Gastroenterology

Gastroenterology

Volume 135, Issue 1, July 2008, Pages 91-99
Gastroenterology

Clinical–Alimentary Tract
Clinical Relevance of Helicobacter pylori cagA and vacA Gene Polymorphisms

https://doi.org/10.1053/j.gastro.2008.03.041Get rights and content

Background & Aims: The Helicobacter pylori gene cagA and s1 or m1 forms of vacA are more common in disease-associated strains. Recently, forms of cagA encoding multiple type C EPIYA segments (which increase phosphorylation-dependent CagA activity) and a new type i1 “intermediate region” polymorphism in vacA (which confers toxicity) have been described. We assessed the association of new and established cagA and vacA polymorphisms with disease. Methods: We studied 203 H pylori–infected subjects (53 gastric cancer [GC], 52 peptic ulcer [PU], and 98 gastritis). vacA signal, mid and intermediate region polymorphisms, cagA presence, and EPIYA-C segment number were analyzed by polymerase chain reaction. Results: cagA-positive strains were significantly associated with GC and PU (P < .001 and P < .05). GC risk was further associated with the number of cagA EPIYA-C segments (odds ratio [OR] = 7.37, 95% confidence interval [CI] = 1.98–27.48 for 1 EPIYA-C segment; OR = 32.5, 95% CI = 8.41–125.58 for 2 or more EPIYA-C segments). Increasing number of EPIYA-C segments also increased the risk of intestinal metaplasia. Type s1 and i1 vacA alleles were also associated with GC and type i1 vacA with PU (OR = 2.58, 95% CI = 1.19–5.61), including a significant association with duodenal ulcer. In multivariate analysis, the associations of cagA EPIYA-C segment number with GC and intestinal metaplasia as well as vacA i1 type association with PU remained. Conclusions: We confirmed the associations of cagA and vacA polymorphisms with disease but now define their most important features. For cancer risk, among Western strains, the most important factor is the number of cagA EPIYA-C segment. For PU risk, it is the intermediate region type of vacA.

Section snippets

Patients

In this retrospective study, we selected 203 H pylori–infected subjects. A total of 150 patients with benign diseases were selected from a series of 1145 consecutive outpatients admitted to the Endoscopic Unit of the University Hospital of Padova for investigation of dyspepsia. The selection criteria were as follows: (1) presence of H pylori infection (see Supplementary Table 1 for definition; see supplementary material online at www.gastrojournal.org), (2) no previous treatment for H pylori

vacA Typing

Of our 203 samples, 4 and 53 had untypeable vacA s and m regions, respectively. We performed successful vacA i region typing at a later date on DNA from 171 available cases. Typing of 10 cases (1 GC, 4 PU, and 5 gastritis) showed probable mixed strain infection in that both s1 and s2 or both i1 and i2 or both m1 and m2 vacA alleles, or a combination, were found. These cases were not included in subsequent association analyses.

The Polymorphic Structure of vacA

To study the structure of vacA in our samples, we excluded strains

Discussion

The most widely researched and best-established H pylori virulence factors are the vacuolating cytotoxin, VacA, and the cytotoxin-associated protein A, CagA.2, 18, 19, 29 CagA has received renewed interest following the demonstration that the 3′ region of the cagA gene varies in size due to a variable number of repeats encoding type C EPIYA phosphorylation sites.8 For vacA, a new polymorphic region (the i region) has been described and shown to be a major determinant of toxicity; vacA type i1

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    Supported by AIRC regional grant 2005 and by Cancer Research UK and CORE, the digestive diseases charity.

    The authors report they have no conflict to disclose.

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