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Laboratory of Research in Bacteriology,1 Department of Pathology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil2
Received 16 April 2003/ Returned for modification 28 May 2003/ Accepted 1 June 2003
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There is now evidence for the existence of different strains of H. pylori with different degrees of virulence (2, 3, 18). The cytotoxin-associated gene cagA was the first gene found to be differentially present in H. pylori isolates and is considered a marker for the presence of the cag pathogenicity island (4). In addition to other putative virulence properties encoded by the cag pathogenicity island, several genes of the island encode proteins, such as interleukin-8, that enhance the gastric inflammatory response to the infection.
A cagA-positive status has been associated with severe clinical outcomes in some Western countries (3, 14, 18). Conversely, since the majority of H. pylori-infected individuals in Asian countries harbor cagA-positive strains, associations of cagA status and diseases are not observed in Asia (11, 20). The recently described blood group antigen-binding adhesin BabA has been shown to mediate adherence of H. pylori to Lewis b (-1,3/4-difucosylated) receptors on gastric epithelium (8). Although three bab alleles have been identified (babA1, babA2, and babB), only the babA2 gene product is necessary for Lewis b binding activity (8, 16). Studies in Western countries have demonstrated associations between babA2-positive status and duodenal ulcer as well as gastric carcinoma (7). However, in Asian countries, most of the circulating H. pylori strains are babA2 positive, whether or not they were isolated from asymptomatic or diseased patients (9, 10, 12, 20). In addition to these differences between Western and Eastern countries, the prevalence of babA2-positive H. pylori strains also seems to vary among the Western populations, being much lower in patients from Portugal (13) than in those from Germany, the United States, or Colombia (7, 20). Since there are few studies on this subject, specifically evaluating patients with gastric carcinoma, the frequency of babA2 H. pylori strains may vary around the world and because the clinical relevance of babA2-positive strains has not been determined in Brazil, we investigated associations between babA2 and cagA genotypes and different H. pylori infection outcomes, adjusting for confounding factors.
H. pylori strains isolated from the gastric mucosa of 208 Brazilian patients (mean age, 48.37 ± 16.16 years; age range, 18 to 84 years) (104 females, 104 males) from the State of Minas Gerais between 1999 and 2002 were studied. They were selected from nonconsecutive H. pylori-positive patients who underwent endoscopy for evaluation of dyspeptic symptoms at the University Hospital, Federal University of Minas Gerais, Belo Horizonte, Brazil. Of the 208 patients, 80 had duodenal ulcer (mean age, 41.29 ± 14.32 years; age range, 18 to 76 years), 52 had gastric distal carcinoma (mean age, 59.83 ± 13.30 years; age range, 32 to 84 years), and 76 did not have a peptic ulcer or gastric carcinoma (mean age, 46.93 ± 15.87 years; age range, 18 to 80 years). Informed consent was obtained from all patients, and research protocols were approved by the Ethics Committee of the University Hospital.
Two H. pylori strains isolated from Portuguese patients, whose babA gene was sequenced previously (13), were graciously provided by the researchers and included as positive and negative controls. For cagA detection, cagA-positive (ATCC 49503) and cagA-negative (TX30A) strains were used as controls. DNA from the H. pylori strains isolated in BHM (17) was extracted with QIAamp (Qiagen, Hilden, Germany) and PCR amplified for cagA and babA2 by the methods of Peek et al. (15) and Gerhard et al. (7), respectively. Integrity of DNA was confirmed by ureA PCR (5). Hematoxylin-eosin-stained sections of the antral and oxyntic mucosae were analyzed in terms of the degree of inflammatory reaction and activity and scored as follows: 0, none; 1, mild; 2, moderate; and 3, marked (6).
Data were analyzed with SPSS statistical software package (version 10.0; SPSS Inc., Chicago, Ill.). An association between the severity of the antral and oxyntic gastritis with babA2 or cagA status was evaluated in the patients without duodenal ulcer and gastric carcinoma by the Mann-Whitney two-tailed test. Models of logistic regression adjusting for potential confounding factors, such as age and gender, were constructed, as it has previously been demonstrated that the presence of some virulence markers increase with age (1). Since babA2 and cagA were closely linked, cagA status was included as an independent variable when babA2 was the reference, and vice versa.
Ninety-six (46.15%) and 166 (79.81%) strains were babA2 and cagA positive, respectively (Table 1). The frequency of babA2 was similar to that seen in Portugal (13) and may be related to Brazilian population origin but is completely different from the data observed in other Western and Asian countries (7, 10, 12, 20). This regional difference may be due to an actual low frequency of the gene in the H. pylori strains that circulate in Portugal and Brazil or to variability within the gene that impairs PCR amplification. Although we cannot rule out the last possibility, it seems less probable, since the annealing sites of the primers we used were not from the region with the greatest diversity observed in babA2 (between nucleotides 612 and 1046) (16). In accordance with the results from Germany (7), we observed a strong and independent association between the presence of the babA2 gene and duodenal ulcer as well as gastric carcinoma (Table 2). In contrast, Yamaoka et al. (20) failed to detect an independent association between the babA2 gene and duodenal ulcer even in Western populations. This may be due to the lower power of discrimination that occurs when the covariates are very frequent, as is the case of cagA and babA2 in the population they studied. Our data demonstrated that although babA2- and cagA-positive genotypes were associated with each other (P = 0.039) in Minas Gerais, Brazil, they were also independently associated with duodenal ulcer and gastric carcinoma, even after adjusting for confounding factors. However, the odds ratios for cagA-positive status were higher than those for babA2, which implies that cagA-positive status is more helpful in discriminating H. pylori-associated diseases. The presence of both babA2 and cagA was associated with more marked antral inflammation (P = 0.05 for both). Other inflammation variables were not associated with the presence of babA2 (P > 0.25), but a significant association was also seen between cagA-positive status and corpus inflammation (P = 0.05) and activity (P = 0.025).
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