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Meta-analysis of genome-wide association studies on the intolerance of angiotensin-converting enzyme inhibitors

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Objectives

To identify single nucleotide polymorphisms (SNPs) associated with switching from an angiotensin-converting enzyme (ACE)-inhibitor to an angiotensin receptor blocker.

Methods

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.

Results

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].

Conclusion

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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Keywords: adverse drug reaction; angio-oedema; angiotensin-converting enzyme inhibitors; angiotensin-converting enzyme-inhibitor intolerance; cough; genome-wide association study

Document Type: Research Article

Affiliations: 1: Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University 2: Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and School of Medicine, University of Dundee, Dundee 3: Department of Cardiology, Division of Heart and Lungs, University Medical Center, Durrer Centre for Cardiovascular Research, Netherlands Heart Institute, Utrecht, Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK 4: Department of Epidemiology, Erasmus Medical Center, Rotterdam 5: Department of Epidemiology, Erasmus Medical Center, Rotterdam, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA 6: Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Publication date: March 1, 2017

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