Journal
CLINICAL PHARMACOLOGY & THERAPEUTICS
Volume 106, Issue 1, Pages 245-253Publisher
WILEY
DOI: 10.1002/cpt.1375
Keywords
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Categories
Funding
- International Serious Adverse Events Consortium
- Abbott
- Amgen
- Daiichi-Sankyo
- GlaxoSmithKline
- Merck
- Novartis
- Pfizer
- Roche
- Sanofi-Aventis
- Takeda
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council-Industrial CASE studentship
- AstraZeneca (PI AKD)
- National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit at the Nottingham University Hospitals NHS Trust and University of Nottingham
- EC 5th Framework program [QLRI-CT-2002-02757]
- Spanish Medicine Agency, Fondo Europeo de Desarrollo Regional - FEDER [P10-CTS-6470, FIS PI12/00378, PI16/01748]
- Instituto de Salud Carlos III
- Swedish Medical Products Agency
- Swedish Society of Medicine [2008-21619]
- Swedish Research Council [Medicine 521-2011-2440, 521-2014-3370, 2017-00641]
- Swedish Heart and Lung Foundation [20120557]
- NIHR Biomedical Research Centre at Guy's and St. Thomas' NHS Foundation Trust and King's College London
- MRC [MR/N005953/1, MR/L006758/1] Funding Source: UKRI
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Some patients prescribed flucloxacillin (similar to 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 x 10(-97)). HLA-B*57:03 also showed an association (OR = 79.21; P = 1.2 x 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 x 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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