Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles

the International Drug-Induced Liver Injury Consortium (iDILIC)

Rannsóknarafurð: Framlag til fræðitímaritsGreinritrýni

23 Tilvitnanir (Scopus)

Útdráttur

Some patients prescribed flucloxacillin (~ 0.01%) develop drug-induced liver injury (DILI). HLA-B*57:01 is an established genetic risk factor for flucloxacillin DILI. To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single-nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA-B*57:01 was the major risk factor (allelic odds ratio (OR) = 36.62; P = 2.67 × 10−97). HLA-B*57:03 also showed an association (OR = 79.21; P = 1.2 × 10−6). Within the HLA-B protein sequence, imputation showed valine97, common to HLA-B*57:01 and HLA-B*57:03, had the largest effect (OR = 38.1; P = 9.7 × 10−97). We found no HLA-B*57 association with DILI due to other isoxazolyl penicillins (n = 6) or amoxicillin (n = 15) and no significant non-HLA signals for any penicillin-related DILI.

Upprunalegt tungumálEnska
Síður (frá-til)245-253
Síðufjöldi9
FræðitímaritClinical Pharmacology and Therapeutics
Bindi106
Númer tölublaðs1
DOI
ÚtgáfustaðaÚtgefið - júl. 2019

Athugasemd

Funding Information:
The genomewide association study and iDILIC case enrollment and sample collection was funded by the International Serious Adverse Events Consortium with (phase II) membership support from Abbott, Amgen, Daiichi-Sankyo, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Takeda, and the Wellcome Trust. T.C.C. was funded by a Biotechnology and Biological Sciences Research Council-Industrial CASE studentship with AstraZeneca (PI AKD). This is a summary of independent research partly (the DILIGEN and iDILIC sample collection) funded by the National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit at the Nottingham University Hospitals NHS Trust and University of Nottingham. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. G. P. A. is the gastrointestinal and liver disorder theme lead for the NIHR Nottingham Biomedical Research Centre (Reference no: BRC-1215-20003). The EUDRAGENE collaboration (M.M.) received support from the EC 5th Framework program (QLRI-CT-2002-02757). The Spanish Drug-Induced Liver Injury Registry (R.J.A. and M.I.L.) is partly funded by the Spanish Medicine Agency, Fondo Europeo de Desarrollo Regional - FEDER (P10-CTS-6470, FIS PI12/00378, PI16/01748). CIBERehd is funded by Instituto de Salud Carlos III. The Swedish case collection (SWEDEGENE) (P.H. and M.W.) has received support from the Swedish Medical Products Agency, the Swedish Society of Medicine (2008-21619), Swedish Research Council (Medicine 521-2011-2440 and 521-2014-3370), and Swedish Heart and Lung Foundation (20120557).

Funding Information:
The genomewide association study and iDILIC case enrollment and sample collection was funded by the International Serious Adverse Events Consortium with (phase II) membership support from Abbott, Amgen, Daiichi-Sankyo, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Takeda, and the Wellcome Trust. T.C.C. was funded by a Biotechnology and Biological Sciences Research Council-Industrial CASE studentship with AstraZeneca (PI AKD). This is a summary of independent research partly (the DILIGEN and iDILIC sample collection) funded by the National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit at the Nottingham University Hospitals NHS Trust and University of Nottingham. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. G. P. A. is the gastrointestinal and liver disorder theme lead for the NIHR Nottingham Biomedical Research Centre (Reference no: BRC-1215-20003). The EUDRAGENE collaboration (M.M.) received support from the EC 5th Framework program (QLRI-CT-2002-02757). The Spanish Drug-Induced Liver Injury Registry (R.J.A. and M.I.L.) is partly funded by the Spanish Medicine Agency, Fondo Europeo de Desarrollo Regional - FEDER (P10-CTS-6470, FIS PI12/00378, PI16/01748). CIBERehd is funded by Instituto de Salud Carlos III. The Swedish case collection (SWEDEGENE) (P.H. and M.W.) has received support from the Swedish Medical Products Agency, the Swedish Society of Medicine (2008-21619), Swedish Research Council (Medicine 521-2011-2440 and 521-2014-3370), and Swedish Heart and Lung Foundation (20120557). The Swedish Twin Registry which provided control data is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no. 2017-00641. M.M. was supported by the NIHR Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics

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