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

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 ARBinduced angioedema.

Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker–Induced Angioedema

“…Genome-wide association study results from the Vanderbilt study were used for replication. 22 Data were available for 438 Europeans and 214 black Americans. Population demographic of the genotyped Vanderbilt population has been previously described.…”

“…Other genes, serpin family E member 1 gene (SERPINE1) and the coagulation factor XII gene (F12), have been associated with hereditary angioedema. None of them have been significantly replicated in the only two published genome-wide association studies, where intronic variants in the calcium-activated potassium channel subunit alpha-1 (KCNMA1) were significantly associated with ACEI-AE in a Swedish cohort (SWEDEGENE study) 12 and a variant of the protein kinase C theta gene (PRKCQ) tended to be protective in a European American cohort. 13 In addition, studies have reported that the risk of ACEI-AE varies according to ethnicity and gender, with women and black Africans being more likely to develop this particular ADR 5,6,[14][15][16][17][18] .…”

“…Although previous studies assessed common variants in the association between ACEI and angioedema, 12,13 they have had limited success in identifying a genetic basis for this ADR. This study used next-generation sequencing technology to assess the influence of low frequency variants with intermediate penetrance and higher relative risks and combined association with common variants with ACEI-AE and ARB-AE, using cases and controls recruited in Scotland, Sweden, Denmark, the Netherlands, and England.…”

Common variants near the bradykinin receptor B2 gene are associated with angioedema induced by angiotensin-converting-enzyme inhibitor treatment - a genome wide association study

“…To assess the reproducibility of our findings, the lead variant that reached the genome-wide significant threshold ( P < 5 × 10 −8 ) was tested in the Swedegene GWAS data on ACEi-associated angioedema. [16] Significance threshold for replication was set at P < 0.05. To maximize the statistical power to detect associated genetic variants of small effect, we further conducted a meta-analysis of the two interrogated cohorts using summary statistics from the discovery and replication data.…”

“…[11,13,14] In recent years, two genome-wide association studies (GWAS) have been conducted on ACEi-associated angioedema, however, none of the findings reported in these two studies were validated in independent replication cohorts. [12,16]…”