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

Objective Angioedema 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 Participants A 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. Exposure Single-nucleotide polymorphisms associated with ACEi-associated angioedema. Main outcome Hospital record of angioedema. Results The 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 × 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 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 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). Conclusion In 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement J.G is the guarantor of this study. This work was supported by The John and Birthe Meyer Foundation, The Research Foundation at Rigshospitalet, Villadsen Family Foundation, The Arvid Nilsson Foundation, The Hallas-Moeller Emerging Investigator Novo Nordisk (NNF17OC0031204), Novo Nordisk Foundation (grants NNF17OC0027594 and NNF14CC0001), The Swedish Research Council (Medicine 521 2011 2440, 521 2014 3370 and 2018 03307), Swedish Heart and Lung Foundation (20120557, 20140291 and 20170711), Medical Products Agency, Selanders Foundation, Thureus Foundation and Clinical Research Support (Avtal om Laekarutbildning och Forskning) at Uppsala University. The Swedish Twin Registry is managed by Karolinska Institutet, and receives funding through the Swedish Research Council under grant no. 2017-00641. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by The Danish National Ethical Committee (1708829) and the Danish Data Protection Agency (general approval number 2012-58-0004, and local number: RH-2007-30-4129/I-suite 00678). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data will be made available upon request to the corresponding author.