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)

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 - 1 Jul 2019

Fingerprint

Floxacillin
Chemical and Drug Induced Liver Injury
HLA Antigens
Alleles
Penicillins
Odds Ratio
Amoxicillin
Valine
Single Nucleotide Polymorphism
Genotype

Keywords

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

Cite this

Nicoletti, P., Aithal, G. P., Chamberlain, T. C., Coulthard, S. A., 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 & Therapeutics, 106(1), 245-253. https://doi.org/10.1002/cpt.1375
Nicoletti, Paola ; Aithal, Guruprasad P. ; Chamberlain, Thomas C. ; Coulthard, Sally A. ; Alshabeeb, Mohammad ; Grove, Jane I. ; Andrade, Raul J. ; Bjornsson, Einar S. ; Dillon, John F. ; Hallberg, Pär ; Lucena, M. Isabel ; Maitland-van der Zee, Anke Hilse ; Martin, Jennifer H. ; Molokhia, Mariam ; Pirmohamed, Munir ; Wadelius, Mia ; Shen, Yufeng ; Nelson, Matthew R. ; Daly, Ann K. / Drug-Induced Liver Injury due to Flucloxacillin : Relevance of Multiple Human Leukocyte Antigen Alleles. In: Clinical Pharmacology & Therapeutics. 2019 ; Vol. 106, No. 1. pp. 245-253.
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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.",
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note = "The genome-wide association study and iDILIC case enrolment and sample collection was funded by the International Serious Adverse Events Consortium with (Phase 2) membership support from Abbott, Amgen, Daiichi-Sankyo, GlaxoSmithKline,Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Takeda, and the Wellcome Trust. TCC was funded by a BBSRCIndustrial CASE studentship with AstraZeneca (PI AKD). This is a summary of independent research partly (the DILIGEN and iDILIC sample collection) funded by the National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit at the Nottingham University Hospitals NHS Trust and University of Nottingham. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. GPA is the gastrointestinal and liver disorder theme lead for the NIHR Nottingham BRC (Reference no: BRC-1215-20003). The EUDRAGENE collaboration (MM) received support from the EC 5th Framework program (QLRI-CT-2002-02757). The Spanish DILI Registry (RJA, MIL) is partly funded by the Spanish Medicine Agency, Fondo Europeo de Desarrollo Regional - FEDER (P10-CTS-6470, FIS PI12/00378, PI16/01748). CIBERehd is funded by Instituto de Salud Carlos 3 III. The Swedish case collection (SWEDEGENE) (PH, MW) has received support from the Swedish Medical Products Agency, the Swedish Society of Medicine (2008-21619), Swedish Research Council (Medicine 521-2011-2440 and 521-2014-3370), and Swedish Heart and Lung Foundation (20120557). The Swedish Twin Registry which provided control data is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no 2017-00641. MM was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",
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Nicoletti, P, Aithal, GP, Chamberlain, TC, Coulthard, SA, Alshabeeb, M, Grove, JI, Andrade, RJ, Bjornsson, ES, 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 2019, 'Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles', Clinical Pharmacology & Therapeutics, vol. 106, no. 1, pp. 245-253. https://doi.org/10.1002/cpt.1375

Drug-Induced Liver Injury due to Flucloxacillin : Relevance of Multiple Human Leukocyte Antigen Alleles. / Nicoletti, Paola; Aithal, Guruprasad P. (Lead / Corresponding author); Chamberlain, Thomas C. ; Coulthard, Sally A.; Alshabeeb, Mohammad ; Grove, Jane I.; Andrade, Raul J.; Bjornsson, Einar S.; Dillon, John F.; Hallberg, Pär; Lucena, M. Isabel; Maitland-van der Zee, Anke Hilse; Martin, Jennifer H.; Molokhia, Mariam; Pirmohamed, Munir; Wadelius, Mia; Shen, Yufeng; Nelson, Matthew R.; Daly, Ann K. (Lead / Corresponding author).

In: Clinical Pharmacology & Therapeutics, Vol. 106, No. 1, 01.07.2019, p. 245-253.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Drug-Induced Liver Injury due to Flucloxacillin

T2 - Relevance of Multiple Human Leukocyte Antigen Alleles

AU - Nicoletti, Paola

AU - Aithal, Guruprasad P.

AU - Chamberlain, Thomas C.

AU - Coulthard, Sally A.

AU - Alshabeeb, Mohammad

AU - Grove, Jane I.

AU - Andrade, Raul J.

AU - Bjornsson, Einar S.

AU - Dillon, John F.

AU - Hallberg, Pär

AU - Lucena, M. Isabel

AU - Maitland-van der Zee, Anke Hilse

AU - Martin, Jennifer H.

AU - Molokhia, Mariam

AU - Pirmohamed, Munir

AU - Wadelius, Mia

AU - Shen, Yufeng

AU - Nelson, Matthew R.

AU - Daly, Ann K.

N1 - The genome-wide association study and iDILIC case enrolment and sample collection was funded by the International Serious Adverse Events Consortium with (Phase 2) membership support from Abbott, Amgen, Daiichi-Sankyo, GlaxoSmithKline,Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Takeda, and the Wellcome Trust. TCC was funded by a BBSRCIndustrial CASE studentship with AstraZeneca (PI AKD). This is a summary of independent research partly (the DILIGEN and iDILIC sample collection) funded by the National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit at the Nottingham University Hospitals NHS Trust and University of Nottingham. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. GPA is the gastrointestinal and liver disorder theme lead for the NIHR Nottingham BRC (Reference no: BRC-1215-20003). The EUDRAGENE collaboration (MM) received support from the EC 5th Framework program (QLRI-CT-2002-02757). The Spanish DILI Registry (RJA, MIL) is partly funded by the Spanish Medicine Agency, Fondo Europeo de Desarrollo Regional - FEDER (P10-CTS-6470, FIS PI12/00378, PI16/01748). CIBERehd is funded by Instituto de Salud Carlos 3 III. The Swedish case collection (SWEDEGENE) (PH, MW) has received support from the Swedish Medical Products Agency, the Swedish Society of Medicine (2008-21619), Swedish Research Council (Medicine 521-2011-2440 and 521-2014-3370), and Swedish Heart and Lung Foundation (20120557). The Swedish Twin Registry which provided control data is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no 2017-00641. MM was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

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KW - HLA genes

KW - adverse drug reactions

KW - genetic polymorphisms

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Nicoletti P, Aithal GP, Chamberlain TC, Coulthard SA, Alshabeeb M, Grove JI et al. Drug-Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles. Clinical Pharmacology & Therapeutics. 2019 Jul 1;106(1):245-253. https://doi.org/10.1002/cpt.1375