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

Pharmacogenet Genomics. 2017 Mar;27(3):112-119. doi: 10.1097/FPC.0000000000000264.


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) 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].

Conclusion: These results indicate that genetic variation in the above-mentioned genes may increase the risk of ACE-inhibitor-induced adverse reactions.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / genetics
  • Adaptor Proteins, Signal Transducing / genetics
  • Aged
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects*
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Antigens, Nuclear / genetics
  • Diabetes Mellitus / drug therapy*
  • Diabetes Mellitus / genetics
  • Female
  • Gene Frequency
  • Gene Regulatory Networks*
  • Genome-Wide Association Study / methods*
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Nerve Tissue Proteins / genetics
  • Odds Ratio
  • Polymorphism, Single Nucleotide*
  • Receptors, GABA-A / genetics


  • Adaptor Proteins, Signal Transducing
  • Angiotensin-Converting Enzyme Inhibitors
  • Antigens, Nuclear
  • GABRG2 protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Receptors, GABA-A
  • SH2B1 protein, human
  • neuronal nuclear antigen NeuN, human
  • Acetyltransferases
  • MBOAT1 protein, human