Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes

doi:10.3389/fgene.2022.914376

. 2022 Jul 18:13:914376.

doi: 10.3389/fgene.2022.914376. eCollection 2022.

Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes

Carina M Mathey¹, Carlo Maj^{2

3}, Annika B Scheer¹, Julia Fazaal¹, Bettina Wedi⁴, Dorothea Wieczorek⁴, Philipp M Amann⁵, Harald Löffler⁵, Lukas Koch⁶, Clemens Schöffl⁶, Heinrich Dickel⁷, Nomun Ganjuur⁷, Thorsten Hornung⁸, Susann Forkel⁹, Jens Greve¹⁰, Gerda Wurpts¹¹, Pär Hallberg¹², Anette Bygum^{13

14}, Christian Von Buchwald¹⁵, Malgorzata Karawajczyk¹⁶, Michael Steffens¹⁷, Julia Stingl¹⁸, Per Hoffmann¹, Stefanie Heilmann-Heimbach¹, Elisabeth Mangold¹, Kerstin U Ludwig¹, Eva R Rasmussen¹⁵, Mia Wadelius¹², Bernhardt Sachs^{11

17}, Markus M Nöthen¹, Andreas J Forstner^{1

19}

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.
³ Centre for Human Genetics, University of Marburg, Marburg, Germany.
⁴ Department of Dermatology and Allergy, Comprehensive Allergy Center, Hannover Medical School, Hannover, Germany.
⁵ Department of Dermatology, SLK Hospital Heilbronn, Heilbronn, Germany.
⁶ Department of Dermatology and Venereology, Medical University Graz, Graz, Austria.
⁷ Department of Dermatology, Venereology and Allergology, St. Josef Hospital, University Medical Center, Ruhr University Bochum, Bochum, Germany.
⁸ Department of Dermatology and Allergy, University Hospital of Bonn, Bonn, Germany.
⁹ Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany.
¹⁰ Department of Otorhinolaryngology-Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany.
¹¹ Department of Dermatology and Allergy, Aachen Comprehensive Allergy Center, University Hospital RWTH Aachen, Aachen, Germany.
¹² Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹³ Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
¹⁴ Clinical Institute, University of Southern Denmark, Odense, Denmark.
¹⁵ Department of Otorhinolaryngology-Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹⁶ Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
¹⁷ Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
¹⁸ Institute for Clinical Pharmacology, RWTH Aachen University, Aachen, Germany.
¹⁹ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.

PMID: 35923707
PMCID: PMC9339951
DOI: 10.3389/fgene.2022.914376

Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes

Carina M Mathey et al. Front Genet. 2022.

. 2022 Jul 18:13:914376.

doi: 10.3389/fgene.2022.914376. eCollection 2022.

Authors

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.
³ Centre for Human Genetics, University of Marburg, Marburg, Germany.
⁴ Department of Dermatology and Allergy, Comprehensive Allergy Center, Hannover Medical School, Hannover, Germany.
⁵ Department of Dermatology, SLK Hospital Heilbronn, Heilbronn, Germany.
⁶ Department of Dermatology and Venereology, Medical University Graz, Graz, Austria.
⁷ Department of Dermatology, Venereology and Allergology, St. Josef Hospital, University Medical Center, Ruhr University Bochum, Bochum, Germany.
⁸ Department of Dermatology and Allergy, University Hospital of Bonn, Bonn, Germany.
⁹ Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Göttingen, Germany.
¹⁰ Department of Otorhinolaryngology-Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany.
¹¹ Department of Dermatology and Allergy, Aachen Comprehensive Allergy Center, University Hospital RWTH Aachen, Aachen, Germany.
¹² Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
¹³ Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
¹⁴ Clinical Institute, University of Southern Denmark, Odense, Denmark.
¹⁵ Department of Otorhinolaryngology-Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹⁶ Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
¹⁷ Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
¹⁸ Institute for Clinical Pharmacology, RWTH Aachen University, Aachen, Germany.
¹⁹ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.

