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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

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/AR...

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Autores principales: Mathey, Carina M., Maj, Carlo, Scheer, Annika B., Fazaal, Julia, Wedi, Bettina, Wieczorek, Dorothea, Amann, Philipp M., Löffler, Harald, Koch, Lukas, Schöffl, Clemens, Dickel, Heinrich, Ganjuur, Nomun, Hornung, Thorsten, Forkel, Susann, Greve, Jens, Wurpts, Gerda, Hallberg, Pär, Bygum, Anette, Von Buchwald, Christian, Karawajczyk, Malgorzata, Steffens, Michael, Stingl, Julia, Hoffmann, Per, Heilmann-Heimbach, Stefanie, Mangold, Elisabeth, Ludwig, Kerstin U., Rasmussen, Eva R., Wadelius, Mia, Sachs, Bernhardt, Nöthen, Markus M., Forstner, Andreas J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339951/
https://www.ncbi.nlm.nih.gov/pubmed/35923707
http://dx.doi.org/10.3389/fgene.2022.914376
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author Mathey, Carina M.
Maj, Carlo
Scheer, Annika B.
Fazaal, Julia
Wedi, Bettina
Wieczorek, Dorothea
Amann, Philipp M.
Löffler, Harald
Koch, Lukas
Schöffl, Clemens
Dickel, Heinrich
Ganjuur, Nomun
Hornung, Thorsten
Forkel, Susann
Greve, Jens
Wurpts, Gerda
Hallberg, Pär
Bygum, Anette
Von Buchwald, Christian
Karawajczyk, Malgorzata
Steffens, Michael
Stingl, Julia
Hoffmann, Per
Heilmann-Heimbach, Stefanie
Mangold, Elisabeth
Ludwig, Kerstin U.
Rasmussen, Eva R.
Wadelius, Mia
Sachs, Bernhardt
Nöthen, Markus M.
Forstner, Andreas J.
author_facet Mathey, Carina M.
Maj, Carlo
Scheer, Annika B.
Fazaal, Julia
Wedi, Bettina
Wieczorek, Dorothea
Amann, Philipp M.
Löffler, Harald
Koch, Lukas
Schöffl, Clemens
Dickel, Heinrich
Ganjuur, Nomun
Hornung, Thorsten
Forkel, Susann
Greve, Jens
Wurpts, Gerda
Hallberg, Pär
Bygum, Anette
Von Buchwald, Christian
Karawajczyk, Malgorzata
Steffens, Michael
Stingl, Julia
Hoffmann, Per
Heilmann-Heimbach, Stefanie
Mangold, Elisabeth
Ludwig, Kerstin U.
Rasmussen, Eva R.
Wadelius, Mia
Sachs, Bernhardt
Nöthen, Markus M.
Forstner, Andreas J.
author_sort Mathey, Carina M.
collection PubMed
description 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.
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spelling pubmed-93399512022-08-02 Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes Mathey, Carina M. Maj, Carlo Scheer, Annika B. Fazaal, Julia Wedi, Bettina Wieczorek, Dorothea Amann, Philipp M. Löffler, Harald Koch, Lukas Schöffl, Clemens Dickel, Heinrich Ganjuur, Nomun Hornung, Thorsten Forkel, Susann Greve, Jens Wurpts, Gerda Hallberg, Pär Bygum, Anette Von Buchwald, Christian Karawajczyk, Malgorzata Steffens, Michael Stingl, Julia Hoffmann, Per Heilmann-Heimbach, Stefanie Mangold, Elisabeth Ludwig, Kerstin U. Rasmussen, Eva R. Wadelius, Mia Sachs, Bernhardt Nöthen, Markus M. Forstner, Andreas J. Front Genet Genetics 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. Frontiers Media S.A. 2022-07-18 /pmc/articles/PMC9339951/ /pubmed/35923707 http://dx.doi.org/10.3389/fgene.2022.914376 Text en 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. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Mathey, Carina M.
Maj, Carlo
Scheer, Annika B.
Fazaal, Julia
Wedi, Bettina
Wieczorek, Dorothea
Amann, Philipp M.
Löffler, Harald
Koch, Lukas
Schöffl, Clemens
Dickel, Heinrich
Ganjuur, Nomun
Hornung, Thorsten
Forkel, Susann
Greve, Jens
Wurpts, Gerda
Hallberg, Pär
Bygum, Anette
Von Buchwald, Christian
Karawajczyk, Malgorzata
Steffens, Michael
Stingl, Julia
Hoffmann, Per
Heilmann-Heimbach, Stefanie
Mangold, Elisabeth
Ludwig, Kerstin U.
Rasmussen, Eva R.
Wadelius, Mia
Sachs, Bernhardt
Nöthen, Markus M.
Forstner, Andreas J.
Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes
title Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes
title_full Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes
title_fullStr Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes
title_full_unstemmed Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes
title_short Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes
title_sort molecular genetic screening in patients with ace inhibitor/angiotensin receptor blocker-induced angioedema to explore the role of hereditary angioedema genes
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339951/
https://www.ncbi.nlm.nih.gov/pubmed/35923707
http://dx.doi.org/10.3389/fgene.2022.914376
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