Meta-analysis of ACE inhibitor–induced angioedema identifies novel risk locus
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Meta-analysis of ACE inhibitor–induced angioedema identifies novel risk locus. / Mathey, Carina M.; Maj, Carlo; Eriksson, Niclas; Krebs, Kristi; Westmeier, Julia; David, Friederike S.; Koromina, Maria; Scheer, Annika B.; Szabo, Nora; Wedi, Bettina; Wieczorek, Dorothea; Amann, Philipp M.; Löffler, Harald; Koch, Lukas; Schöffl, Clemens; Dickel, Heinrich; Ganjuur, Nomun; Hornung, Thorsten; Buhl, Timo; Greve, Jens; Wurpts, Gerda; Aygören-Pürsün, Emel; Steffens, Michael; Herms, Stefan; Heilmann-Heimbach, Stefanie; Hoffmann, Per; Schmidt, Börge; Mavarani, Laven; Andresen, Trine; Sørensen, Signe Bek; Andersen, Vibeke; Vogel, Ulla; Landén, Mikael; Bulik, Cynthia M.; Bygum, Anette; Magnusson, Patrik K. E.; von Buchwald, Christian; Hallberg, Pär; Rye Ostrowski, Sisse; Sørensen, Erik; Pedersen, Ole B.; Ullum, Henrik; Erikstrup, Christian; Bundgaard, Henning; Milani, Lili; Rasmussen, Eva Rye; Wadelius, Mia; Ghouse, Jonas; Sachs, Bernhardt; Nöthen, Markus M.; Forstner, Andreas J.; Estonian Biobank Research Team; DBDS Genomic Consortium.
I: Journal of Allergy and Clinical Immunology, Bind 153, Nr. 4, 2024, s. 1073-1082.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Meta-analysis of ACE inhibitor–induced angioedema identifies novel risk locus
AU - Mathey, Carina M.
AU - Maj, Carlo
AU - Eriksson, Niclas
AU - Krebs, Kristi
AU - Westmeier, Julia
AU - David, Friederike S.
AU - Koromina, Maria
AU - Scheer, Annika B.
AU - Szabo, Nora
AU - Wedi, Bettina
AU - Wieczorek, Dorothea
AU - Amann, Philipp M.
AU - Löffler, Harald
AU - Koch, Lukas
AU - Schöffl, Clemens
AU - Dickel, Heinrich
AU - Ganjuur, Nomun
AU - Hornung, Thorsten
AU - Buhl, Timo
AU - Greve, Jens
AU - Wurpts, Gerda
AU - Aygören-Pürsün, Emel
AU - Steffens, Michael
AU - Herms, Stefan
AU - Heilmann-Heimbach, Stefanie
AU - Hoffmann, Per
AU - Schmidt, Börge
AU - Mavarani, Laven
AU - Andresen, Trine
AU - Sørensen, Signe Bek
AU - Andersen, Vibeke
AU - Vogel, Ulla
AU - Landén, Mikael
AU - Bulik, Cynthia M.
AU - Bygum, Anette
AU - Magnusson, Patrik K. E.
AU - von Buchwald, Christian
AU - Hallberg, Pär
AU - Rye Ostrowski, Sisse
AU - Sørensen, Erik
AU - Pedersen, Ole B.
AU - Ullum, Henrik
AU - Erikstrup, Christian
AU - Bundgaard, Henning
AU - Milani, Lili
AU - Rasmussen, Eva Rye
AU - Wadelius, Mia
AU - Ghouse, Jonas
AU - Sachs, Bernhardt
AU - Nöthen, Markus M.
AU - Forstner, Andreas J.
AU - Estonian Biobank Research Team
AU - DBDS Genomic Consortium
N1 - Publisher Copyright: © 2024 The Authors
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - angioedema
KW - angiotensin-converting enzyme inhibitor
KW - angiotensin-converting enzyme inhibitor–induced angioedema
KW - Genome-wide association study
KW - meta-analysis
U2 - 10.1016/j.jaci.2023.11.921
DO - 10.1016/j.jaci.2023.11.921
M3 - Journal article
C2 - 38300190
AN - SCOPUS:85186255164
VL - 153
SP - 1073
EP - 1082
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 4
ER -
ID: 385141534