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Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles
Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA;Sema4, Stamford, CT USA.
Nottingham Univ Hosp NHS Trust, Nottingham Biomed Res Ctr, NIHR, Nottingham, England;Univ Nottingham, Nottingham, England.ORCID iD: 0000-0003-3924-4830
Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England;Univ British Columbia, Vancouver, BC, Canada.
Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England.
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2019 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 106, no 1, p. 245-253Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019. Vol. 106, no 1, p. 245-253
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Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:uu:diva-390905DOI: 10.1002/cpt.1375ISI: 000474029300041PubMedID: 30661239OAI: oai:DiVA.org:uu-390905DiVA, id: diva2:1343909
Funder
Swedish Research Council, Medicine 521-2011-2440Swedish Research Council, 521-2014-3370Swedish Research Council, 2017-00641Swedish Heart Lung Foundation, 20120557Swedish Society of Medicine, 2008-21619GlaxoSmithKline (GSK)Wellcome trustAstraZenecaEU, European Research Council, QLRI-CT-2002-02757Available from: 2019-08-19 Created: 2019-08-19 Last updated: 2019-08-19Bibliographically approved

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