Angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism and ACE inhibitor-related cough: a meta-analysis

PLoS One. 2012;7(6):e37396. doi: 10.1371/journal.pone.0037396. Epub 2012 Jun 19.


Objective: An insertion/deletion (I/D) variant in the angiotensin-converting enzyme (ACE) gene was associated with ACE inhibitor (ACEI)-related cough in previous studies. However, the results were inconsistent. Our objective was to assess the relationship between the ACE I/D polymorphism and ACEI-related cough by meta-analysis and to summarize all studies that are related to ACE I/D polymorphism and ACEI-cough and make a summary conclusion to provide reference for the researchers who attempt to conduct such a study.

Methods: Databases including PubMed, EMbase, Cochrane Library, and China National Knowledge Infrastructure, were searched for genetic association studies. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. Metaregression and subgroup analyses were performed to identify the source of heterogeneity.

Results: Eleven trials, including 906 cases (ACEI-related cough) and 1,175 controls, were reviewed in the present meta-analysis. The random effects pooled OR was 1.16 (95%CI: 0.78-1.74, p=0.46) in the dominant model and 1.61 (95%CI: 1.18-2.20, p=0.003) in the recessive model. Heterogeneity was found among and within studies. Metaregression indicated that the effect size was positively associated with age and negatively associated with follow-up duration of ACEI treatment. Subgroup analysis revealed a significant association between ACE I/D polymorphism and ACEI-related cough in studies with mean age >60 y, but not in studies with mean age ≤ 60 y. No heterogeneity was found within each mean age subgroup. We also found no association between ACE I/D polymorphism and ACEI-related cough in studies with follow-up>2 mo or in studies in Caucasians. No heterogeneity was detected in these two subgroups.

Conclusions: Synthesis of the available evidence supports ACE I/D polymorphism as an age-dependent predictor for risk of ACEI-related cough.

Publication types

  • Meta-Analysis

MeSH terms

  • Alleles
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects*
  • Case-Control Studies
  • Cough / chemically induced*
  • Cough / genetics*
  • Gene Deletion*
  • Gene Frequency
  • Genotype
  • Humans
  • Mutagenesis, Insertional*
  • Peptidyl-Dipeptidase A / genetics*
  • Polymorphism, Genetic


  • Angiotensin-Converting Enzyme Inhibitors
  • Peptidyl-Dipeptidase A