RT Journal Article
T1 High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis
A1 Cismaru, Anca Liliana
A1 Grimm, Livia
A1 Rudin, Deborah
A1 Ibanez, Luisa
A1 Liakoni, Evangelia
A1 Bonadies, Nicolas
A1 Kreutz, Reinhold
A1 Hallberg, Par
A1 Wadelius, Mia
A1 Haschke, Manuel
A1 Largiader, Carlo R.
A1 Amstutz, Ursula
A1 EuDAC Collaborators, 
K1 drug-induced agranulocytosis
K1 metamizole (dipyrone)
K1 HLA
K1 pharmacogenetics
K1 high-throughput sequencing
K1 next generation sequencing
K1 genetic association studies
K1 Induced liver-injury
K1 Blood dyscrasias
K1 High-resolution
K1 Read alignment
K1 Hypersensitivity
K1 Genotype
K1 Allele
K1 Loci
K1 Hla-b-asterisk-5701
K1 Safety
AB Background and Objective:Agranulocytosis is a rare and potentially life-threatening complication of metamizole (dipyrone) intake that is characterized by a loss of circulating neutrophil granulocytes. While the mechanism underlying this adverse drug reaction is not well understood, involvement of the immune system has been suggested. In addition, associations between genetic variants in the Human Leukocyte Antigen (HLA) region and agranulocytosis induced by other drugs have been reported. The aim of the present study was to assess whether genetic variants in classical HLA genes are associated with the susceptibility to metamizole-induced agranulocytosis (MIA) in a European population by targeted resequencing of eight HLA genes. Design:A case-control cohort of Swiss patients with a history of neutropenia or agranulocytosis associated with metamizole exposure (n= 53), metamizole-tolerant (n= 39) and unexposed controls (n= 161) was recruited for this study. A high-throughput resequencing (HTS) and high-resolution typing method was used to sequence and analyze eight HLA loci in a discovery subset of this cohort (n= 31 cases,n= 38 controls). Identified candidate alleles were investigated in the full Swiss cohort as well as in two independent cohorts from Germany and Spain using HLA imputation from genome-wide SNP array data. In addition, variant calling based on HTS data was performed in the discovery subset for the class I genesHLA-A, -B, and -Cusing the HLA-specific mapperhla-mapper. Results:Eight candidate alleles (p
PB Frontiers media sa
YR 2020
FD 2020-08-21
LK https://hdl.handle.net/10668/28247
UL https://hdl.handle.net/10668/28247
LA en
DS RISalud
RD Apr 12, 2025