High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis

Cismaru, Anca Liliana; Grimm, Livia; Rudin, Deborah; Ibáñez, Luisa; Liakoni, Evangelia; Bonadies, Nicolas; Kreutz, Reinhold; Hallberg, Pär; Wadelius, Mia; Haschke, Manuel; Largiadèr, Carlo R.; Amstutz, Ursula

doi:10.3389/fgene.2020.00951

Cited by 4 publications

(2 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, the strongest pharmacogenetic associations pertaining to drug-induced agranulocytosis up to date mostly involved immune-related genes such as specific HLA alleles [15][16][17][44][45][46]66,67], even though these findings have yet to be corroborated by mechanistic studies. Here, on the other hand, in line with a previous association study focused on classical HLA genes in the same cohort [68], none of the candidate loci identified as leading markers in our genome-wide meta-analysis involved genes that would support an immune-mediated mechanism underlying MIA. These findings thus suggest that the underlying mechanism for MIA may differ from other agranulocytosis-inducing drugs.…”

Section: Discussionsupporting

confidence: 80%

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

Cismaru

Rudin

Ibáñez

et al. 2020

Genes

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 80%

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

Cismaru

Rudin

Ibáñez

et al. 2020

Genes

Self Cite

View full text Add to dashboard Cite

show abstract

“…This could also lead to the conclusion that the extremely short median onset times of 2 days (Andersohn et al, 2007) may actually be rechallenge times and that then the shorter onset times in the treatment with metamizole should be taken into account when monitoring the blood count during therapy. A dependence of metamizole-induced agranulocytosis on certain HLA gene variants cannot be ruled out, but there is no clear evidence for this to date (Shah, 2019;Cismaru et al, 2020). Estimates of the incidence of agranulocytosis with metamizole treatment vary widely regionally and in the literature (from, for example, 1 case per 143,000 therapy cycles over 2 weeks in a Berlin study (Huber et al, 2015) to 1 case per 1,439 treatments in Sweden (Hedenmalm and Spigset, 2002).…”

Section: Metamizole (Synonyms: Novamine Sulfone Dipyrone)mentioning

confidence: 99%

Drug-Induced Idiosyncratic Agranulocytosis - Infrequent but Dangerous

Rattay

Benndorf

2021

Front. Pharmacol.

View full text Add to dashboard Cite

Drug-induced agranulocytosis is a life-threatening side effect that usually manifests as a severe form of neutropenia associated with fever or signs of sepsis. It can occur as a problem in the context of therapy with a wide variety of drug classes. Numerous drugs are capable of triggering the rare idiosyncratic form of agranulocytosis, which, unlike agranulocytosis induced by cytotoxic drugs in cancer chemotherapy, is characterised by “bizzare” type B or hypersensitivity reactions, poor predictability and a mainly low incidence. The idiosyncratic reactions are thought to be initiated by chemically reactive drugs or reactive metabolites that react with proteins and may subsequently elicit an immune response, particularly directed against neutrophils and their precursors. Cells or organs that exhibit specific metabolic and biotransformation activity are therefore frequently affected. In this review, we provide an update on the understanding of drug-induced idiosyncratic agranulocytosis. Using important triggering drugs as examples, we will summarise and discuss the chemical, the biotransformation-related, the mechanistic and the therapeutic basis of this clinically relevant and undesirable side effect.

show abstract

Metamizole-induced agranulocytosis (MIA): a mini review

Tomidis Chatzimanouil,

Goppelt,

Zeissig

et al. 2023

Mol Cell Pediatr

View full text Add to dashboard Cite

Metamizole is an analgesic, antipyretic, and spasmolytic drug in Germany only approved for the treatment of severe pain or high fever that does not respond to other measures. In recent years, an increased use has been described among both adults and children, often against the approved indication. The most important side effect of metamizole is the development of agranulocytosis (neutrophil count < 500/µL). Incidence of metamizole-induced agranulocytosis (MIA) ranges depending on the study from 0.96 cases per million per year to 1:1602 per patient and metamizole prescription. The risk of agranulocytosis in children remains unclear, but is probably lower than in adults. Female gender and older age are associated with higher incidence, reflecting prescription distribution. MIA is dose-independent and risk seems to increase with duration of intake. In patients with past exposure, re-exposure may lead to rapid onset. MIA is believed to be induced either through immunologic or toxic mechanisms. MIA presents with fever, sore throat, fatigue, and mucosal inflammation, up to ulceration. Even in the case of suspected MIA, treatment with metamizole should be immediately paused and an examination of the blood cell count is required. In case of local or systemic infections, empirical therapy with broad-spectrum antibiotics should be administered. G-CSF therapy should be limited to patients with poor prognostic factors. The patient should be monitored closely until the neutrophil count returns to normal. Re-exposure to metamizole must be avoided.

show abstract

High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis

Cited by 4 publications

References 81 publications

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

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

Drug-Induced Idiosyncratic Agranulocytosis - Infrequent but Dangerous

Metamizole-induced agranulocytosis (MIA): a mini review

Contact Info

Product

Resources

About