Research Article: VacA and CagA Status as Biomarker of Two Opposite End Outcomes of Helicobacter pylori Infection (Gastric Cancer and Duodenal Ulcer) in a Moroccan Population

Date Published: January 26, 2017

Publisher: Public Library of Science

Author(s): Mounia El Khadir, Samia Alaoui Boukhris, Dafr-Allah Benajah, Karima El Rhazi, Sidi Adil Ibrahimi, Mohamed El Abkari, Taoufiq Harmouch, Chakib Nejjari, Mustapha Mahmoud, Mohamed Benlemlih, Bahia Bennani, Mohammed Soutto.

http://doi.org/10.1371/journal.pone.0170616

Abstract

Helicobacter pylori (H. pylori) infection induces inflammation of the gastric mucosa, which may progress to precancerous lesions leading to gastric cancer. Pathological determinism is associated to some virulence genes of the bacterium, notably the vacA and cagA genes. The present study aimed to determine the H. pylori genotypes distribution and their association with sex, age and gastric diseases in a Moroccan population. Gastric biopsy was taken from 1079 consenting patients. The specimens were processed by PCR to identify H. pylori and to determine the genotypic profile by PCR characterizing vacA s, vacA m and vacA i regions directly from biopsies H. pylori positives. VacA genotyping revealed the predominance of vacA m2 (53.2%), vacA s2 (52.9%) and vacA i2 (52%). The most virulent vacA alleles (s1, i1 and m1) are more predominant in men (47.3%, 41.9% and 46.1% respectively) than in women (38.3%, 33.3% and 37% respectively). However, the association between vacA genotypes and age did not reach a statistical significant value. Logistic regression analysis results show that vacA i1m1 and vacA i1m2 genotypes were strongly associated with the risk of GC, the Odds Ratio (95% confidence interval) was 29.73 [5.08–173.73] and 9.17 [2.06–40.82] respectively, while vacAs1/cagA+ seems to be a risk factor for DU since it is inversely associated with GC (OR was 0.13 [0.02–0.75]. The results of this study suggest that vacA i1 genotype independently to vacAm status may be of a clinical usefulness and will help to identify patients at a high risk of GC development.

Partial Text

Gastric cancer is the third common cause of cancer mortality in the world. Multiple epidemiological studies have documented an increased incidence of gastric cancer with increased prevalence of H. pylori infection. In Morocco, as in other African and South East Asian countries, there is a paradox between the high prevalence of H. pylori infection (59.7%) [1], and low incidence of gastric cancer (5.6%) [2]. The difference of the geographic distribution of H. pylori infection and gastric cancer incidence suggests the presence of the determining factors which could influence the interaction between pathogen and host. Those factors include: human genetic polymorphism, environmental influences and the high genomic diversity of H. pylori. Overall, the genetic diversity of the bacteria occurs mainly in the virulence factors such as the cytotoxin-associated gene (cagA) and the vacuolating cytotoxin (vacA). CagA protein is a 120- to 140-kDa protein that is translocated into host cells by the type IV cag secretion system after bacterial attachment, altering thereafter the cell-signaling mechanisms in gastric cells. VacA protein is a cytotoxin inducing vacuolation of the epithelial cell; the gene is present in all strains but only some of them have a vacuolating activity. This variation is attributed to variations in vacA gene structures within the three regions: the signal sequence region (s-region) (s1 or s2), mid-region (m-region) (m1 or m2) and the intermediate-region (i-region) (i1, i2 or i3) [3–5]. The polymorphism of these two virulent factors has been the subject of numerous investigations [6–9].

A total of 1079 patients from urban and rural areas of north center of Morocco and consulting for abdominal pain or discomfort were included in this study. They were 519 women (48.1%) and 560 men (51.9%). The clinical exam shows that 738 patients were with chronic gastritis, 260 with peptic ulcer disease (PUD), 119 with gastric ulcer [GU], 133 duodenal ulcers [DU], 8 with GU and DU and 81 patients were with gastric cancer (GC) [adenocarcinoma or gastric lymphoma]. All GC cases were confirmed by histological exam.

The H. pylori infection is strongly associated with peptic ulcer disease (PUD), gastric carcinoma, and gastric mucosa-associated lymphoid tissue (MALT) [15]. This bacterium is known for its high genetic diversity that occurs mainly in the bacterium virulence factors as the cytotoxin-associated gene (cagA) and the vacuolating cytotoxin (vacA) gene. The variability that affects these two genes may be useful to better understand the differences in the pathogenesis and the role of each genotype in the occurrence of the pathology. In fact, polymorphisms within vacA have been analyzed in several previous studies, but they have primarily focused on the signal region (s region) and the mid-region (m region), both of which have been used to predict the clinical outcome of infected patients. In Morocco, we have previously studied the polymorphism of vacA in those two regions (signal sequences (s) and mid-region (m)) and established their correlation to clinical outcomes and also to histological lesions[1,10]. Of note, in this study, we confirmed that the studied population was predominantly infected by the less virulent H. pylori strains (vacA s2m2) and we confirmed a significant association between vacA m1 and GC. However, it will be for interest to study vacA i alone and in combination to cagA status and to s and m vacA region in a large sampling to better characterize isolates that may lead to severe diseases, mainly the GC.

This study indicates that: i) H. pylori strains isolated from Moroccan patients are extremely diverse, ii) the less virulent strain vacA s2i2m2 is the most predominant in Morocco which can partially explain the African enigma, iii) vacAs1/cagA+ seems to be a risk factor for DU, iv) vacA i1 genotype (independently to vacA m status) isstrongly associated to the GC. So, patients infected with this genotype may need more attention. Therefore, vacA i1 may be of a clinical usefulness to identify patients at a high risk of GC development.

 

Source:

http://doi.org/10.1371/journal.pone.0170616

 

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