Genome-wide association study of angioedema induced by angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment.
Eva Rye RasmussenPär HallbergEkaterina V BaranovaNiclas ErikssonMalgorzata KarawajczykCaroline JohanssonMarco CavalliCyrielle MaroteauAbirami VeluchamyGunilla IslanderSvante HugossonIngrid TerreehorstFolkert W. AsselbergsPia NorlingHans-Erik JohanssonHugo KohnkeAnn-Christine SyvänenMoneeza K SiddiquiChim C LangPatrik K E MagnussonQun-Ying YueClaes WadeliusChristian von BuchwaldAnette BygumAna AlfirevicAnke H Maitland-van der ZeeColin Neil Alexander PalmerMia WadeliusPublished in: The pharmacogenomics journal (2020)
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.
Keyphrases
- angiotensin converting enzyme
- angiotensin ii
- copy number
- genome wide
- genome wide association study
- heart failure
- genome wide analysis
- transcription factor
- small molecule
- gene expression
- blood pressure
- genome wide identification
- type diabetes
- cardiovascular disease
- cystic fibrosis
- machine learning
- left ventricular
- combination therapy
- oxidative stress
- endothelial cells
- skeletal muscle
- hiv infected
- dna binding
- cardiac resynchronization therapy
- weight loss
- human immunodeficiency virus
- big data
- diabetic rats
- adverse drug