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

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.

Role of Pharmacogenetics in Adverse Drug Reactions: An Update towards Personalized Medicine

“…Thus, the study of the genetic basis of ADR has to consider the complex interplay between the genetic information and environmental factors in a given disease condition (Afsar et al, 2019). Finally, it must be considered that the huge variability of genetic information is transmitted from one generation to the other, not always unaltered, inserting a further degree of variability, with possible great clinical relevance (Cismaru et al, 2020).…”

The Uncertainties of Metamizole Use

“…The most promising single-nucleotide polymorphisms that met marginal significance in a joint metaanalysis were rs55898176 and rs4427239, the latter located in SVEP1 (Sushi, von Willebrand factor type A, EGF and pentraxin domaincontaining protein 1), a gene previously implicated in hematopoiesis. 9 Aside from the life-threatening risk of agranulocytosis, anaphylaxis is a feared risk of metamizole. The estimates of incidence are 8.1 (3.5-19) per 10,000 exposed patients and are thus much higher compared with the risk of agranulocytosis, but in a range similar to diclofenac's incidence of 7.2 (2.6-20) cases of anaphylaxis per 10,000.…”

“…As clozapine‐induced agranulocytosis was shown to be associated with the presence of specific HLA‐alleles, 8 similar attempts have been made in three European populations for metamizole‐induced agranulocytosis, however without revealing strong results. The most promising single‐nucleotide polymorphisms that met marginal significance in a joint meta‐analysis were rs55898176 and rs4427239, the latter located in SVEP1 (Sushi, von Willebrand factor type A, EGF and pentraxin domain‐containing protein 1), a gene previously implicated in hematopoiesis 9 …”

Pharmacogenomic Determinants of Interindividual Drug Response Variability: From Discovery to Implementation

“…In addition to the GWAS by Cismaru et al [ 1 ], several candidate gene pharmacogenomic studies were also reported in this Special Issue. For example, de Carvalho et al [ 2 ] employed a targeted genotyping panel of candidate genes and variants to study children from Brazil with acute lymphoblastic leukemia (ALL) undergoing chemotherapy with 6-mercaptopurine (6-MP) and methotrexate (MTX).…”

“…Cismaru et al [ 1 ] performed a genome-wide association study (GWAS) to identify genetic variants implicated in metamizole-induced agranulocytosis (MIA) and neutropenia among three European populations. In their 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 ).…”