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Open AccessArticle

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

1
Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland
2
Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland
3
Department of Clinical Pharmacology & Toxicology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland
4
Department of Biomedicine, University of Basel, 4051 Basel, Switzerland
5
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
6
Department of Clinical Pharmacology & Toxicology, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland
7
Institute of Pharmacology, University of Bern, 3012 Bern, Switzerland
8
Department of Hematology and Central Hematology Laboratory, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland
9
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
10
Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, 47005 Valladolid, Spain
11
Servicio Farmacologia Clinica, Instituto de Investigación Biomedica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29010 Málaga, Spain
12
Instituto de Parasitología y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientiíficas, 18016 Granada, Spain
13
Servei d’Hematologia i Banc de Sang, Hospital General de Catalunya, 08190 Sant Cugat del Vallès, Spain
14
Department of Population Health Sciences, King’s College London, London WC2R 2LS, UK
15
Uppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden
16
Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden
*
Author to whom correspondence should be addressed.
EuDAC collaborative authors are listed in the Acknowledgements.
Genes 2020, 11(11), 1275; https://doi.org/10.3390/genes11111275
Received: 18 September 2020 / Revised: 23 October 2020 / Accepted: 27 October 2020 / Published: 29 October 2020
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. View Full-Text
Keywords: drug-induced agranulocytosis; metamizole; dipyrone; genome-wide association study; pharmacogenetics drug-induced agranulocytosis; metamizole; dipyrone; genome-wide association study; pharmacogenetics
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MDPI and ACS Style

Cismaru, A.L.; Rudin, D.; Ibañez, L.; Liakoni, E.; Bonadies, N.; Kreutz, R.; Carvajal, A.; Lucena, M.I.; Martin, J.; Sancho Ponce, E.; Molokhia, M.; Eriksson, N.; EuDAC collaborators; Krähenbühl, S.; Largiadèr, C.R.; Haschke, M.; Hallberg, P.; Wadelius, M.; Amstutz, U. Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations. Genes 2020, 11, 1275.

AMA Style

Cismaru AL, Rudin D, Ibañez L, Liakoni E, Bonadies N, Kreutz R, Carvajal A, Lucena MI, Martin J, Sancho Ponce E, Molokhia M, Eriksson N, EuDAC collaborators, Krähenbühl S, Largiadèr CR, Haschke M, Hallberg P, Wadelius M, Amstutz U. Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations. Genes. 2020; 11(11):1275.

Chicago/Turabian Style

Cismaru, Anca L.; Rudin, Deborah; Ibañez, Luisa; Liakoni, Evangelia; Bonadies, Nicolas; Kreutz, Reinhold; Carvajal, Alfonso; Lucena, Maria I.; Martin, Javier; Sancho Ponce, Esther; Molokhia, Mariam; Eriksson, Niclas; EuDAC collaborators; Krähenbühl, Stephan; Largiadèr, Carlo R.; Haschke, Manuel; Hallberg, Pär; Wadelius, Mia; Amstutz, Ursula. 2020. "Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations" Genes 11, no. 11: 1275.

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