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Drug‐Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles
Abstract
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 valine 97 , 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 .
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“HLA polymorphisms shown to be significantly associated with multiple drugs include HLA-A*02:01 for AC and cefazolin DILI and HLA-B*35:01 for multiple HDS products, including green tea extract, turmeric, and Polygonum multiform.”
From The contemporary epidemiology, causes, and management of drug-induced liver injury (2026) · cites this paper as [35]
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Metadata
- Authors
- Nicoletti, P., Aithal, G. P., Chamberlain, T. C., Coulthard, S., Alshabeeb, M., Grove, J. I., Andrade, R. J., Bjornsson, E., Dillon, J. F., Hallberg, P., Lucena, M. I., Maitland‐van der Zee, A. H., Martin, J. H., Molokhia, M., Pirmohamed, M., Wadelius, M., Shen, Y., Nelson, M. R., Daly, A. K., & the International Drug‐Induced Liver Injury Consortium (iDILIC)
- Affiliations
- Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York USA
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre Nottingham University Hospital NHS Trust and University of Nottingham Nottingham UK
- Institute of Cellular Medicine Newcastle University Newcastle upon Tyne UK
- UGC Digestivo y Servicio de Farmacología Clínica Instituto de Investigación Biomédica de Málaga (IBIMA) Hospital Universitario Virgen de la Victoria Universidad de Málaga Málaga Spain
- Division of Gastroenterology and Hepatology Department of Internal Medicine The National University Hospital of Iceland Reykjavik Iceland
- Medical Research Institute University of Dundee Ninewells Hospital Dundee UK
- Department of Medical Sciences and Science for Life Laboratory Uppsala University Uppsala Sweden
- Department of Respiratory Medicine Academic Medical Center (AMC) University of Amsterdam Amsterdam The Netherlands
- School of Medicine and Public Health University of Newcastle Callaghan New South Wales Australia
- School of Population Health and Environmental Sciences Faculty of Life Sciences and Medicine King's College London UK
- Department of Molecular and Clinical Pharmacology University of Liverpool Liverpool UK
- The Herbert Irving Comprehensive Cancer Center Columbia University New York New York USA
- Target Sciences GSK King of Prussia Pennsylvania USA
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2019-03-19
- Volume
- 106
- Issue
- 1
- Pages
- 245-253
- ISSN
- 0009-9236
- 1532-6535
- Cited by
- 91
- References
- 35
- Language
- en
- Funders
- Abbott Laboratories
- Amgen
- Daiichi-Sankyo
- GlaxoSmithKline
- Merck
- Novartis
- Pfizer
- Roche
- Sanofi
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council
- National Institute for Health Research
- Nottingham University Hospitals NHS Trust
- University of Nottingham
- European Regional Development Fund (P10‐CTS‐6470, FIS PI12/00378, PI16/01748)
- Instituto de Salud Carlos III
- Svenska Läkaresällskapet (2008‐21619)
- Vetenskapsrådet (Medicine 521‐2011‐2440, 521‐2014‐3370, 2017‐00641)
- King’s College London
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