Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations
Cismaru, Anca Liliana (University of Bern)
Rudin, Deborah (University of Basel)
Ibáñez, Luisa (Hospital Universitari Vall d'Hebron)
Liakoni, Evangelia (University of Bernd)
Bonadies, Nicolas (Inselspital Bern University Hospital)
Kreutz, Reinhold (Charité - Universitätsmedizin Berlin)
Carvajal, Alfonso (Universidad de Valladolid)
Lucena, Maria Isabel (Instituto de Investigación Biomédica de Málaga)
Martín, Javier (Instituto de Parasitología y Biomedicina "López-Neyra")
Sancho Ponce, Esther (Hospital General de Catalunya)
Molokhia, Mariam (King's College London)
Eriksson, Niclas (Uppsala University)
Krähenbühl, Stephan (University Hospital Basel (Basilea, Suïssa))
Largiadèr, Carlo R. (Bern University Hospital)
Haschke, Manuel (University of Bern)
Hallberg, Pär (Uppsala University)
Wadelius, Mia (Uppsala University)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	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 < 1 × 10 −7) 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. 41-6. 68, p = 1. 01 × 10 −7) and rs4427239 (OR = 5. 47, 95%CI: 2. 81-10. 65, p = 5. 75 × 10 −7), 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.
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Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Drug-induced agranulocytosis ; Metamizole ; Dipyrone ; Genome-wide association study ; Pharmacogenetics
Published in:	Genes, Vol. 11 (october 2020) , ISSN 2073-4425

DOI: 10.3390/genes11111275
PMID: 33138277

21 p, 1.8 MB

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