Meta-analysis of ACE inhibitor–induced angioedema identifies novel risk locus - 04/04/24

Doi : 10.1016/j.jaci.2023.11.921

Carina M. Mathey ^a, Carlo Maj, PhD ^b,^c, Niclas Eriksson, PhD ^d,^e, Kristi Krebs, PhD ^f, Julia Westmeier, PhD ^a, Friederike S. David, MSc ^a, Maria Koromina, PhD ^g, Annika B. Scheer ^a, Nora Szabo ^a, Bettina Wedi, MD ^h, Dorothea Wieczorek, MD ^h, Philipp M. Amann, MD ⁱ, Harald Löffler, MD ^j, Lukas Koch, MD ^k, Clemens Schöffl, MD ^k, Heinrich Dickel, MD ^l, Nomun Ganjuur, MD ^l,^m, Thorsten Hornung, MD ⁿ, Timo Buhl, MD ^o, Jens Greve, MD ^p, Gerda Wurpts, MD ^q, Emel Aygören-Pürsün, MD ^r, Michael Steffens, MD ^s, Stefan Herms ^a, Stefanie Heilmann-Heimbach, PhD ^a, Per Hoffmann, PhD ^a, Börge Schmidt, PhD ^t, Laven Mavarani, PhD ^t, Trine Andresen, PhD ^u, Signe Bek Sørensen, PhD ^u, Vibeke Andersen, PhD ^u,^v,^w, Ulla Vogel, PhD ^x, Mikael Landén, MD, PhD ^y,^z, Cynthia M. Bulik, PhD ^z,^aa,^ab,
Estonian Biobank Research Team^∗
Names of all the members of the Estonian Biobank Research Team and the DBDS Genomic Consortium are provided in this article’s Online Repository at www.jacionline.org.
DBDS Genomic Consortium^∗
Names of all the members of the Estonian Biobank Research Team and the DBDS Genomic Consortium are provided in this article’s Online Repository at www.jacionline.org.
Anette Bygum, MD, DMSci ^ac,^ad, Patrik K.E. Magnusson, PhD ^z, Christian von Buchwald, MD, DMSci ^ae, Pär Hallberg, MD, PhD ^e, Sisse Rye Ostrowski, MD, PhD, DMSci ^af,^ag, Erik Sørensen, PhD ^af, Ole B. Pedersen, MD ^ag, Henrik Ullum, MD, PhD ^ah, Christian Erikstrup, MD, PhD ^ai,^aj, Henning Bundgaard, MD, PhD, DMSci ^ag, Lili Milani, PhD ^f, Eva Rye Rasmussen, MD, PhD ^ae,^ak, Mia Wadelius, MD, PhD ^e, Jonas Ghouse, MD, PhD ^al,^am,^{^{‡
These authors have contributed equally to this work and share senior authorship.}}, Bernhardt Sachs, MD ^q,^s,^{^{‡
These authors have contributed equally to this work and share senior authorship.}}, Markus M. Nöthen, MD ^a,^{^{‡
These authors have contributed equally to this work and share senior authorship.}}, Andreas J. Forstner, MD ^a,^an,^{^{‡
These authors have contributed equally to this work and share senior authorship.},}^⁎
^a Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany
^b Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany
^c Centre for Human Genetics, University of Marburg, Marburg, Germany
^d Uppsala Clinical Research Center, Uppsala, Sweden
^e Department of Medical Sciences, Clinical Pharmacogenomics and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
^f Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
^g Icahn School of Medicine, Mount Sinai, New York, NY
^h Department of Dermatology and Allergy, Comprehensive Allergy Center, Hannover Medical School, Hannover, Germany
ⁱ Department of Medicine, Faculty of Medicine and Dentistry, Danube Private University, Krems, Austria
^j Department of Dermatology, SLK Hospital Heilbronn, Heilbronn, Germany
^k Department of Dermatology and Venereology, Medical University Graz, Graz, Austria
^l Department of Dermatology, Venereology and Allergology, St Josef Hospital, University Medical Center, Ruhr University Bochum, Bochum, Germany
^m Institute of Health Care Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
ⁿ Department of Dermatology and Allergy, University Hospital of Bonn, Bonn, Germany
^o Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany
^p Department of Otorhinolaryngology—Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
^q Department of Dermatology and Allergy, Aachen Comprehensive Allergy Center, University Hospital RWTH Aachen, Aachen, Germany
^r Department for Children and Adolescents, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany
^s Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany
^t Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
^u Molecular Diagnostics and Clinical Research Unit, Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
^v Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
^w OPEN, University of Southern Denmark, Odense, Denmark
^x National Research Centre for the Working Environment, Copenhagen, Denmark
^y Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
^z Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
^aa Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC
^ab Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC
^ac Department of Clinical Institute, University of Southern Denmark, Odense, Denmark
^ad Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
^ae Department of Otorhinolaryngology—Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
^af Department of Clinical Immunology, Copenhagen Hospital Biobank Unit, Rigshospitalet, Copenhagen, Denmark
^ag Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
^ah Statens Serum Institute, Copenhagen, Denmark
^ai Departments of Clinical Immunology, Aarhus University, Aarhus, Denmark
^aj Departments of Clinical Medicine, Aarhus University, Aarhus, Denmark
^ak Departments of Private Practice Ølsemaglevej, Køge, Denmark
^al Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
^am Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
^an Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany

^∗Corresponding author: Andreas J. Forstner, MD, Institute of Human Genetics, University Hospital Bonn, Venusberg-Campus 1, Bonn 53127, Germany.Institute of Human GeneticsUniversity Hospital BonnVenusberg-Campus 1Bonn53127Germany

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.

Le texte complet de cet article est disponible en PDF.

Key words : Genome-wide association study, meta-analysis, angiotensin-converting enzyme inhibitor, angioedema, angiotensin-converting enzyme inhibitor–induced angioedema

Abbreviations used : ACEi, ACEi-AE, BDKRB2, CADD, CHB-CVDC/DBDS, EDEM2, EPCR, eQTL, EstBB, F5, GWAS, LD, OR, PIP, PROCR, PRS, QC, SNP, UKB

Plan

Export

Vol 153 - N° 4

P. 1073-1082 - avril 2024 Retour au numéro

Article précédent

Persistent esophageal changes after histologic remission in eosinophilic esophagitis
Melanie A. Ruffner, Tetsuo Shoda, Megha Lal, Zoe Mrozek, Amanda B. Muir, Jonathan M. Spergel, Evan S. Dellon, Marc E. Rothenberg

| Article suivant

Impaired interferon response in plasmacytoid dendritic cells from children with persistent wheeze
Isabelle Coenen, Emma de Jong, Anya C. Jones, Siew-Kim Khoo, Shihui Foo, Shanshan Wu Howland, Florent Ginhoux, Peter N. Le Souëf, Patrick G. Holt, Deborah H. Strickland, Ingrid A. Laing, Jonatan Leffler

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

connectez-vous ou créez un compte

Meta-analysis of ACE inhibitor–induced angioedema identifies novel risk locus - 04/04/24

Abstract

Background

Objective

Methods

Results

Conclusions

Plan

Export citations

Fichier

Contenu

Accès rapides

Mon compte

Aide & support

Plateformes Elsevier Masson

Déclaration CNIL