Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment
(2020) In Pharmacogenomics Journal 20(6). p.770-783- 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... (More)
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.
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- author
- publishing date
- 2020-02-21
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Pharmacogenomics Journal
- volume
- 20
- issue
- 6
- pages
- 770 - 783
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:32080354
- scopus:85079767042
- ISSN
- 1470-269X
- DOI
- 10.1038/s41397-020-0165-2
- language
- English
- LU publication?
- no
- id
- cf0a34e2-b271-48d3-8513-9063b0b0e728
- date added to LUP
- 2020-03-19 07:13:52
- date last changed
- 2025-01-10 08:17:03
@article{cf0a34e2-b271-48d3-8513-9063b0b0e728,
abstract = {{<p>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<sup>−5</sup>). 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<sup>−8</sup>). 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.</p>}},
author = {{Rasmussen, Eva Rye and Hallberg, Pär and Baranova, Ekaterina V. and Eriksson, Niclas and Karawajczyk, Malgorzata and Johansson, Caroline and Cavalli, Marco and Maroteau, Cyrielle and Veluchamy, Abirami and Islander, Gunilla and Hugosson, Svante and Terreehorst, Ingrid and Asselbergs, Folkert W. and Norling, Pia and Johansson, Hans Erik and Kohnke, Hugo and Syvänen, Ann Christine and Siddiqui, Moneeza K. and Lang, Chim C. and Magnusson, Patrik K.E. and Yue, Qun Ying and Wadelius, Claes and von Buchwald, Christian and Bygum, Anette and Alfirevic, Ana and Maitland-van der Zee, Anke H. and Palmer, Colin N.A. and Wadelius, Mia}},
issn = {{1470-269X}},
language = {{eng}},
month = {{02}},
number = {{6}},
pages = {{770--783}},
publisher = {{Nature Publishing Group}},
series = {{Pharmacogenomics Journal}},
title = {{Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment}},
url = {{http://dx.doi.org/10.1038/s41397-020-0165-2}},
doi = {{10.1038/s41397-020-0165-2}},
volume = {{20}},
year = {{2020}},
}