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Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens

Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens

Title: Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens
Author: Nicoletti, Paola
Devarbhavi, Harshad
Goel, Ashish
Venkatesan, Radha
Eapen, Chundamannil E.
Grove, Jane I.
Zafer, Samreen
Björnsson, Einar Stefán
Lucena, M. Isabel
Andrade, Raul J.
... 8 more authors Show all authors
Date: 2021-04
Language: English
Scope: 11
University/Institute: Landspitali - The National University Hospital of Iceland
Department: Office of Division of Clinical Services I
Faculty of Medicine
Series: Clinical Pharmacology and Therapeutics; 109(4)
ISSN: 0009-9236
DOI: https://doi.org/10.1002/cpt.2100
Subject: Lifrarsjúkdómar; Lyfjanotkun; Adult; Aged; Antitubercular Agents/adverse effects; Arylamine N-Acetyltransferase/genetics; Asians; Chemical and Drug Induced Liver Injury/genetics; Female; Genome-Wide Association Study; Genotype; Histocompatibility Antigens Class I/genetics; Humans; Isoniazid/adverse effects; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors; Whites
URI: https://hdl.handle.net/20.500.11815/3228

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Nicoletti , P , Devarbhavi , H , Goel , A , Venkatesan , R , Eapen , C E , Grove , J I , Zafer , S , Björnsson , E S , Lucena , M I , Andrade , R J , Pirmohamed , M , Wadelius , M , Larrey , D , Maitland-van der Zee , A H , Ibanez , L , Watkins , P B , Daly , A K & Aithal , G P 2021 , ' Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens ' , Clinical Pharmacology and Therapeutics , vol. 109 , no. 4 , pp. 1125-1135 . https://doi.org/10.1002/cpt.2100


Drug-induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs, especially in isoniazid (INH)-containing regimens. To investigate genetic risk factors, we performed a genomewide association study (GWAS) involving anti-TB DILI cases (55 Indian and 70 European) and controls (1,199 Indian and 10,397 European). Most cases were treated with a standard anti-TB drug regimen; all received INH. We imputed single nucleotide polymorphism and HLA genotypes and performed trans-ethnic meta-analysis on GWAS and candidate gene genotypes. GWAS found one significant association (rs117491755) in Europeans only. For HLA, HLA-B*52:01 was significant (meta-analysis odds ratio (OR) 2.67, 95% confidence interval (CI) 1.63–4.37, P = 9.4 × 10−5). For N-acetyltransferase 2 (NAT2), NAT2*5 frequency was lower in cases (OR 0.69, 95% CI 0.57–0.83, P = 0.01). NAT2*6 and NAT2*7 were more common, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases (OR 1.89, 95% CI 0.84–4.22, P = 0.004). We conclude HLA genotype makes a small contribution to TB drug-related DILI and that the NAT2 contribution is complex, but consistent with previous reports when differences in the metabolic effect of NAT2*5 compared with those of NAT2*6 and NAT2*7 are considered.


The genomewide association study and iDILIC case enrollment and sample collection in Europe and India 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. 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 and NIHR Nottingham Biomedical Research Centre (BRC-1215-20003) at the Nottingham University Hospitals NHS Trust and University of Nottingham. G.P.A. is the gastrointestinal and liver disorder theme lead for the NIHR Nottingham BRC (Reference no: BRC-1215-20003). The Spanish DILI Registry (R.J.A. and M.I.L.) 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 III. The Swedish case collection (SWEDEGENE) (M.W.) 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. M.P. is an NIHR Emeritus Senior Investigator. J.I.G, E.B, M.I.L, R.A, A.K.D. and G.P.A. are supported by IMI2 TransBioLine Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. © 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

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