To identify single nucleotide polymorphisms (SNPs) associated with switching from an angiotensin-converting enzyme (ACE)-inhibitor to an angiotensin receptor blocker.
Two cohorts of patients starting ACE-inhibitors were identified within the Rotterdam Study in the Netherlands and the Genetics of Diabetes Audit and Research in Tayside Scotland study in Scotland. Cases were intolerant patients who switched from an ACE-inhibitor to an angiotensin receptor blocker and controls were individuals who used ACE-inhibitors continuously for at least 2 years and did not switch. Genome-wide association study (GWAS) using an additive model was run in these sets and the results were meta-analysed using Genome-Wide Association Meta Analysis software.
A total of 972 cases out of 5161 ACE-inhibitor starters were identified. Eight SNPs within four genes reached the genome-wide association study significance level (P<5×10–8) in the meta-analysis [RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), γ-aminobutyric acid receptor subunit γ-2, sarcoma (Src) homology 2 (SH2) B adaptor protein 1 and membrane bound O-acyltransferase domain containing 1]. The strongest associated SNP was located in an intron of RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), which contains an RNA binding protein [rs2061538: minor allele frequency=0.16, odds ratio=1.52 (95% confidence interval: 1.32–1.76), P=6.2×10–9].
These results indicate that genetic variation in the above-mentioned genes may increase the risk of ACE-inhibitor-induced adverse reactions.
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aDepartment of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University
bDepartment of Cardiology, Division of Heart and Lungs, University Medical Center
cDurrer Centre for Cardiovascular Research, Netherlands Heart Institute, Utrecht
dDepartment of Epidemiology, Erasmus Medical Center, Rotterdam
eDepartment of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
fCentre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee
gInstitute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK
hDepartment of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
* Seyed H. Mahmoudpour, Abirami Veluchamy, Anke H. Maitland-van der Zee and Colin N.A. Palmer contributed equally to the writing of this article.
Correspondence to Colin N.A. Palmer, Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Division of Cardiovascular & Diabetes Medicine, Level 5, Mailbox 12 Ninewells Hospital and Medical School, Dundee DD1 9SY, UK Tel: +44 138 238 3155; fax: +44 138 266 8278; e-mail: firstname.lastname@example.org
Received September 1, 2016
Accepted December 5, 2016