{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:47:29Z","timestamp":1778546849974,"version":"3.51.4"},"reference-count":38,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,7,18]],"date-time":"2020-07-18T00:00:00Z","timestamp":1595030400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008890","name":"University of Dundee","doi-asserted-by":"publisher","award":["2017\u201000641,"],"award-info":[{"award-number":["2017\u201000641,"]}],"id":[{"id":"10.13039\/100008890","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006736","name":"Universitetssjukhuset \u00d6rebro","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006736","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003509","name":"\u00d6rebro Universitet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003509","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004196","name":"Odense Universitetshospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004047","name":"Karolinska Institutet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007051","name":"Uppsala Universitet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003761","name":"Universitair Medisch Centrum Utrecht","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003761","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:p>Angioedema occurring in the head and neck region is a rare and sometimes life\u2010threatening adverse reaction to angiotensin\u2010converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI\u2010induced angioedema (ACEI\u2010AE) or ARB\u2010induced angioedema (ARB\u2010AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI\u2010AE, ARB\u2010AE, and 658 controls) was performed using exome\u2010enriched sequence data. A common variant of the <jats:italic>F5<\/jats:italic> gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI\u2010AE and ARB\u2010AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89\u20134.25). A burden test analysis of five rare missense variants in <jats:italic>F5<\/jats:italic> was also found to be associated with ACEI\u2010AE or ARB\u2010AE, <jats:italic>P<\/jats:italic>\u00a0=\u00a02.09\u00a0\u00d7\u00a010<jats:sup>\u22123<\/jats:sup>. A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49\u20133.27, <jats:italic>P<\/jats:italic>\u00a0=\u00a06.30\u00a0\u00d7\u00a010<jats:sup>\u22129<\/jats:sup>) times the odds of having ACEI\u2010AE or ARB\u2010AE. The increased risk due to the common Leiden allele was confirmed in a genome\u2010wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect\u2010causing variant in black African and Asian populations. We found that deleterious missense variants in <jats:italic>F5<\/jats:italic> are associated with an increased risk of ACEI\u2010AE or ARB\u2010AE.<\/jats:p>","DOI":"10.1002\/cpt.1927","type":"journal-article","created":{"date-parts":[[2020,6,4]],"date-time":"2020-06-04T16:09:39Z","timestamp":1591286979000},"page":"1195-1202","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Exome Sequencing Reveals Common and Rare Variants in <i>F5<\/i> Associated With ACE Inhibitor and Angiotensin Receptor Blocker\u2013Induced Angioedema"],"prefix":"10.1111","volume":"108","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7816-5508","authenticated-orcid":false,"given":"Cyrielle","family":"Maroteau","sequence":"first","affiliation":[{"name":"Division of Population Health and Genomics Ninewells Hospital and Medical School University of Dundee Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moneeza Kalhan","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Division of Population Health and Genomics Ninewells Hospital and Medical School University of Dundee Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abirami","family":"Veluchamy","sequence":"additional","affiliation":[{"name":"Division of Population Health and Genomics Ninewells Hospital and Medical School University of Dundee Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fiona","family":"Carr","sequence":"additional","affiliation":[{"name":"Division of Population Health and Genomics Ninewells Hospital and Medical School University of Dundee Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myra","family":"White","sequence":"additional","affiliation":[{"name":"Division of Population Health and Genomics Ninewells Hospital and Medical School University of Dundee Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew J.","family":"Cassidy","sequence":"additional","affiliation":[{"name":"Tayside Centre for Genomic Analysis School of Medicine University of Dundee Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekaterina V.","family":"Baranova","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht University Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva R.","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head &amp; Neck Surgery and Audiology, Rigshospitalet University of Copenhagen Denmark"},{"name":"OPEN Patient data Explorative Network Odense University Hospital Odense Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2152-4343","authenticated-orcid":false,"given":"Niclas","family":"Eriksson","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences Clinical Pharmacology and Science for Life Laboratory Uppsala University Uppsala Sweden"},{"name":"Uppsala Clinical Research Centre Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katarzyna M.","family":"Bloch","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology University of Liverpool Liverpool UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy J.