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 -