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

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  • Eva Rye Rasmussen
  • Pär Hallberg
  • Ekaterina V Baranova
  • Niclas Eriksson
  • Malgorzata Karawajczyk
  • Caroline Johansson
  • Marco Cavalli
  • Cyrielle Maroteau
  • Abirami Veluchamy
  • Gunilla Islander
  • 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
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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.

TidsskriftThe pharmacogenomics journal
Udgave nummer6
Sider (fra-til)770-783
Antal sider14
StatusUdgivet - dec. 2020

Bibliografisk note

Funding Information:
Acknowledgements We are grateful to all physicians, research nurses and supporting staff, who assisted in recruiting patients and controls or administering phenotype databases. In particular, Dr Leif Nordang, Dr Nina Bylund, and assistant Eva Prado, Uppsala University Hospital, RN Ulrica Ramqvist, RN Charlotta Haglund, and assistant Sofie Collin, Uppsala University, Sweden; Prof. Frantz Rom Poulsen (Open Patient Data Explorative Network), Odense University Hospital, Odense, Denmark; Dr Alexander SF Doney (GoDARTS bio resource) and Prof. Sara Marshall, Ninewells Hospital, Dundee, RN Diane van Ecker and RN Ruth Westhead, University of Liverpool, Liverpool, UK; Dr L.J.J.M. Bauwens, Westfriesgasthuis, Hoorn, Dr M. van der Torn, Westfriesgasthuis, Hoorn, Dr Chris Nieuwhof, UMC Maastricht, Dr Heike Röckmann, UMC Utrecht, Mr M.Q.N.G. Ruigrok, VUMC Amsterdam, Ms H.D.M. Smidt-Huizinga, UMC Groningen, and Ms M.H. Bugter, UMC Groningen, Netherlands. Lastly, we are grateful to Prof. Nancy J Brown at Vanderbilt University Medical Center for generously sharing GWAS data from the American study. This research was supported by the Swedish Research Council (Medicine 521–2011–2440, 521–2014–3370 and 2018-03307), Swedish Heart and Lung Foundation (20120557, 20140291 and 20170711), Medical Products Agency, Selander’s Foundation, Thureus’ Foundation, Clinical Research Support Avtal om Läkarutbildning och Forskning at Uppsala University, and Swedish Diabetes foundation (DIA2017-269). PREDICTION-ADR received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under Grant Agreement no. 602108. UCP studies were funded by the Netherlands Heart Foundation and the Dutch Top Institute Pharma Mondriaan Project. Folkert Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. We acknowledge the Swedish Twin Registry for access to data from controls. The Swedish Twin Registry is managed by Karolinska Institutet, and receives funding through the Swedish Research Council under grant no. 2017-00641. Genotyping of the discovery cohort was performed by the SNP&SEQ Technology Platform at Uppsala University ( The facility is part of the National Genomics Infrastructure supported by the Swedish Research Council for Infrastructures and Science for Life Laboratory, Sweden. The SNP&SEQ Technology Platform is also supported by the Knut and Alice Wallenberg Foundation. Computations were done on resources provided by the Swedish National Infrastructure for Computing through the Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX).

Funding Information:
Conflict of interest No funder took part in the study design, recruitment, analysis, interpretation of data, writing of the report or in the decision to submit the paper for publication.The study was part of Dr Eva Rye Rasmussen’s PhD thesis, which was financially supported by CSL Behring and by Shire with an investigator initiated research grant (grant no. IIR-DNK-001219). No other conflicts of interest exist.

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