Genome-Wide association between EYA1 and Aspirin-induced peptic ulceration
Stephane Bourgeois,
Daniel F. Carr,
Crispin O. Musumba,
Alexander Penrose,
Celestine Esume,
Andrew P. Morris,
Andrea L. Jorgensen,
J. Eunice Zhang,
D. Mark Pritchard,
Panos Deloukas,
Munir Pirmohamed
Affiliations
Stephane Bourgeois
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London UK
Daniel F. Carr
Department of Pharmacology and Therapeutics, University of Liverpool, UK
Crispin O. Musumba
Department of Pharmacology and Therapeutics, University of Liverpool, UK
Alexander Penrose
Department of Pharmacology and Therapeutics, University of Liverpool, UK
Celestine Esume
Department of Pharmacology and Therapeutics, University of Liverpool, UK
Andrew P. Morris
Department of Pharmacology and Therapeutics, University of Liverpool, UK; Department of Health Data Science, University of Liverpool, UK; Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, Manchester, UK
Andrea L. Jorgensen
Department of Health Data Science, University of Liverpool, UK
J. Eunice Zhang
Department of Pharmacology and Therapeutics, University of Liverpool, UK
D. Mark Pritchard
Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK
Panos Deloukas
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London UK; Professor Panos Deloukas, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, T: 020 7882 2103
Munir Pirmohamed
Department of Pharmacology and Therapeutics, University of Liverpool, UK; Corresponding author at: Wolfson Centre for Personalised Medicine, Department of Pharmacology and Therapeutics, University of Liverpool, Block A: Waterhouse Buildings, 1-5 Brownlow Street, Liverpool, L69 3GL.
ABSTRACT: Background: Low-dose aspirin can cause gastric and duodenal ulceration, hereafter called peptic ulcer disease (PUD). Predisposition is thought to be related to clinical and genetic factors; our aim was to identify genetic risk factors associated with aspirin-induced PUD. Methods: Patients (n=1478) were recruited from 15 UK hospitals. Cases (n=505) were defined as patients with endoscopically confirmed PUD within 2 weeks of using aspirin and non-aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). They were compared to two control groups: patients with endoscopically confirmed PUD without any history of NSAID use within 3 months of diagnosis (n=495), and patients with no PUD on endoscopy (n=478). A genome-wide association study (GWAS) of aspirin-induced cases (n=247) was compared to 476 controls. The results were validated by replication in another 84 cases and 162 controls. Findings: The GWAS identified one variant, rs12678747 (p=1·65×10−7) located in the last intron of EYA1 on chromosome 8. The association was replicated in another sample of 84 PUD patients receiving aspirin (p=0·002). Meta-analysis of discovery and replication cohort data for rs12678747, yielded a genome-wide significant association (p=3·12×10−11; OR=2·03; 95% CI 1·65-2·50). Expression of EYA1 was lower at the gastric ulcer edge when compared with the antrum. Interpretation: Genetic variation in an intron of the EYA1 gene increases the risk of endoscopically confirmed aspirin-induced PUD. Reduced EYA1 expression in the upper gastrointestinal epithelium may modulate risk, but the functional basis of this association will need mechanistic evaluation. Funding: Department of Health Chair in Pharmacogenetics, MRC Centre for Drug Safety Science and the Barts Cardiovascular NIHR Biomedical Research Centre, British Heart Foundation (BHF)