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.

Abstract

© 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.

Citation

Nicoletti, P., Aithal, G. P., Chamberlain, T. C., Coulthard, S., Alshabeeb, M., Grove, J. I., Andrade, R. J., Bjornsson, E., Dillon, J. F., Hallberg, P., Lucena, M. I., Maitland-van der Zee, A. H., Martin, J. H., Molokhia, M., Pirmohamed, M., Wadelius, M., Shen, Y., Nelson, M. R., & 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. https://doi.org/10.1002/cpt.1375

• 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
• DOI: https://doi.org/10.1002/cpt.1375
• Keywords: drug-induced liver injury, HLA genes, adverse drug reactions, genetic polymorphisms
• Public URL: https://nottingham-repository.worktribe.com/output/1445407
• Publisher URL: https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.1375
• Contract Date: Jan 10, 2019