Polygenic risk score for ACE-inhibitor-associated cough based on the discovery of new genetic loci

Jonas Ghouse, Vinicius Tragante, Ayesha Muhammad, Gustav Ahlberg, Morten W Skov, Dan M Roden, Ingileif Jónsdóttir, Laura Andreasen, Pia Rengtved Lundegaard, Linea C Trudsø, Karina Banasik, Søren Brunak, Sisse R Ostrowski, Christian Torp-Pedersen, Ole V Pedersen, Erik Sørensen, Lars Køber, Kasper Iversen, Unnur Þorsteinsdóttir, Guðmundur ÞorgeirssonHenrik Ullum, Daniel F Gudbjartsson, Jonathan D Mosley, Hilma Holm, Kári Stefánsson, Henning Bundgaard, Morten Salling Olesen

Research output: Contribution to journalArticlepeer-review


AIMS: To search for sequence variants associated with ACEi discontinuation and to test their association with ACEi-associated adverse drug reactions (ADRs). METHODS AND RESULTS: A genome-wide association study (GWAS) on ACEi discontinuation was conducted, including 33 959 ACEi-discontinuers and 44 041 controls. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. Controls were defined as persons who continued ACEi treatment for at least 1 year. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed for ACEi discontinuation risk by mixed model regression analysis. Summary statistics from the individual cohorts were meta-analyzed with a fixed-effects model. To test for association with specific ACEi-associated ADRs, any genome-wide significant (P < 5 × 10-8) ACEi discontinuation variants was tested for association with ACEi-associated cough and angioedema. A polygenetic risk score (PRS) based on ACEi discontinuation GWAS data was constructed and tested for association with ACEi-associated cough and angioedema in two population-based samples. In total, seven genetic genome-wide loci were identified, of which six were previously unreported. The strongest association with ACEi discontinuation was at 20q13.3 (NTSR1; OR: 1.21; 95% CI: 1.17-1.24; P = 2.1 × 10-34). Five of seven lead variants were associated with ACEi-associated cough, whereas none were associated with ACEi-associated angioedema. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose-response manner but not with ACEi-associated angioedema. ACEi discontinuation was genetically correlated with important causes for cough, including gastro-esophageal reflux disease, allergic rhinitis, hay fever, and asthma, which indicates partly shared genetic underpinning between these traits. CONCLUSION: This study showed the advantage of using prescription patterns to discover genetic links with ADRs. In total, seven genetic loci that associated with ACEi discontinuation were identified. There was evidence of a strong association between our ADR phenotype and ACEi-associated cough. Taken together, these findings increase insight into the pathophysiological processes that underlie ACEi-associated ADRs.

Original languageEnglish
Pages (from-to)4707-4718
Number of pages12
JournalEuropean Heart Journal
Issue number45
Early online date25 Jun 2022
Publication statusPublished - 1 Dec 2022

Bibliographical note

Publisher Copyright:
© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Other keywords

  • ACE inhibitors
  • ACE-inhibitor associated cough
  • ADR
  • Adverse drug reaction
  • Drug discontinuation
  • GWAS
  • Genome-wide association study
  • Genome-Wide Association Study
  • Humans
  • Risk Factors
  • Genetic Loci
  • Angioedema/chemically induced
  • Cough/chemically induced
  • Angiotensin-Converting Enzyme Inhibitors/adverse effects


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