Affiliations of authors: C. Figueiredo, Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal; J. C. Machado, IPATIMUP, and Faculty of Medicine, University of Porto, Porto.
Correspondence to: Céu Figueiredo, Ph.D., IPATIMUP, Rua Dr. Roberto Frias s/n, 4200465, Porto, Portugal (e-mail: cfigueiredo{at}ipatimup.pt).
As indicated in the above correspondence, the Helicobacter pylori strain-type-specific gastric cancer (GC) risks observed in our study (1) were, indeed, higher than those in the studies mentioned by Kamangar et al. However, there is at least one study (2) that shows an increased risk for GC in subjects infected with cagA-positive versus cagA-negative H. pylori strains, with an odds ratio (OR) of 9.5 (95% confidence interval [CI] = 3.6 to 26.8). This risk for GC was even further increased (OR = 25.9, 95% CI = 5.8 to 75.3) when the analysis was restricted to distal GC.
Kamangar et al. also raised the concern that these discrepant OR estimates may be related to the features of our study design. First, sex and age adjustments in the logistic regression analysis were not reported in our study because the comparison of strain-type frequencies with sex and age of the case patients and control subjects did not reveal any statistically significant association. Sex and age are well-established risk factors for GC and, as expected, adjustments for these covariates resulted in an increase (not a decrease) in the OR estimates. For example, the sex- and age-adjusted OR for GC associated with cagA-positive strains was 36.6 (95% CI = 9.6 to 139.7).
Second, the phenotypic frequencies of the ABO and Rhesus blood group genetic systems in our case patients and control subjects were similar to those observed in the general population (i.e., A = 44%, B = 8%, AB = 4%, O = 44%, Rh-positive = 85%, and Rh-negative = 15%). Moreover, both case patients and control subjects were recruited from the same geographic area. Therefore, there is no reason to believe that our study groups are not representative of the general population, at least in terms of genetic and geographic background.
Third, we agree with Kamangar et al. that some selection bias could have been introduced by the fact that some of our GC case patients did not have adequate material for H. pylori genotyping. However, to the best of our knowledge, our study has the largest number of GC cases genotyped for H. pylori-virulence-associated cagA and vacA genes in gastric tissue.
Fourth, we agree with Kamangar et al. that the difference in sensitivity between serology and tissue genotyping cannot fully account for the discrepant risk estimates for GC reported among different studies.
Finally, the consideration that differential strain susceptibility to gastric acid could contribute to a higher cagA-positive strain colonization rate among GC patients is difficult to interpret, partly because it questions the role of cagA as a virulence factor and partly because there are numerous studies demonstrating the importance of cagA in strain virulence (35). Moreover, if H. pylori cagA-positive strains are more sensitive to gastric acid than cagA-negative strains, then how does one explain the predominance of cagA-positive strains in high-acid situations such as in duodenal ulcers?
In conclusion, the reasoning underlying the discrepancy in OR estimates between our study and those of others is not easily addressed. Factors such as the worldwide heterogeneous prevalence of type-specific H. pylori strains (6) and the genetic background of the host population are likely to contribute to discrepancies in GC risk associated with specific H. pylori strain types. As noted in the accompanying editorial (7), it is too early to generalize from this work. Nevertheless, we believe that the outcomes of this type of study (i.e., identification of risk factors and a better definition of risk) are important because they might be able to provide the means to identify individuals who are at greatest risk of developing GC. As a consequence, it may become possible to target such individuals with selective interventions designed to prevent and/or reduce the incidence of GC in the general population.
REFERENCES
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2 Queiroz DM, Mendes EN, Rocha GA, Oliveira AM, Oliveira CA, Magalhães PP, et al. cagA-positive Helicobacter pylori and risk for developing gastric carcinoma in Brazil. Int J Cancer 1998;78:1359.[CrossRef][Medline]
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5 Israel DA, Salama N, Arnold CN, Moss SF, Ando T, Wirth HP, et al. Helicobacter pylori strain-specific differences in genetic content, identified by microarray, influence host inflammatory responses. J Clin Invest 2001;107:61120.
6 van Doorn LJ, Figueiredo C, Megraud F, Pena S, Midolo P, Queiroz DM, et al. Geographic distribution of vacA allelic types of Helicobacter pylori. Gastroenterology 1999;116:82330.[Medline]
7 Blaser MJ. Polymorphic bacteria persisting in polymorphic hosts: assessing Helicobacter pylori-related risks for gastric cancer. J Natl Cancer Inst 2002;94:16623.
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