Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus

Carina M Mathey; Carlo Maj; Niclas Eriksson; Kristi Krebs; Julia Westmeier; Friederike S David; Maria Koromina; Annika B Scheer; Nora Szabo; Bettina Wedi; Dorothea Wieczorek; Philipp M Amann; Harald Löffler; Lukas Koch; Clemens Schöffl; Heinrich Dickel; Nomun Ganjuur; Thorsten Hornung; Timo Buhl; Jens Greve; Gerda Wurpts; Emel Aygören-Pürsün; Michael Steffens; Stefan Herms; Stefanie Heilmann-Heimbach; Per Hoffmann; Börge Schmidt; Laven Mavarani; Trine Andresen; Signe Bek Sørensen; Vibeke Andersen; Ulla Vogel; Mikael Landén; Cynthia M Bulik; Estonian Biobank Research Team; DBDS Genomic Consortium; Anette Bygum; Patrik K E Magnusson; Christian von Buchwald; Pär Hallberg; Sisse Rye Ostrowski; Erik Sørensen; Ole B Pedersen; Henrik Ullum; Christian Erikstrup; Henning Bundgaard; Lili Milani; Eva Rye Rasmussen; Mia Wadelius; Jonas Ghouse; Bernhardt Sachs; Markus M Nöthen; Andreas J Forstner

doi:10.1016/j.jaci.2023.11.921

Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus

J Allergy Clin Immunol. 2024 Apr;153(4):1073-1082. doi: 10.1016/j.jaci.2023.11.921. Epub 2024 Jan 31.

Authors

Carina M Mathey¹, Carlo Maj², Niclas Eriksson³, Kristi Krebs⁴, Julia Westmeier¹, Friederike S David¹, Maria Koromina⁵, Annika B Scheer¹, Nora Szabo¹, Bettina Wedi⁶, Dorothea Wieczorek⁶, Philipp M Amann⁷, Harald Löffler⁸, Lukas Koch⁹, Clemens Schöffl⁹, Heinrich Dickel¹⁰, Nomun Ganjuur¹¹, Thorsten Hornung¹², Timo Buhl¹³, Jens Greve¹⁴, Gerda Wurpts¹⁵, Emel Aygören-Pürsün¹⁶, Michael Steffens¹⁷, Stefan Herms¹, Stefanie Heilmann-Heimbach¹, Per Hoffmann¹, Börge Schmidt¹⁸, Laven Mavarani¹⁸, Trine Andresen¹⁹, Signe Bek Sørensen¹⁹, Vibeke Andersen²⁰, Ulla Vogel²¹, Mikael Landén²², Cynthia M Bulik²³; Estonian Biobank Research Team; DBDS Genomic Consortium; Anette Bygum²⁴, Patrik K E Magnusson²⁵, Christian von Buchwald²⁶, Pär Hallberg²⁷, Sisse Rye Ostrowski²⁸, Erik Sørensen²⁹, Ole B Pedersen³⁰, Henrik Ullum³¹, Christian Erikstrup³², Henning Bundgaard³⁰, Lili Milani⁴, Eva Rye Rasmussen³³, Mia Wadelius²⁷, Jonas Ghouse³⁴, Bernhardt Sachs³⁵, Markus M Nöthen¹, Andreas J Forstner³⁶

Affiliations

¹ Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
² Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany; Centre for Human Genetics, University of Marburg, Marburg, Germany.
³ Uppsala Clinical Research Center, Uppsala, Sweden; Department of Medical Sciences, Clinical Pharmacogenomics and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁴ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁵ Icahn School of Medicine, Mount Sinai, New York, NY.
⁶ Department of Dermatology and Allergy, Comprehensive Allergy Center, Hannover Medical School, Hannover, Germany.
⁷ Department of Medicine, Faculty of Medicine and Dentistry, Danube Private University, Krems, Austria.
⁸ Department of Dermatology, SLK Hospital Heilbronn, Heilbronn, Germany.
⁹ Department of Dermatology and Venereology, Medical University Graz, Graz, Austria.
¹⁰ Department of Dermatology, Venereology and Allergology, St Josef Hospital, University Medical Center, Ruhr University Bochum, Bochum, Germany.
¹¹ Department of Dermatology, Venereology and Allergology, St Josef Hospital, University Medical Center, Ruhr University Bochum, Bochum, Germany; Institute of Health Care Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹² Department of Dermatology and Allergy, University Hospital of Bonn, Bonn, Germany.
¹³ Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany.
¹⁴ Department of Otorhinolaryngology-Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany.
¹⁵ Department of Dermatology and Allergy, Aachen Comprehensive Allergy Center, University Hospital RWTH Aachen, Aachen, Germany.
¹⁶ Department for Children and Adolescents, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany.
¹⁷ Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
¹⁸ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
¹⁹ Molecular Diagnostics and Clinical Research Unit, Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
²⁰ Molecular Diagnostics and Clinical Research Unit, Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; OPEN, University of Southern Denmark, Odense, Denmark.
²¹ National Research Centre for the Working Environment, Copenhagen, Denmark.
²² Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC.
²⁴ Department of Clinical Institute, University of Southern Denmark, Odense, Denmark; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
²⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁶ Department of Otorhinolaryngology-Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
²⁷ Department of Medical Sciences, Clinical Pharmacogenomics and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
²⁸ Department of Clinical Immunology, Copenhagen Hospital Biobank Unit, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁹ Department of Clinical Immunology, Copenhagen Hospital Biobank Unit, Rigshospitalet, Copenhagen, Denmark.
³⁰ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³¹ Statens Serum Institute, Copenhagen, Denmark.
³² Departments of Clinical Immunology, Aarhus University, Aarhus, Denmark; Departments of Clinical Medicine, Aarhus University, Aarhus, Denmark.
³³ Department of Otorhinolaryngology-Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Departments of Private Practice Ølsemaglevej, Køge, Denmark.
³⁴ 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.
³⁵ Department of Dermatology and Allergy, Aachen Comprehensive Allergy Center, University Hospital RWTH Aachen, Aachen, Germany; Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
³⁶ Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany; Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany. Electronic address: [email protected].

PMID: 38300190
DOI: 10.1016/j.jaci.2023.11.921

Abstract

Background: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited.

Objective: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology.

Methods: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE.

Results: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort.

Conclusions: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Keywords: Genome-wide association study; angioedema; angiotensin-converting enzyme inhibitor; angiotensin-converting enzyme inhibitor–induced angioedema; meta-analysis.

Publication types

Meta-Analysis

MeSH terms

Angioedema* / chemically induced
Angioedema* / genetics
Angiotensin-Converting Enzyme Inhibitors / adverse effects
Bradykinin
Drug-Related Side Effects and Adverse Reactions*
Genome-Wide Association Study
Humans

Substances

Angiotensin-Converting Enzyme Inhibitors
Bradykinin