Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment

Research output: Contribution to journalArticle

Abstract

Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for hypertension, heart failure and diabetes complications. This candidate gene and genome-wide association study aimed to identify genetic variants predisposing to angioedema induced by these drugs. The discovery cohort consisted of 173 cases and 4890 controls recruited in Sweden. In the candidate gene analysis, ETV6, BDKRB2, MME, and PRKCQ were nominally associated with angioedema (p < 0.05), but did not pass Bonferroni correction for multiple testing (p < 2.89 × 10−5). In the genome-wide analysis, intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) gene on chromosome 10 were significantly associated with angioedema (p < 5 × 10−8). Whilst the top KCNMA1 hit was not significant in the replication cohort (413 cases and 599 ACEi-exposed controls from the US and Northern Europe), a meta-analysis of the replication and discovery cohorts (in total 586 cases and 1944 ACEi-exposed controls) revealed that each variant allele increased the odds of experiencing angioedema 1.62 times (95% confidence interval 1.05–2.50, p = 0.030). Associated KCNMA1 variants are not known to be functional, but are in linkage disequilibrium with variants in transcription factor binding sites active in relevant tissues. In summary, our data suggest that common variation in KCNMA1 is associated with risk of angioedema induced by ACEi or ARB treatment. Future whole exome or genome sequencing studies will show whether rare variants in KCNMA1 or other genes contribute to the risk of ACEi- and ARB-induced angioedema.

Details

Authors
  • Eva Rye Rasmussen
  • Pär Hallberg
  • Ekaterina V. Baranova
  • Niclas Eriksson
  • Malgorzata Karawajczyk
  • Caroline Johansson
  • Marco Cavalli
  • Cyrielle Maroteau
  • Abirami Veluchamy
  • Svante Hugosson
  • Ingrid Terreehorst
  • Folkert W. Asselbergs
  • Pia Norling
  • Hans Erik Johansson
  • Hugo Kohnke
  • Ann Christine Syvänen
  • Moneeza K. Siddiqui
  • Chim C. Lang
  • Patrik K.E. Magnusson
  • Qun Ying Yue
  • Claes Wadelius
  • Christian von Buchwald
  • Anette Bygum
  • Ana Alfirevic
  • Anke H. Maitland-van der Zee
  • Colin N.A. Palmer
  • Mia Wadelius
External organisations
  • University of Copenhagen
  • Odense University Hospital
  • Uppsala University
  • Utrecht University
  • Uppsala University Hospital
  • University of Dundee
  • Skåne University Hospital
  • Örebro University Hospital
  • Academic Medical Center of University of Amsterdam (AMC)
  • University Medical Center Utrecht
  • Sickla Health Centre
  • Karolinska Institutet
  • WHO Uppsala Monitoring Centre
  • University of Southern Denmark
  • University of Liverpool
  • Copenhagen University Hospital
  • Q-linea AB
  • Ninewells Hospital and Medical School
  • Örebro University
  • University College London
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pharmacology and Toxicology
  • Medical Genetics
Original languageEnglish
JournalPharmacogenomics Journal
Publication statusE-pub ahead of print - 2020 Feb 21
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes