{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:13:23Z","timestamp":1791976403274,"version":"4.4.0"},"reference-count":96,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T00:00:00Z","timestamp":1603929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008367","name":"SNF","doi-asserted-by":"publisher","award":["31003A_160206"],"award-info":[{"award-number":["31003A_160206"]}],"id":[{"id":"10.13039\/100008367","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Carlos III Spanish Health Institute","award":["FIS10\/02632"],"award-info":[{"award-number":["FIS10\/02632"]}]},{"name":"European Regional Development Fund FEDER","award":["-"],"award-info":[{"award-number":["-"]}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["Medicine 521-2011-2440,521-2014-3370 and 2018-03307"],"award-info":[{"award-number":["Medicine 521-2011-2440,521-2014-3370 and 2018-03307"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Swedish Heart and Lung Foundation","award":["20120557,20140291 and 20170711"],"award-info":[{"award-number":["20120557,20140291 and 20170711"]}]},{"name":"Federal Institute for Drugs and Medical Devices (Bonn, Germany)","award":["-"],"award-info":[{"award-number":["-"]}]},{"name":"EC 5th Framework program","award":["QLRI-CR-2002-02757"],"award-info":[{"award-number":["QLRI-CR-2002-02757"]}]},{"name":"Serious Adverse Events Consortium","award":["-"],"award-info":[{"award-number":["-"]}]},{"name":"National Institute for Health Research Biomedical Research Center at Guy\u2019s and St Thomas\u2019 National Health Service Foundation Trust and King\u2019s College London","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p &lt; 1 \u00d7 10\u22127) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41\u20136.68, p = 1.01 \u00d7 10\u22127) and rs4427239 (OR = 5.47, 95%CI: 2.81\u201310.65, p = 5.75 \u00d7 10\u22127), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.<\/jats:p>","DOI":"10.3390\/genes11111275","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T21:21:00Z","timestamp":1604006460000},"page":"1275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations"],"prefix":"10.3390","volume":"11","author":[{"given":"Anca","family":"Cismaru","sequence":"first","affiliation":[{"name":"Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland"},{"name":"Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3069-9732","authenticated-orcid":false,"given":"Deborah","family":"Rudin","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology &amp; Toxicology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland"},{"name":"Department of Biomedicine, University of Basel, 4051 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1175-0574","authenticated-orcid":false,"given":"Luisa","family":"Iba\u00f1ez","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Service, Hospital Universitari Vall d\u2019Hebron, Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, Fundaci\u00f3 Institut Catal\u00e0 de Farmacolog\u00eda, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2239-1378","authenticated-orcid":false,"given":"Evangelia","family":"Liakoni","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology &amp; Toxicology, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland"},{"name":"Institute of Pharmacology, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8761-2066","authenticated-orcid":false,"given":"Nicolas","family":"Bonadies","sequence":"additional","affiliation":[{"name":"Department of Hematology and Central Hematology Laboratory, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhold","family":"Kreutz","sequence":"additional","affiliation":[{"name":"Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Institut f\u00fcr Klinische Pharmakologie und Toxikologie, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Carvajal","sequence":"additional","affiliation":[{"name":"Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, 47005 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Lucena","sequence":"additional","affiliation":[{"name":"Servicio Farmacologia Clinica, Instituto de Investigaci\u00f3n Biomedica de M\u00e1laga, Hospital Universitario Virgen de la Victoria, Universidad de M\u00e1laga, 29010 M\u00e1laga, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Martin","sequence":"additional","affiliation":[{"name":"Instituto de Parasitolog\u00eda y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cienti\u00edficas, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Sancho Ponce","sequence":"additional","affiliation":[{"name":"Servei d\u2019Hematologia i Banc de Sang, Hospital General de Catalunya, 08190 Sant Cugat del Vall\u00e8s, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Molokhia","sequence":"additional","affiliation":[{"name":"Department of Population Health Sciences, King\u2019s College London, London WC2R 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2152-4343","authenticated-orcid":false,"given":"Niclas","family":"Eriksson","sequence":"additional","affiliation":[{"name":"Uppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"EuDAC collaborators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Kr\u00e4henb\u00fchl","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology &amp; Toxicology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Largiad\u00e8r","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Haschke","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology &amp; Toxicology, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland"},{"name":"Institute of Pharmacology, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e4r","family":"Hallberg","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, 751 85 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Amstutz","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/BF00278592","article-title":"Metamizole: Reassessment of its therapeutic role","volume":"38","author":"Arellano","year":"1990","journal-title":"Eur. 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