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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	NSAID ulcer Aspirin GWAS Medicine R Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/e356fc46996447cfa33cfd26c73f0564
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spelling	oai:doaj.org-article:e356fc46996447cfa33cfd26c73f05642021-12-04T04:34:42ZGenome-Wide association between EYA1 and Aspirin-induced peptic ulceration2352-396410.1016/j.ebiom.2021.103728https://doaj.org/article/e356fc46996447cfa33cfd26c73f05642021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352396421005223https://doaj.org/toc/2352-3964ABSTRACT: 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)Stephane BourgeoisDaniel F. CarrCrispin O. MusumbaAlexander PenroseCelestine EsumeAndrew P. MorrisAndrea L. JorgensenJ. Eunice ZhangD. Mark PritchardPanos DeloukasMunir PirmohamedElsevierarticleNSAIDulcerAspirinGWASMedicineRMedicine (General)R5-920ENEBioMedicine, Vol 74, Iss , Pp 103728- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	NSAID ulcer Aspirin GWAS Medicine R Medicine (General) R5-920
spellingShingle	NSAID ulcer Aspirin GWAS Medicine R Medicine (General) R5-920 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 Genome-Wide association between EYA1 and Aspirin-induced peptic ulceration
description	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)
format	article
author	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
author_facet	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
author_sort	Stephane Bourgeois
title	Genome-Wide association between EYA1 and Aspirin-induced peptic ulceration
title_short	Genome-Wide association between EYA1 and Aspirin-induced peptic ulceration
title_full	Genome-Wide association between EYA1 and Aspirin-induced peptic ulceration
title_fullStr	Genome-Wide association between EYA1 and Aspirin-induced peptic ulceration
title_full_unstemmed	Genome-Wide association between EYA1 and Aspirin-induced peptic ulceration
title_sort	genome-wide association between eya1 and aspirin-induced peptic ulceration
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/e356fc46996447cfa33cfd26c73f0564
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Genome-Wide association between EYA1 and Aspirin-induced peptic ulceration

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