期刊
PHARMACOGENOMICS JOURNAL
卷 20, 期 6, 页码 770-783出版社
SPRINGERNATURE
DOI: 10.1038/s41397-020-0165-2
关键词
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资金
- Swedish Research Council [521-2011-2440, 521-2014-3370, 2018-03307, 2017-00641]
- Swedish Heart and Lung Foundation [20120557, 20140291, 20170711]
- Medical Products Agency
- Selander's Foundation
- Thureus' Foundation
- Clinical Research Support Avtal om Lakarutbildning och Forskning at Uppsala University
- Swedish Diabetes foundation [DIA2017-269]
- European Community's Seventh Framework Programme (FP7/2007-2013) [602108]
- Netherlands Heart Foundation
- Dutch Top Institute Pharma Mondriaan Project
- UCL Hospitals NIHR Biomedical Research Centre
- Knut and Alice Wallenberg Foundation
- Swedish Research Council for Infrastructures and Science for Life Laboratory, Sweden
- Swedish Research Council [2018-03307] Funding Source: Swedish Research Council
- Vinnova [2018-03307] Funding Source: Vinnova
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 x 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 x 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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