Probabilidad Condicional, Independencia y Teorema de Ba yes

One of the hypotheses that attempts to explain the difference in gastric adenocarcinoma incidence between populations worldwide is that individual strains

of Helicobacter pylori have different degrees of pathogenicity. In support of this

hypothesis, a number of differences have been demonstrated between strains of

Helicobacter pylori cultured from different populations. Amongst the most

significant differences is the presence or absence of the Cag pathogenicity island, a group of genes that allows intra-cytosolic injection of bacterial components into epithelial cells. This group of genes is present in 60% of H. pylori strains isolated in Western populations, but is almost universal in strains isolated from the Far East (135). Similarly, there is heterogeneity in the sequence of the ubiquitously expressed VacA cytotoxin (136), and the adhesion molecules SabA (137) and BabA (138, 139) that alter the interaction of Helicobacter pylori with gastric mucosa. Each of these bacterial virulence factors has the potential to generically increase the pathogenicity of Helicobacter pylori infection, increasing the risk of developing both benign and malignant disease. More recently, DupA has become the first

Helicobacter pylori virulence factor recognised to potentially influence the type of

pathology induced by chronic Helicobacter pylori infection (140).

1.2.4.1.1 The cag pathogenicity island

The cag pathogenicity island is a group of 31 genes, most of which encode a type IV bacterial secretion system. This construct acts to facilitate the transfer of bacterial proteins directly into a host eukaryotic cell, allowing transfer of the Helicobacter

protein CagA, which is also encoded within the Cag pathogenicity island (cagPAI), and peptidoglycan, into the cell. Meta-analysis of the effect of CagA seropositivity on risk of gastric cancer (clinically used as a surrogate for infection with a CagA and cagPAI positive strain of H.pylori) demonstrated a relative risk of 1.64 (95% CI 1.21 – 2.24) over infection with CagA negative strains (141).

CagA binds to and activates SHP-2, CSK and CRK, all of which have Src-homology domains. These interactions have a number of cellular effects including RAS MAPK pathway and NF-κB classical pathway activation as well as stabilisation of β-catenin, interruption of tight junctions and cytoskeletal remodelling. In-vitro, this can be

58 observed by the addition of CagA to AGS gastric cell line culture, which results in cell scattering and a change in cellular morphology (142, 143). In-vivo, transgenic expression of CagA results in spontaneous gastric hyperplasia and carcinogenesis (144). Epidemiological studies suggest that, in Western populations, there is a positive correlation between atrophic gastritis and gastric adenocarcinoma and CagA positive strains of Helicobacter pylori (145-147). Similar data do not exist for Asian populations due to the almost ubiquitous nature of CagA positivity.

CagA also has a number of different isoforms which are differentially distributed geographically. The CagA molecule has a variable region in its C-terminal portion that is made up of several EPIYA (glutamic acid-proline-isoleucine-tyrosine-alanine)) motifs. The sequence surrounding the EPIYA motif defines each segment as either EPIYA-A, -B, -C or-D. EPIYA A and B motifs are universally expressed in Western isolates of CagA positive H. pylori. EPIYA-C is expressed in 1, 2 or 3 repeats in Western isolates of CagA, and confers increasing pathogenicity with increasing numbers of motifs (148). EPIYA –D is present only in isolates from the Far East.

EPIYA–D containing isoforms of CagA have greater Shp2 binding activity than others. When mice expressing Western and East Asian CagA subtypes are compared, greater susceptibility to carcinogenesis is observed in the mice expressing the East Asian variant (149).

1.2.4.1.2 VacA

VacA is a ubiquitously expressed cytotoxin, but it demonstrates genetic heterogeneity with a differential global distribution. There are two regions of heterogeneity within the VacA gene; one in the signalling domain, giving genotypes s1 and s2, the other in the midpoint of the gene, giving genotypes m1 and m2 (150). Genotype s1 has a strong association with both benign and malignant gastric disease. In a Western population, the relative risk for gastric cancer associated with this allele is 8.28 (95% CI 2.75–24.95) (136). In East Asian Helicobacter strains, this genotype is almost ubiquitous, and there are no data available on any association with different pathology in such populations.

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1.2.4.1.3 DupA

DupA is a homolog of the type IV secretory system protein vir. In a study examining samples from a total of 5008 patients, it was found to be expressed in 25.1% of cases, and its expression was positively correlated with increased risk of peptic ulcer disease. DupA positivity conferred a 3.1 (95% CI 1.7-5.7) fold relative risk of duodenal ulcer, but its presence was negatively correlated with gastric cancer risk, conferring a relative risk of 0.42 (95% CI 0.2-0.9) in this study (140).

1.2.4.1.4 Other bacterial virulence factors

In addition to cag PAI and VacA, there are other proposed virulence factors that act on bacterial adherence to epithelial cells, including BabA (138), a blood group antigen binding adhesin, which has a reported polymorphism described as BabA2. In a Chinese population, infection with a BabA2 positive organism conferred relative risks of 7.5 (95% CI: 2.3-24.3) and 7.4 (95% CI: 2.2-25.3) for developing gastric atrophy and gastric metaplasia when compared with BaBA2 negative infections (139). The sialic acid binding adhesion SabA is also considered to be a putative virulence factor for Helicobacter pylori as it has a role in bacterial adhesion, and there is genetic heterogeneity of the gene encoding it that is distributed in a similar geographical pattern to gastric cancer cases, however the effect of these polymorphisms on cancer or other pathological risk has yet to be demonstrated (137, 151).