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

Eva Rye Rasmussen, P. r 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. MagnussonQun-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.

Original languageEnglish
Pages (from-to)770-783
Number of pages14
Journalpharmacogenomics journal
Issue number6
Publication statusPublished - Dec 2020

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