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

Lookup NU author(s): Dr Tom Chamberlain, Dr Sally Coulthard, Mohammad Alshabeeb, Professor Ann Daly

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by John Wiley & Sons, Inc., 2019.

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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 genome-wide association study involving 197 flucloxacillin DILI cases and 6835 controls. We imputed SNP and HLA genotypes. HLA-B*57:01 was the major risk factor (allelic OR=36.62, P=2.67x10-97). HLA-B*57:03 also showed an association (OR=79.21, P=1.2x10-6). 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=9.7x10-97). 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.


Publication metadata

Author(s): Nicoletti P, Aithal GP, Chamberlain TC, Coulthard S, Alshabeeb M, Grove JI, Andrade RJ, Bjornsson E, Dillon JF, Hallberg P, Lucena MI, Maitland-van der Zee AH, Martin JH, Molokhia M, Pirmohamed M, Wadelius M, Shen Y, Nelson MR, Daly AK

Publication type: Article

Publication status: Published

Journal: Clinical Pharmacology & Therapeutics

Year: 2019

Volume: 106

Issue: 1

Pages: 245-253

Print publication date: 01/07/2019

Online publication date: 19/01/2019

Acceptance date: 17/12/2018

Date deposited: 19/12/2018

ISSN (print): 0009-9236

ISSN (electronic): 1532-6535

Publisher: John Wiley & Sons, Inc.

URL: https://doi.org/10.1002/cpt.1375

DOI: 10.1002/cpt.1375


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