Meta-analysis of ACE inhibitor–induced angioedema identifies novel risk locus
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Journal of Allergy and Clinical Immunology |
| Vol/bind | 153 |
| Udgave nummer | 4 |
| Sider (fra-til) | 1073-1082 |
| ISSN | 0091-6749 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
This work was funded by in-house resources of both the Federal Institute for Drugs and Medical Devices (BfArM) and the Institute of Human Genetics, University Hospital of Bonn (grant nos. V-17454/68502/2017-2020 and V2021.5/68502/2022-2024). The research was supported by the Swedish Research Council, Swedish Heart and Lung Foundation, and Clinical Research Support Avtal om Läkarutbildning och Forskning at Uppsala University. The Swedish Twin Registry at Karolinska Institutet that provided controls was supported by and received funding from the Swedish Research Council. The SNP&SEQ Technology Platform at Uppsala University that performed part of the genotyping is supported by the Swedish Research Council. Computations were in part done on resources provided by the Uppsala Multidisciplinary Center for Advanced Computational Science. Swedegene receives funding from the Swedish Research Council. Data analyses were carried out in part in the High-Performance Computing Center of the University of Tartu. The Anorexia Nervosa Genetics Initiative is an initiative of the Klarman Family Foundation. Funding support for the VanMar cohorts was provided by the National Heart, Lung, and Blood Institute (NHLBI) grants R01-HL079184 and U01-HL065962, and the RIKEN Institute. L.M. and K.K. are supported by funding from Estonian Research Council grants (grant no. PRG184). M.K. is supported by Baszucki Brain Research Fund, Milken Institute Center for Strategic Philanthropy. J.G. is supported by BRIDGE—Translational Excellence Programme (NNF20SA0064340). T.A. is supported by the Region of Southern Denmark. M.L. received funding support from the Klarman Foundation.We thank all patients and control individuals for their participation in this study. We are grateful to Munkhtsetseg Altankhuyag, Dr Shimalee Andarawewa, Yenny Angela, Firas Asper, Dr Jens Bäte, Dr Karl-Enno Doehml, Dr Eva-Vanessa Ebert, Dr Burkhard Espey, Nina Evertz, Dr Susann Forkel, Marlina Gebert, PD Dr Thomas Gerhardt, Dr Lisa Hofmann, Dr Marcus Joest, PD Dr Johannes Just, Sophie Kläschen, Dimitri Korotkin, Magdalene Kunst, Dr Christin Löffler, Larissa Mosler, Manuel Nick, Dr Thomas Neiße, Monika Orda, Dr Stefani Röseler, Dr Evelyn Schneider, Marie Schuppe, Linda Sebesteny-Sorokin, Galina Shiderova, PD Dr Ullrich Straßen, Dr Julius Vahl, and Dr Brigitta Weltermann for their participation in the patient recruitment of the vARIANCE study. We are grateful to all physicians, research nurses, and supporting staff who assisted SWEDEGENE: Dr Malgorzata Karawajczyk, Dr Hans-Erik Johansson, Dr Leif Nordang, Dr Nina Bylund, Caroline Johansson, Hugo Kohnke, assistant Eva Prado (Uppsala University Hospital, Sweden), RN Ulrica Ramqvist, RN Charlotta Haglund, and assistant Sofie Collin (Uppsala University, Sweden). Furthermore, we thank Christine Schmäl for her critical reading of the manuscript. The Estonian Biobank Research Team has contributed to data creation and QC. The samples and associated genotype and phenotype data of the VanMar cohorts used in this study were provided by Vanderbilt University Medical Center (dbGaP accession phs000438.v1.p1). This research has been conducted using the UKB Resource (application no. 60928). The views and opinions expressed in this article are those of the authors, and do not necessarily reflect the official opinion of the German Federal Institute for Drugs and Medical Devices.
Funding Information:
This work was funded by in-house resources of both the Federal Institute for Drugs and Medical Devices (BfArM) and the Institute of Human Genetics, University Hospital of Bonn (grant nos. V-17454/68502/2017-2020 and V2021.5/68502/2022-2024). The research was supported by the Swedish Research Council , Swedish Heart and Lung Foundation, and Clinical Research Support Avtal om Läkarutbildning och Forskning at Uppsala University . The Swedish Twin Registry at Karolinska Institutet that provided controls was supported by and received funding from the Swedish Research Council . The SNP&SEQ Technology Platform at Uppsala University that performed part of the genotyping is supported by the Swedish Research Council . Computations were in part done on resources provided by the Uppsala Multidisciplinary Center for Advanced Computational Science. Swedegene receives funding from the Swedish Research Council. Data analyses were carried out in part in the High-Performance Computing Center of the University of Tartu. The Anorexia Nervosa Genetics Initiative is an initiative of the Klarman Family Foundation . Funding support for the VanMar cohorts was provided by the National Heart, Lung, and Blood Institute (NHLBI) grants R01-HL079184 and U01-HL065962, and the RIKEN Institute. L.M. and K.K. are supported by funding from Estonian Research Council grants (grant no. PRG184). M.K. is supported by Baszucki Brain Research Fund, Milken Institute Center for Strategic Philanthropy. J.G. is supported by BRIDGE—Translational Excellence Programme (NNF20SA0064340). T.A. is supported by the Region of Southern Denmark. M.L. received funding support from the Klarman Foundation.
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© 2024 The Authors
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