title: Meta-analysis of genome-wide association studies on the intolerance of angiotensin-converting enzyme inhibitors.
abstract: 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) 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].
  
  
  
  These results indicate that genetic variation in the above-mentioned genes may increase the risk of ACE-inhibitor-induced adverse reactions.
authors.affiliation: 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.
authors.forename: Seyed H
authors.initials: SH
authors.lastname: Mahmoudpour
authors.forename: Abirami
authors.initials: A
authors.lastname: Veluchamy
authors.forename: Moneeza K
authors.initials: MK
authors.lastname: Siddiqui
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Souverein
authors.forename: Catherine E
authors.initials: CE
authors.lastname: de Keyser
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Chim C
authors.initials: CC
authors.lastname: Lang
authors.forename: Alexander S F
authors.initials: AS
authors.lastname: Doney
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.forename: Anthonius
authors.initials: A
authors.lastname: de Boer
authors.forename: Anke H
authors.initials: AH
authors.lastname: Maitland-van der Zee
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
mesh_terms: D000123:Acetyltransferases / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D034961:Antigens, Nuclear / Q000235:genetics; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000806:Angiotensin-Converting Enzyme Inhibitors; D034961:Antigens, Nuclear; C546279:GABRG2 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; C518910:SH2B1 protein, human; C506808:neuronal nuclear antigen NeuN, human; D000123:Acetyltransferases; C521271:MBOAT1 protein, human