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

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.

Cohort profile: Copenhagen Hospital Biobank - Cardiovascular Disease Cohort (CHB-CVDC): Construction of a large-scale genetic cohort to facilitate a better understanding of heart diseases.

PURPOSE: The aim of Copenhagen Hospital Biobank-Cardiovascular Disease Cohort (CHB-CVDC) is to establish a cohort that can accelerate our understanding of CVD initiation and progression by jointly studying genetics, diagnoses, treatments and risk factors. PARTICIPANTS: The CHB-CVDC is a large genomic cohort of patients with CVD. CHB-CVDC currently includes 96 308 patients. The cohort is part of CHB initiated in 2009 in the Capital Region of Denmark. CHB is continuously growing with ~40 000 samples/year. Patients in CHB were included in CHB-CVDC if they were above 18 years of age and assigned at least one cardiovascular diagnosis. Additionally, up-to 110 000 blood donors can be analysed jointly with CHB-CVDC. Linkage with the Danish National Health Registries, Electronic Patient Records, and Clinical Quality Databases allow up-to 41 years of medical history. All individuals are genotyped using the Infinium Global Screening Array from Illumina and imputed using a reference panel consisting of whole-genome sequence data from 8429 Danes along with 7146 samples from North-Western Europe. Currently, 39 539 of the patients are deceased. FINDINGS TO DATE: Here, we demonstrate the utility of the cohort by showing concordant effects between known variants and selected CVDs, that is, >93% concordance for coronary artery disease, atrial fibrillation, heart failure and cholesterol measurements and 85% concordance for hypertension. Furthermore, we evaluated multiple study designs and the validity of using Danish blood donors as part of CHB-CVDC. Lastly, CHB-CVDC has already made major contributions to studies of sick sinus syndrome and the role of phytosterols in development of atherosclerosis. FUTURE PLANS: In addition to genetics, electronic patient records, national socioeconomic and health registries extensively characterise each patient in CHB-CVDC and provides a promising framework for improved understanding of risk and protective variants. We aim to include other measurable biomarkers for example, proteins in CHB-CVDC making it a platform for multiomics cardiovascular studies.