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

Cismaru, Anca Liliana; Rudin, Deborah; Ibañez, Luisa; Liakoni, Evangelia; Bonadies, Nicolas; Kreutz, Reinhold; Carvajal, Alfonso; Lucena, Maria Isabel; Martin, Javier; Sancho Ponce, Esther; Molokhia, Mariam; Eriksson, Niclas; EuDAC, Collaborators; Krähenbühl, Stephan; Largiadèr, Carlo R.; Haschke, Manuel Martin; Hallberg, Pär; Wadelius, Mia; Amstutz, Ursula (2020). Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations. Genes, 11(11) MDPI, Molecular Diversity Preservation International 10.3390/genes11111275

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of General Internal Medicine (DAIM) > Clinic of General Internal Medicine
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Cismaru, Anca Liliana; Liakoni, Evangelia; Bonadies, Nicolas; Largiadèr, Carlo Rodolfo; Haschke, Manuel Martin and Amstutz, Ursula

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2073-4425

Publisher:

MDPI, Molecular Diversity Preservation International

Language:

English

Submitter:

Karin Balmer

Date Deposited:

11 Nov 2020 15:26

Last Modified:

01 Dec 2020 17:13

Publisher DOI:

10.3390/genes11111275

PubMed ID:

33138277

Uncontrolled Keywords:

dipyrone drug-induced agranulocytosis genome-wide association study metamizole pharmacogenetics

BORIS DOI:

10.7892/boris.147776

URI:

https://boris.unibe.ch/id/eprint/147776

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