Abstract
Helicobacter pylori (HP) is a bacterium that colonizes the human stomach and can establish a long-term infection of the gastric mucosa. Persistent Hp infection often induces gastritis and is associated with the development of peptic ulcer disease, atrophic gastritis, and gastric adenocarcinoma. Virulent HP isolates harbor the cag (cytotoxin-associated genes) pathogenicity island (cagPAI), a 40 kb stretch of DNA that encodes components of a type IV secretion system (T4SS). This T4SS forms a pilus for the injection of virulence factors into host target cells, such as the CagA oncoprotein. We analyzed the genetic variability in cagA and other selected genes of the HP cagPAI (cagC, cagE, cagL, cagT, cagV and cag Gamma) using DNA extracted from frozen gastric biopsies or from clinical isolates. Study subjects were 95 cagA+ patients that were histologically diagnosed with chronic gastritis or gastric cancer in Venezuela and Mexico, areas with high prevalence of Hp infection. Sequencing reactions were carried out by both Sanger and next-generation pyrosequencing (454 Roche) methods. We found a total of 381 variants with unambiguous calls observed in at least 10% of the originally tested samples and reference strains. We compared the frequencies of these genetic variants between gastric cancer and chronic gastritis cases. Twenty-six SNPs (11 non-synonymous and 14 synonymous) showed statistically significant differences (P<0.05), and two SNPs, in position 1039 and 1041 of cagE, showed a highly significant association with cancer (p-value = 2.07×10−6), and the variant codon was located in the VirB3 homology domain of Agrobacterium. The results of this study may provide preliminary information to target antibiotic treatment to high-risk individuals, if effects of these variants are confirmed in further investigations.
Highlights
Helicobacter pylori (HP) is one of the most common chronic bacterial infection in humans
The best characterized HP virulence marker is the cytotoxinassociated gene pathogenicity island, a 40 kb region of chromosomal DNA encoding approximately 31 genes that forms a type IV secretion system (T4SS) to translocate bacterial products into the host cell. cagA resides within cagPAI and is responsible for most of the HP-associated malignant phenotypes: it triggers IL-8 secretion priming an inflammatory response, promotes cell proliferation, scattering and migration either through phosphorylation-dependent and independent mechanisms [9,10]
Results in the other cagPAI genes Genetic variability of cagC cagE, cagT, cagV and cag Gamma was assessed by 454 sequencing and of cagL by Sanger sequencing
Summary
Helicobacter pylori (HP) is one of the most common chronic bacterial infection in humans. Approximately 10–15% of the infected individuals are estimated to experience clinically adverse sequelae, including peptic ulcers, gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue lymphoma (MALT) [2]. Despite extensive effort worldwide, what determines these variable clinical outcomes has not been fully elucidated, but believed to be combinations of environmental (e.g., smoking and diet) [3], host genetics and HP virulence factors [3,4,5]. The best characterized HP virulence marker is the cytotoxinassociated gene pathogenicity island (cagPAI), a 40 kb region of chromosomal DNA encoding approximately 31 genes that forms a type IV secretion system (T4SS) to translocate bacterial products into the host cell. The cagPAI is present in approximately 95% of East Asian isolates and it is less frequent in isolates from low risk Western countries [11,12,13]
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