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

Anca Cismaru,Reinhold Kreutz,Javier Martin,Carlo Largiadèr,Manuel Haschke,Mariam Molokhia,Stephan Krähenbühl,Maria Lucena,Eudac Collaborators ,Niclas Eriksson,Nicolas Bonadies,Mia Wadelius,Alfonso Carvajal,Esther Sancho Ponce,Deborah Rudin,Ursula Amstutz,Luisa Ibañez,Pär Hallberg,Evangelia Liakoni

doi:10.3390/genes11111275

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.

Highlights

Metamizole, or dipyrone, is an analgesic and antipyretic drug used to manage different types of pain as well as fever and often serves as an alternative to therapy with conventional non-steroidal anti-inflammatory drugs (NSAIDs)
Studies of idiosyncratic drug-induced agranulocytosis identified genes associated with increased risk either in the human leukocyte antigen (HLA) region or in other regions involved in immune responses for culprit drugs such as clozapine, carbimazole and sulfasalazine [15,16,17,18,19]
Of the 96 cases of metamizole-induced agranulocytosis identified, ten were excluded after adjudication: eight cases in MIA/metamizole-induced neutropenia (MIN)-CH and two cases in European Drug-induced Agranulocytosis Consortium (EuDAC)-ES

Summary

Introduction

Metamizole, or dipyrone, is an analgesic and antipyretic drug used to manage different types of pain as well as fever and often serves as an alternative to therapy with conventional non-steroidal anti-inflammatory drugs (NSAIDs). Despite a well-known favorable gastrointestinal safety profile [1,2,3], spontaneous adverse drug reaction (ADR) reports with risk estimates varying between different countries [4,5,6] provide accounts of metamizole-induced blood dyscrasias. These include metamizole-induced neutropenia (MIN) and a more severe form, agranulocytosis (MIA) characterized by a decrease in circulating neutrophil granulocytes below 1.5 × 109 cells/L, and 0.5 × 109 cells/L, respectively [7,8]. Studies of idiosyncratic drug-induced agranulocytosis identified genes associated with increased risk either in the human leukocyte antigen (HLA) region or in other regions involved in immune responses for culprit drugs such as clozapine, carbimazole and sulfasalazine [15,16,17,18,19]

Methods

Results

Discussion

Conclusion