Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations.

Autor: Cismaru AL; Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland.; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland., Rudin D; Department of Clinical Pharmacology & Toxicology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland.; Department of Biomedicine, University of Basel, 4051 Basel, Switzerland., Ibañez L; Clinical Pharmacology Service, Hospital Universitari Vall d'Hebron, Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, Fundació Institut Català de Farmacología, 08035 Barcelona, Spain., Liakoni E; Department of Clinical Pharmacology & Toxicology, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland.; Institute of Pharmacology, University of Bern, 3012 Bern, Switzerland., Bonadies N; Department of Hematology and Central Hematology Laboratory, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland., Kreutz R; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Klinische Pharmakologie und Toxikologie, 10117 Berlin, Germany., Carvajal A; Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, 47005 Valladolid, Spain., Lucena MI; Servicio Farmacologia Clinica, Instituto de Investigación Biomedica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29010 Málaga, Spain., Martin J; Instituto de Parasitología y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientiíficas, 18016 Granada, Spain., Sancho Ponce E; Servei d'Hematologia i Banc de Sang, Hospital General de Catalunya, 08190 Sant Cugat del Vallès, Spain., Molokhia M; Department of Population Health Sciences, King's College London, London WC2R 2LS, UK., Eriksson N; Uppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden., EuDAC Collaborators, Krähenbühl S; Department of Clinical Pharmacology & Toxicology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland., Largiadèr CR; Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland., Haschke M; Department of Clinical Pharmacology & Toxicology, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland.; Institute of Pharmacology, University of Bern, 3012 Bern, Switzerland., Hallberg P; Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden., Wadelius M; Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden., Amstutz U; Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland.
Jazyk: angličtina
Zdroj: Genes [Genes (Basel)] 2020 Oct 29; Vol. 11 (11). Date of Electronic Publication: 2020 Oct 29.
DOI: 10.3390/genes11111275
Abstrakt: 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.
Databáze: MEDLINE