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Abstract

Thank you for the opportunity to reply to the comments of Ogiwara, Graham, and Yamaoka regarding our recent publication in Gastroenterology.1Rhead J.L. Letley D.P. Mohammadi M. et al.A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer.Gastroenterology. 2007; 133: 926-936Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar We were very interested to read their data on vacA i-region typing of 314 Helicobacter pylori strains isolated from East Asian and Southeast Asian countries, and see no conflict between their findings and the conclusions we have drawn from our own data.1Rhead J.L. Letley D.P. Mohammadi M. et al.A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer.Gastroenterology. 2007; 133: 926-936Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar In a recent abstract, we described the i-region types of 13 vacA s1/m2 strains isolated in China, which we also found to be invariably i1 type.2Rhead J.L. Letley D.P. Zhang Y. et al.An important new determinant of vacA toxicity is prevalent among Chinese Helicobacter pylori strains.Helicobacter. 2005; 10: 470Google Scholar At the time, we speculated that a high prevalence of strains with the more virulent vacA s1/i1 type may contribute to the high incidence of gastric adenocarcinoma in China. The results of Ogiwara et al confirm our findings for a much larger number of strains, and clearly show that the vacA i1 type predominates in East Asia. The authors also highlight the importance of gastric cancer in this region of the world. However, in contrast to their interpretation, we believe that these data fully support our claim that vacA i-region type is an important indicator of H pylori virulence; one would expect a high predominance of virulent strains in geographical regions where the prevalence of H pylori-related gastric cancer is high. Given that the majority of H pylori infections remain asymptomatic, it is important to determine factors which increase disease risk. We agree with the generally accepted view that H pylori-related disease risk is conferred by a combination of strain virulence, host response, and environmental factors. Lu, Yamaoka, and Graham3Lu H. Yamaoka Y. Graham D.Y. Helicobacter pylori virulence factors: facts and fantasies.Curr Opin Gastroenterol. 2005; 21: 653-659Crossref PubMed Scopus (100) Google Scholar have previously proposed attributes that an H pylori virulence factor should conform to, and vacA meets, these requirements. In populations where vacA diversity is common, vacA typing has proved a useful marker of disease risk, and we cited examples of such studies in our original article.1Rhead J.L. Letley D.P. Mohammadi M. et al.A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer.Gastroenterology. 2007; 133: 926-936Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar In terms of epidemiologic consistency across populations, in populations where H pylori strains are largely homogenous for vacA type, this virulence factor obviously cannot be useful for determining individual gastric disease risk, and such cases highlight the need to determine other important factors affecting H pylori infection outcome. However, in such regions, one would still expect vacA polymorphism to make a major contribution to H pylori-related pathology at the population level. With regard to biological plausibility, several injurious effects have been described for VacA both in vitro and in animal models.4Gebert B. Fischer W. Haas R. The Helicobacter pylori vacuolating cytotoxin: from cellular vacuolation to immunosuppressive activities.Rev Physiol Biochem Pharmacol. 2004; 152: 205-220Crossref PubMed Scopus (48) Google Scholar However, we agree that the predominant action by which VacA predisposes to upper GI disease remains unclear. In contrast to Ogiwara et al’s implied assertion, we have shown the specific importance of the vacA i region in mechanistic experiments using partial allelic exchange.1Rhead J.L. Letley D.P. Mohammadi M. et al.A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer.Gastroenterology. 2007; 133: 926-936Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar To summarize, in populations where vacA diversity in H pylori strains is found to be common, specific polymorphisms of this virulence factor are potential markers of individual disease risk. Where vacA typing identifies geographical regions where strains are predominantly homogeneous in vacA type, the specific vacA type present may be an important contributor to the prevalence of H pylori-related pathology in the population. vacA i-Region SubtypingGastroenterologyVol. 134Issue 4PreviewWe read with interest the article entitled “A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer” by Rhead et al1 in the September 2007 issue of Gastroenterology. Virtually all Helicobacter pylori strains possess a vacuolating cytotoxin gene, vacA; however, there is considerable variation in vacuolating activities among strains, and this variation is primarily due to differences in vacA gene structure at the signal region (s1 and s2) and the midregion (m1 and m2). Full-Text PDF