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

ObjectiveAngioedema is a rare, but potentially life-threatening adverse reaction, associated with angiotensin-converting-enzyme inhibitors (ACEi). Identification of potential genetic factors related to this adverse event may help identify at-risk patients. Design, Setting and ParticipantsA genome-wide association study (GWAS) involving patients of European descent, all taking ACEi was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as persons with an angioedema event and a filled prescription for an ACEi 180 days prior to the event. Controls were defined as persons with continuous treatment with ACEi without any history of angioedema. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were computed for angioedema risk by logistic mixed model regression analysis. Summary statistics from the discovery and the replication cohorts were analyzed with a fixed effects meta-analysis model. ExposureSingle-nucleotide polymorphisms associated with ACEi-associated angioedema. Main outcomeHospital record of angioedema. ResultsThe discovery cohort consisted of 462 cases and 53,391 ACEi-treated controls. The replication cohort consisted of 144 cases and 1,345 ACEi-treated controls. In the discovery cohort, we identified one locus, residing at chromosome 14q32.2, that was associated with angioedema at the genome-wide significance level of P <5 x 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 x 10-9). This variant was validated in our replication cohort with similar direction and effect size (OR 1.60; 95 % CI 1.13 to 2.25; P = 7.2 x 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mmHg per T allele; 95 % CI -0.83 to -0.10; P = 0.013) and diastolic blood pressure (-0.26 mmHg per T allele; 95 % CI -0.46 to -0.05; P = 0.013). ConclusionIn this GWAS, involving individuals treated with ACEi, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with ACEi-related angioedema. BDKRB2 genotype-directed therapy may aid in improving safety in evidence-based clinical decision-making.