Original Investigation
Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors

https://doi.org/10.1016/j.jacc.2021.05.054Get rights and content
Under an Elsevier user license
open archive

Abstract

Background

Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients.

Objectives

The aim of this study was to identify genetic factors associated with ACE inhibitor–associated angioedema.

Methods

A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model.

Results

The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor–treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor–treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 × 10–8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 × 10−9). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 × 10−3). We found that carriers of the risk allele had significantly lower systolic (−0.46 mm Hg per T allele; 95% CI: −0.83 to −0.10; P = 0.013) and diastolic (−0.26 mm Hg per T allele; 95% CI: −0.46 to −0.05; P = 0.013) blood pressure.

Conclusions

In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with increased risk for ACE inhibitor–related angioedema.

Key Words

ACE inhibitors
ADR
adverse drug reaction
angioedema
bradykinin
bradykinin receptor B2

Abbreviations and Acronyms

ACE
angiotensin-converting enzyme
CI
confidence interval
eQTL
expression quantitative trait loci
FDR
false discovery rate
GWAS
genomewide association study
LD
linkage disequilibrium
MR
Mendelian randomization
OR
odds ratio
PC
principal components
PRS
polygenic risk score
SMR
summary data–based Mendelian randomization
SNP
single-nucleotide polymorphism

Cited by (0)

Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.