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 GreveGerda 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, 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, Estonian Biobank Research Team, DBDS Genomic Consortium

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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.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Issue number4
Pages (from-to)1073-1082
Publication statusPublished - Apr 2024

Bibliographical note

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© 2024 The Authors


  • angioedema
  • angiotensin-converting enzyme inhibitor
  • angiotensin-converting enzyme inhibitor–induced angioedema
  • Genome-wide association study
  • meta-analysis
  • Genome-Wide Association Study
  • Humans
  • Bradykinin
  • Drug-Related Side Effects and Adverse Reactions
  • Angiotensin-Converting Enzyme Inhibitors/adverse effects
  • Angioedema/chemically induced


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