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Medicine Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anette","family":"Bygum","sequence":"additional","affiliation":[{"name":"OPEN Patient data Explorative Network Odense University Hospital Odense Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3465-3280","authenticated-orcid":false,"given":"Par","family":"Hallberg","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences Clinical Pharmacology and Science for Life Laboratory Uppsala University Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malgorzata","family":"Karawajczyk","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences Clinical Chemistry Uppsala University Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrik K. E.","family":"Magnusson","sequence":"additional","affiliation":[{"name":"Swedish Twin Registry Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qun\u2010Ying","family":"Yue","sequence":"additional","affiliation":[{"name":"Uppsala Monitoring Centre WHO Collaborating Centre Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann\u2010Christine","family":"Syv\u00e4nen","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences Molecular Medicine and Science for Life Laboratory Uppsala University Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"von Buchwald","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head &amp; Neck Surgery and Audiology, Rigshospitalet University of Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Alfirevic","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology University of Liverpool Liverpool UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anke H.","family":"Maitland\u2010van der Zee","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht University Utrecht The Netherlands"},{"name":"Department of Respiratory Medicine Amsterdam University Medical Centre, location AMC University of Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6368-2622","authenticated-orcid":false,"given":"Mia","family":"Wadelius","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences Clinical Pharmacology and Science for Life Laboratory Uppsala University Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin N. A.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Division of Population Health and Genomics Ninewells Hospital and Medical School University of Dundee Dundee UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"PREDICTION\u2010ADR","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,7,18]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612820666141112160013"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ehj.2004.06.003"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.98.21.2358"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12867"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.otohns.2008.03.029"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.108.111393"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2014.138"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2014.121"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehx467"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1086\/496899"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2017.05.235"},{"key":"e_1_2_10_12_1","author":"Rasmussen E.R.","year":"2020","journal-title":"Genome\u2010wide association study of angioedema induced by angiotensin\u2010converting enzyme inhibitor and angiotensin receptor blocker treatment."},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e328363c137"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"861\u2013865","DOI":"10.1046\/j.1365-2125.1999.00093.x","article-title":"Angioedema due to ACE inhibitors: increased risk in patients of African origin","volume":"48","author":"Gibbs C.R.","year":"1999","journal-title":"Br. J. Clin. Pharmacol."},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/1476402"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(96)90161-7"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/fcp.12313"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1177\/1060028016682251"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41397-020-0148-3"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2016-013351"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1017\/thg.2012.104"},{"key":"e_1_2_10_22_1","article-title":"Genome\u2010wide association study of angiotensin\u2010converting\u2010enzyme (ACE) inhibitor\u2010induced angioedema imputed to the Haplotype Reference Consortium panel","author":"Baranova E.V.","year":"2018","journal-title":"Precision Med."},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr330"},{"key":"e_1_2_10_24_1","unstructured":"Purcell S.P LINK\/SEQ: a library for the analysis of genetic variation data. <https:\/\/atgu.mgh.harvard.edu\/plinkseq> (2020). Accessed June 26 2020."},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw079"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/kxs014"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.06.024"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-11-288"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v036.i03"},{"key":"e_1_2_10_30_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"The R Development Core Team","year":"2007"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-1995"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1086\/509899"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.064105"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.iac.2006.08.001"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2017.00206"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/369064a0"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH06-01-0062"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0104461"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcpt.1927","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.1927","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.1927","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.1927","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T13:37:53Z","timestamp":1699364273000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.1927"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,18]]},"references-count":38,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["10.1002\/cpt.1927"],"URL":"https:\/\/doi.org\/10.1002\/cpt.1927","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,18]]},"assertion":[{"value":"2020-02-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}