Genome-Wide association between EYA1 and Aspirin-induced peptic ulceration.

Stephane Bourgeois,Celestine Esume,Andrew P Morris,Panos Deloukas,Crispin O Musumba,Munir Pirmohamed,D Mark Pritchard,Daniel F Carr,J Eunice Zhang,Alexander Penrose,Andrea L Jorgensen

doi:10.1016/j.ebiom.2021.103728

Abstract

BackgroundLow-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.MethodsPatients (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.FindingsThe 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.InterpretationGenetic 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.FundingDepartment of Health Chair in Pharmacogenetics, MRC Centre for Drug Safety Science and the Barts Cardiovascular NIHR Biomedical Research Centre, British Heart Foundation (BHF)

Highlights

Low-dose aspirin (75-325mg/day) is taken by up to 30% of the general population [1], its use rising with age
We focused on aspirin because this was the most common Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) associated with peptic ulceration in our cohort
Of the 723 samples genotyped on the Illumina Omni 2¢5 single nucleotide polymorphism (SNP) array, eight samples were excluded from all further analysis following a decision to withdraw from the study, one patient was found to have previously undergone GI surgery, and one had previous NSAID treatment, 26 samples did not cluster with the remainder of the cohort in the principal component analysis (PCA), one had an “other” self-declared ethnicity, and 10 samples had a missing phenotype, leaving 676 samples for analysis, 235 of which were cases (Table 1)

Summary

Introduction

Low-dose aspirin (75-325mg/day) is taken by up to 30% of the general population [1], its use rising with age. We performed a genome-wide association study that identified an intronic variant in the EYA1 gene associated with endoscopically confirmed aspirin-induced peptic ulceration. 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. Interpretation: Genetic variation in an intron of the EYA1 gene increases the risk of endoscopically confirmed aspirin-induced PUD.

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