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. 

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

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.914376

DOI=10.3389/fgene.2022.914376

ISSN=1664-8021

ABSTRACT=<p>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 <italic>via</italic> systematic molecular genetic screening in a large cohort of ACEi/ARB-induced angioedema cases. Targeted re-sequencing of five HAE-associated genes (<italic>SERPING1</italic>, <italic>F12</italic>, <italic>PLG</italic>, <italic>ANGPT1</italic>, and <italic>KNG1</italic>) 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) &gt;5%] or rare (MAF &lt; 5%) variants. However, several non-significant trends suggestive of possible protective effects were observed. The lowest <italic>p</italic>-value for an individual variant was found in <italic>PLG</italic> (rs4252129, p.R523W, <italic>p</italic> = 0.057, <italic>p</italic>.adjust &gt; 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 &lt; 5%, Phred-scaled combined annotation dependent depletion score &gt;10) showed a nominally significant enrichment in controls both: 1) across all five genes; and 2) in the <italic>F12</italic> 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.</p>