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

Nicoletti, Paola; Aithal, Guruprasad P.; Chamberlain, Thomas C.; Coulthard, Sally; Alshabeeb, Mohammad; Grove, Jane I.; Andrade, Raul J.; Bjornsson, Einar; Dillon, John F.; Hallberg, Par; Lucena, M. Isabel; Maitland-van der Zee, Anke H.; Martin, Jennifer H.; Molokhia, Mariam; Pirmohamed, Munir; Wadelius, Mia; Shen, Yufeng; Nelson, Matthew R.; Daly, Ann K.


Paola Nicoletti

Thomas C. Chamberlain

Sally Coulthard

Mohammad Alshabeeb

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Assistant Professor

Raul J. Andrade

Einar Bjornsson

John F. Dillon

Par Hallberg

M. Isabel Lucena

Anke H. Maitland-van der Zee

Jennifer H. Martin

Mariam Molokhia

Munir Pirmohamed

Mia Wadelius

Yufeng Shen

Matthew R. Nelson

Ann K. Daly


© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics 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.


Nicoletti, P., Aithal, G. P., Chamberlain, T. C., Coulthard, S., Alshabeeb, M., Grove, J. I., …Daly, A. K. (2019). Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles. Clinical Pharmacology and Therapeutics, 106(1), 245-253.

Journal Article Type Article
Acceptance Date Dec 17, 2018
Online Publication Date Jan 19, 2019
Publication Date Jul 1, 2019
Deposit Date Jan 7, 2019
Publicly Available Date Jan 20, 2020
Journal Clinical Pharmacology and Therapeutics
Print ISSN 0009-9236
Electronic ISSN 1532-6535
Publisher American Society for Clinical Pharmacology and Therapeutics
Peer Reviewed Peer Reviewed
Volume 106
Issue 1
Pages 245-253
Keywords drug-induced liver injury, HLA genes, adverse drug reactions, genetic polymorphisms
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