The role of CagA status in gastric and extragastric complications of Helicobacter pylori

Two major markers of virulence have been described in H. pylori. The first is a secreted protein (VacA) that is toxic to human cells in tissue culture . This cytotoxin causes vacuolation of epithelial cells in vitro and induce s epithelial cell damage in mice. The second is a 40-Kb pathogenicity islan d for which the gene cagA (cytotoxin-associated gene A) is a marker. Approx imately 60% of H. pylori isolates in Western countries are cagA(+). The pro tein encoded by cagA has a molecular weight of 120-140 kDa and exhibits seq uence heterogeneity among strains isolated from Western and Eastern countri es. Although no specific function has been identified for CagA, there is in creasing evidence that cagA(+) strains are associated with increased intens ity of gastric inflammation and increased mucosal concentration of particul ar cytokines including interleukin 8. Inactivation of picB (Hp 0544) or any of several other genes in the cag island ablates the enhanced IL-8 secreti on of human gastric epithelial cells in tissue culture. Furthermore, person s colonized with cagA(+) strains have an increased risk of developing more severe gastric diseases such as peptic ulcer and distal (non-cardia) gastri c cancer than those harboring cagA(-) strains. We investigated the role of cagA status in both gastroduodenal and extragastroduodenal disease with H. pylori. Among the diseases limited to the antrum and body of the stomach an d the duodenum, we demonstrated a correlation between CagA seropositivity a nd peptic ulcer disease. We also showed correlation between distal gastric cancer rated and CagA prevalence in populations in both developed and devel oping countries. In addition, we found that for several Asian populations, the relationship between CagA seropositivity and gastroduodenal diseases wa s complex. For extragastroduodenal diseases, our results confirmed previous reports that demonstrated that CagA status did not play a role in diseases such as rheumatoid arthritis and hyperemesis gravidarum. However, we found a clear negative association between the presence of a positive response t o CagA and esophageal diseases. Therefore, CagA seropositivity (and thus ga stric carriage) is associated with increased risks of certain diseases (inv olving the lower stomach and duodenum) and decreased risks of GERD and its sequelae. This apparent paradox can best be explained by differences in the interaction of cagA(+) and cagA(-) strains with their hosts.