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

Eva Rye Rasmussen,Pär Hallberg,Claes Wadelius,Ingrid Terreehorst,Anette Bygum,Gunilla Islander,Pia Norling,Folkert W Asselbergs,Hans Johansson ,Caroline Johansson,Niclas Eriksson,Christian Von Buchwald,Ekaterina Baranova ,Marco Cavalli,Patrik K E Magnusson,Moneeza K Siddiqui ,Chim C Lang,Abirami Veluchamy,Qun Ying Yue ,Malgorzata Karawajczyk,Cyrielle Maroteau,Colin N.a Palmer ,Ana Alfirevic,Ann Christine Syvänen ,Svante Hugosson,Hugo Kohnke,Anke‐Hilse Maitland‐Van Der Zee ,Mia Wadelius

doi:10.1038/s41397-020-0165-2

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.

Highlights

Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) containing medications are often used for hypertension, heart failure and diabetes complications, and currently 14% of the population in Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Extended author information available on the last page of the articleSweden is treated with these drugs [1]
This study aimed to identify common genetic risk factors for angioedema induced by ACEi or ARB treatment
Calcium-activated potassium channel genes are expressed in vascular smooth muscle and endothelium, and encode effector proteins crucial for control of vascular tone and blood pressure [50]

Summary

Introduction

Extended author information available on the last page of the article. Being mostly effective and safe, around 0.2–0.7% of patients starting an ACEi, and 0.1–0.2% starting an ARB experience the adverse drug reaction (ADR) angioedema [2,3,4,5,6]. ACEi- and ARB-induced angioedema is characterised by swelling of the reticular dermis and subcutaneous skin layers or mucosa [9, 11, 12]. It is usually localised to the head and neck region, and may become life threatening when breathing is impaired due to swelling in the oral

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