PMID: 35923707
PMCID: PMC9339951
DOI: 10.3389/fgene.2022.914376

Abstract

Angioedema is a relatively rare but potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). As with hereditary forms of angioedema (HAE), this adverse reaction is mediated by bradykinin. Research suggests that ACEi/ARB-induced angioedema has a multifactorial etiology. In addition, recent case reports suggest that some ACEi/ARB-induced angioedema patients may carry pathogenic HAE variants. The aim of the present study was to investigate the possible association between ACEi/ARB-induced angioedema and HAE genes via systematic molecular genetic screening in a large cohort of ACEi/ARB-induced angioedema cases. Targeted re-sequencing of five HAE-associated genes (SERPING1, F12, PLG, ANGPT1, and KNG1) was performed in 212 ACEi/ARB-induced angioedema patients recruited in Germany/Austria, Sweden, and Denmark, and in 352 controls from a German cohort. Among patients, none of the identified variants represented a known pathogenic variant for HAE. Moreover, no significant association with ACEi/ARB-induced angioedema was found for any of the identified common [minor allele frequency (MAF) >5%] or rare (MAF < 5%) variants. However, several non-significant trends suggestive of possible protective effects were observed. The lowest p-value for an individual variant was found in PLG (rs4252129, p.R523W, p = 0.057, p.adjust > 0.999, Fisher's exact test). Variant p.R523W was found exclusively in controls and has previously been associated with decreased levels of plasminogen, a precursor of plasmin which is part of a pathway directly involved in bradykinin production. In addition, rare, potentially functional variants (MAF < 5%, Phred-scaled combined annotation dependent depletion score >10) showed a nominally significant enrichment in controls both: 1) across all five genes; and 2) in the F12 gene alone. However, these results did not withstand correction for multiple testing. In conclusion, our results suggest that HAE-associated mutations are, at best, a rare cause of ACEi/ARB-induced angioedema. Furthermore, we were unable to identify a significant association between ACEi/ARB-induced angioedema and other variants in the investigated genes. Further studies with larger sample sizes are warranted to draw more definite conclusions concerning variants with limited effect sizes, including protective variants.

Keywords: angioedema; angiotensin receptor blocker; angiotensin-converting enzyme inhibitor; genetics; hereditary angioedema; sequencing.

Copyright © 2022 Mathey, Maj, Scheer, Fazaal, Wedi, Wieczorek, Amann, Löffler, Koch, Schöffl, Dickel, Ganjuur, Hornung, Forkel, Greve, Wurpts, Hallberg, Bygum, Von Buchwald, Karawajczyk, Steffens, Stingl, Hoffmann, Heilmann-Heimbach, Mangold, Ludwig, Rasmussen, Wadelius, Sachs, Nöthen and Forstner.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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[1] Ariano A., D'Apolito M., Bova M., Bellanti F., Loffredo S., D'Andrea G., et al. (2020). A Myoferlin Gain‐of‐function Variant Associates with a New Type of Hereditary Angioedema. Allergy 75, 2989–2992. 10.1111/all.14454 - DOI - PubMed

[2] Ariano A., D'Apolito M., Bova M., Bellanti F., Loffredo S., D'Andrea G., et al. (2020). A Myoferlin Gain‐of‐function Variant Associates with a New Type of Hereditary Angioedema. Allergy 75, 2989–2992. 10.1111/all.14454 - DOI - PubMed

[3] Auton A., Auton A., Brooks L. D., Durbin R. M., Garrison E. P., Kang H. M., et al. (2015). A Global Reference for Human Genetic Variation. Nature 526, 68–74. 10.1038/nature15393 - DOI - PMC - PubMed

[4] Auton A., Auton A., Brooks L. D., Durbin R. M., Garrison E. P., Kang H. M., et al. (2015). A Global Reference for Human Genetic Variation. Nature 526, 68–74. 10.1038/nature15393 - DOI - PMC - PubMed

[5] Bafunno V., Firinu D., D'Apolito M., Cordisco G., Loffredo S., Leccese A., et al. (2018). Mutation of the Angiopoietin-1 Gene (ANGPT1) Associates with a New Type of Hereditary Angioedema. J. Allergy Clin. Immunol. 141, 1009–1017. 10.1016/j.jaci.2017.05.020 - DOI - PubMed

[6] Bafunno V., Firinu D., D'Apolito M., Cordisco G., Loffredo S., Leccese A., et al. (2018). Mutation of the Angiopoietin-1 Gene (ANGPT1) Associates with a New Type of Hereditary Angioedema. J. Allergy Clin. Immunol. 141, 1009–1017. 10.1016/j.jaci.2017.05.020 - DOI - PubMed

[7] Banerji A., Blumenthal K. G., Lai K. H., Zhou L. (2017). Epidemiology of ACE Inhibitor Angioedema Utilizing a Large Electronic Health Record. J. Allergy Clin. Immunol. Pract. 5, 744–749. 10.1016/j.jaip.2017.02.018 - DOI - PMC - PubMed

[8] Banerji A., Blumenthal K. G., Lai K. H., Zhou L. (2017). Epidemiology of ACE Inhibitor Angioedema Utilizing a Large Electronic Health Record. J. Allergy Clin. Immunol. Pract. 5, 744–749. 10.1016/j.jaip.2017.02.018 - DOI - PMC - PubMed

[9] Bas M., Adams V., Suvorava T., Niehues T., Hoffmann T. K., Kojda G. (2007). Nonallergic Angioedema: Role of Bradykinin. Allergy 62, 842–856. 10.1111/j.1398-9995.2007.01427.x - DOI - PubMed

[10] Bas M., Adams V., Suvorava T., Niehues T., Hoffmann T. K., Kojda G. (2007). Nonallergic Angioedema: Role of Bradykinin. Allergy 62, 842–856. 10.1111/j.1398-9995.2007.01427.x - DOI - PubMed

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Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes

Affiliations

Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes

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Abstract

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