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Clin Pharmacol Ther. 2019 Jul;106(1):245-253. doi: 10.1002/cpt.1375. Epub 2019 Mar 19.

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

Author information

1
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
Sema4, a Mount Sinai Venture, Stamford, Connecticut, USA.
3
National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, UK.
4
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
5
University of British Columbia, Vancouver, British Columbia, Canada.
6
Developmental Medicine Department, King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia.
7
Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.
8
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.
9
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
10
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The National University Hospital of Iceland, Reykjavik, Iceland.
11
Medical Research Institute, University of Dundee, Ninewells Hospital, Dundee, UK.
12
Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
13
Department of Respiratory Medicine, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.
14
School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
15
School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King's College, London, UK.
16
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
17
The Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
18
Department of Biomedical Informatics, Columbia University, New York, New York, USA.
19
Target Sciences, GSK, King of Prussia, Pennsylvania, USA.

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 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.

PMID:
30661239
DOI:
10.1002/cpt.1375

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