A GWAS on Helicobacter pylori strains points to genetic variants associated with gastric cancer risk
Elvire Berthenet,
Koji Yahara,
Kaisa Thorell,
Ben Pascoe,
Guillaume Meric,
Jane M. Mikhail,
Lars Engstrand,
Helena Enroth,
Alain Burette,
Francis Megraud,
Christine Varon,
John C Atherton,
Sinead Smith,
Thomas S. Wilkinson,
Matthew D. Hitchings,
Daniel Falush,
Samuel K. Sheppard
Affiliations
Elvire Berthenet
Microbiology and Infectious Disease Group, Swansea University Medical School, Swansea University
Koji Yahara
Antimicrobial Resistance Research Centre, National Institute of Infectious Diseases
Kaisa Thorell
Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet
Ben Pascoe
The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath
Guillaume Meric
The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath
Jane M. Mikhail
Microbiology and Infectious Disease Group, Swansea University Medical School, Swansea University
Lars Engstrand
Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet
Helena Enroth
Systems Biology Research Group, School of Biosciences, University of Skövde
Alain Burette
Department of Gastroenterology, Centre Hospitalier Interrégional Edith Cavell/Site de la Basilique
Francis Megraud
Laboratoire de Bactériologie, Centre National de Référence des Campylobacters et des Hélicobacters
Christine Varon
INSERM, University Bordeaux, UMR1053 Bordeaux Research In Translational Oncology, BaRITOn
John C Atherton
Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham
Sinead Smith
Department of Clinical Medicine, School of Medicine, Trinity College Dublin
Thomas S. Wilkinson
Microbiology and Infectious Disease Group, Swansea University Medical School, Swansea University
Matthew D. Hitchings
Microbiology and Infectious Disease Group, Swansea University Medical School, Swansea University
Daniel Falush
The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath
Samuel K. Sheppard
The Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath
Abstract Background 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. 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. Results We 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. Conclusion There 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.
