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

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

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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 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.

    Original languageEnglish
    Pages (from-to)245-253
    Number of pages9
    JournalClinical Pharmacology & Therapeutics
    Volume106
    Issue number1
    Early online date19 Jan 2019
    DOIs
    Publication statusPublished - Jul 2019

    Keywords

    • drug-induced liver injury
    • HLA genes
    • adverse drug reactions
    • genetic polymorphisms

    ASJC Scopus subject areas

    • Pharmacology (medical)
    • Pharmacology

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