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Abstract
Helicobacter pylori, a gastric bacterial pathogen, colonises >50% of the world’s population. Colonisation invariably leads to chronic gastritis, with a small but significant proportion progressing to peptic ulcer disease and gastric cancer (GC). The reason why some individuals progress to severe disease is unknown, but is likely the result of an as yet unidentified combination of bacterial, host and environmental factors. This thesis aimed to elucidate the contribution of host genetics and H. pylori virulence to severe disease, particularly GC, in patients from different ethnicities.
Papers I, II and III investigated a comprehensive set of H. pylori virulence factors for their association with pro-inflammatory signalling in gastric epithelial cells in vitro and disease development. The major H. pylori virulence factors, including the cag PAI, vacA, babA and oipA were highly prevalent in all three ethnic groups resident in Malaysia and Singapore irrespective of the disease state of the host, suggesting all strains from this region are highly virulent. There was significant ethnic variation in the CagA EPIYA-motifs, HP0521 alleles and dupA, confirming that distinct H. pylori strains circulate within particular populations.
Paper IV assessed strains isolated from patients with different levels of inflammation for their ability to cause dendritic cell maturation and activation, and induce pro-inflammatory signalling in gastric epithelial cells in vitro. Strains from a higher inflammatory background induced higher levels of pro-inflammatory cytokine secretion in vitro.
Paper V examined a novel range of host genetic polymorphisms from genes in immune and cell signalling pathways for associations with susceptibility to H. pylori infection or GC. The prevalence of many polymorphisms varied significantly between the ethnic groups (Chinese, Indian and Malay), and several polymorphisms were associated with H. pylori infection (EBBR2+1963G) or GC (PTGS2-1195G, IL1B-1473C) in ethnic Chinese resident in Malaysia and Singapore.
In conclusion, substantial variation exists in the prevalence of genetic polymorphisms and the diversity of circulating strains among ethnic groups, as well as the ability of strains to induce inflammation; these findings may underlie differences in GC development and H. pylori infection. A combination of these factors in the same individual may provide a more complete picture.