Abstract
BackgroundHelicobacter pylori are stomach-dwelling bacteria that are present in about 50% of the global population. Infection is asymptomatic in most cases, but it has been associated with gastritis, gastric ulcers and gastric cancer. Epidemiological evidence shows that progression to cancer depends upon the host and pathogen factors, but questions remain about why cancer phenotypes develop in a minority of infected people. Here, we use comparative genomics approaches to understand how genetic variation amongst bacterial strains influences disease progression.ResultsWe performed a genome-wide association study (GWAS) on 173 H. pylori isolates from the European population (hpEurope) with known disease aetiology, including 49 from individuals with gastric cancer. We identified SNPs and genes that differed in frequency between isolates from patients with gastric cancer and those with gastritis. The gastric cancer phenotype was associated with the presence of babA and genes in the cag pathogenicity island, one of the major virulence determinants of H. pylori, as well as non-synonymous variations in several less well-studied genes. We devised a simple risk score based on the risk level of associated elements present, which has the potential to identify strains that are likely to cause cancer but will require refinement and validation.ConclusionThere are a number of challenges to applying GWAS to bacterial infections, including the difficulty of obtaining matched controls, multiple strain colonization and the possibility that causative strains may not be present when disease is detected. Our results demonstrate that bacterial factors have a sufficiently strong influence on disease progression that even a small-scale GWAS can identify them. Therefore, H. pylori GWAS can elucidate mechanistic pathways to disease and guide clinical treatment options, including for asymptomatic carriers.
Highlights
Helicobacter pylori are stomach-dwelling bacteria that are present in about 50% of the global population
gastric cancer (GC), progressive to cancer” (Prog) and non-atrophic gastritis (NAG) isolates were found in multiple places on the tree, and isolates from Northern Europe clustered at one end of the tree and those from Southern Europe and South America at the other (Fig. 1)
Isolates from patients with gastric cancer are distributed across the tree, and after decomposing the genetic data into principal components, none was found to be significantly associated with the cancer phenotype
Summary
Helicobacter pylori are stomach-dwelling bacteria that are present in about 50% of the global population. Infection is asymptomatic in most cases, but it has been associated with gastritis, gastric ulcers and gastric cancer. We use comparative genomics approaches to understand how genetic variation amongst bacterial strains influences disease progression. The bacterium Helicobacter pylori can colonize the stomach for years without causing any symptoms [1], but its presence is associated with several serious clinical diseases including peptic ulcer, gastric cancer and MALT lymphoma. Progression to clinical disease depends in part upon diet, environment and host factors [2, 3] as well as the genotypes of the bacteria [4]. A better understanding of the role of H. pylori in causing disease and identification of virulent strains would allow intervention to be targeted at patients most at risk of the subsequent disease.
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