Jonas Ghouse1, Gustav Ahlberg2, Laura Andreasen2, Karina Banasik3, Søren Brunak3, Michael Schwinn4, Ina Holst Larsen4, Oscar Petersen4, Erik Sørensen4, Henrik Ullum5, Eva Rye Rasmussen6, Niclas Eriksson7, Pär Hallberg8, Mia Wadelius8, Henning Bundgaard9, Morten S Olesen2. 1. Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: jonasghouse@gmail.com. 2. Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. 3. Translational Disease Systems Biology, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 4. Department of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 5. Statens Serum Institut, Copenhagen, Denmark. 6. Department of Otorhinolaryngology, Head & Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 7. Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden. 8. Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. 9. Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
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.
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.
Authors: Ina H Laursen; Karina Banasik; Amalie D Haue; Oscar Petersen; Peter C Holm; David Westergaard; Henning Bundgaard; Søren Brunak; Ruth Frikke-Schmidt; Hilma Holm; Erik Sørensen; Lise W Thørner; Margit A H Larsen; Michael Schwinn; Lars Køber; Christian Torp-Pedersen; Sisse R Ostrowski; Christian Erikstrup; Mette Nyegaard; Hreinn Stefánsson; Arnaldur Gylfason; Florian Zink; G Bragi Walters; Asmundur Oddsson; Guðmar Þorleifsson; Gisli Másson; Unnur Thorsteinsdottir; Daniel Gudbjartsson; Ole B Pedersen; Kári Stefánsson; Henrik Ullum Journal: BMJ Open Date: 2021-12-30 Impact factor: 3.006
Authors: Carina M Mathey; Carlo Maj; Annika B Scheer; Julia Fazaal; Bettina Wedi; Dorothea Wieczorek; Philipp M Amann; Harald Löffler; Lukas Koch; Clemens Schöffl; Heinrich Dickel; Nomun Ganjuur; Thorsten Hornung; Susann Forkel; Jens Greve; Gerda Wurpts; Pär Hallberg; Anette Bygum; Christian Von Buchwald; Malgorzata Karawajczyk; Michael Steffens; Julia Stingl; Per Hoffmann; Stefanie Heilmann-Heimbach; Elisabeth Mangold; Kerstin U Ludwig; Eva R Rasmussen; Mia Wadelius; Bernhardt Sachs; Markus M Nöthen; Andreas J Forstner Journal: Front Genet Date: 2022-07-18 Impact factor: 4.772