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Lookup NU author(s): Dr Sally Coulthard,
Professor Ann DalyORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
Objective Flupirtine is a nonopioid analgesic with regulatory approval in a number of European countries. Because of the risk of serious liver injury, its use is now limited to short-term pain management. We aimed to identify genetic risk factors for flupirtine-related drug-induced liver injury (DILI) as these are unknown.Materials and methods Six flupirtine-related DILI patients from Germany were included in a genome-wide association study (GWAS) involving a further 614 European cases of DILI because of other drugs and 10588 population controls. DILI was diagnosed by causality assessment and expert review. Human leucocyte antigen (HLA) and single nucleotide polymorphism genotypes were imputed from the GWAS data, with direct HLA typing performed on selected cases to validate HLA predictions. Four replication cases that were unavailable for the GWAS were genotyped by direct HLA typing, yielding an overall total of 10 flupirtine DILI cases.Results In the six flupirtine DILI cases included in the GWAS, we found a significant enrichment of the DRB1*16:01-DQB1*05:02 haplotype compared with the controls (minor allele frequency cases 0.25 and minor allele frequency controls 0.013; P=1.4x10(-5)). We estimated an odds ratio for haplotype carriers of 18.7 (95% confidence interval 2.5-140.5, P=0.002) using population-specific HLA control data. The result was replicated in four additional cases, also with a haplotype frequency of 0.25. In the combined cohort (six GWAS plus four replication cases), the haplotype was also significant (odds ratio 18.7, 95% confidence interval 4.31-81.42, P=6.7x10(-5)).Conclusion We identified a novel HLA class II association for DILI, confirming the important contribution of HLA genotype towards the risk of DILI generally. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
Author(s): Nicoletti P, Werk AN, Sawle A, Shen YF, Urban TJ, Coulthard SA, Bjornsson ES, Cascorbi I, Floratos A, Stammschulte T, Gundert-Remy U, Nelson MR, Aithal GP, Daly AK, on behalf of the International Drug-induced Liver Injury Consortium (iDILIC)
Publication type: Article
Publication status: Published
Journal: Pharmacogenetics and Genomics
Print publication date: 01/05/2016
Acceptance date: 01/02/2016
Date deposited: 01/06/2016
ISSN (print): 1744-6872
ISSN (electronic): 1744-6880
Publisher: Lippincott Williams & Wilkins
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