predicts Risk of Gastric Adenocarcinoma and Peptic Ulcers in Northwestern Iran

“…Strains with the particular vacA genotypes have been found to be good markers for gastroduodenal disease (Atherton et al, 1995). Ogiwara et al (2009) showed that the vacAd1 allele could be considered a more sensitive independent biomarker in the development of gastroduodenal disease, and LatifiNavid et al (2013) have also recently reported that the vacA d1/-i1 alleles from strains with European ancestry could be considered good markers for gastric cancer in Ardabil and Mazanderan (high incidence areas of GC in Iran) (Ogiwara et al, 2009;Latifi-Navid et al, 2013). In the present study, the genotype of the vacA d region was evaluated in H pylori isolated from patients with gastric adenocarcinoma, PUD and gastritis (control group) in East Azerbaijan in the Northwest of Iran.…”

“…In the present study, the genotype of the vacA d region was evaluated in H pylori isolated from patients with gastric adenocarcinoma, PUD and gastritis (control group) in East Azerbaijan in the Northwest of Iran. First, the frequency of vacA d1 was determined and compared with that reported in two previous studies (Ogiwara et al, 2009;Latifi-Navid et al, 2013). In this study, the frequencies for the vacA d1 and d2 alleles were 43.37% and 56/63% respectively in patients with gastric adenocarcinoma, peptic ulcer and gastritis.…”

“…All primer sets were selected from published literature (Lu et al, 2002;Ogiwara et al, 2009). The PCR assay was performed in a reaction volume of 25μL using a commercially available kit (CinnaGen, Iran).…”

“…The d region is divided into d1 (no deletion) and d2 (with a 69 to 81 bp deletion), with d1 identified a risk factor for GC and PUD in Western strains. Nearly all H pylori isolates from East Asia have been found to have a genotype of vacA d1 (Ogiwara et al, 2009).…”

Helicobacter Pylori vacA d1 Genotype is associated with Gastric Cancer but not Peptic Ulcers in Kurdistan Region, Northern Iraq

“…The d region is divided into d1 and d2 with d1 identified a risk factor for GC and PUD in Western strains. Nearly all H pylori isolates from East Asia have been found to have a genotype of vacA d1 (Ogiwara et al, 2009). Our results showed that the overall prevalence of vacA d1 genotype is lower than that found in Iran this could contribute to the differences in gastric cancer rates seen between these communities.…”