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

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 À7 ) 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 À11 ; 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.

East Asian-specific and cross-ancestry genome-wide meta-analyses provide mechanistic insights into peptic ulcer disease

“…With H. pylori (HP) infection and the use of non-steroidal anti-inflammatory drugs (NSAIDs) being two of the most common causes of GU and DU 3 , genetic factors also play a critical role in the development of PUD 4 . Previous genome-wide association studies (GWASs) of PUD had identified multiple loci, mainly HP-related, in Europeans 5,6 . Given the relatively high prevalence of PUD and HP infection in East Asians and the remarkably limited number of risk loci identified in East Asian populations 2,7 , GWAS with a larger sample size of EAS ancestry individuals would be required to enhance our understanding of genetic etiology of PUD.…”