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

Nicoletti, Paola, Devarbhavi, Harshad, Goel, Ashish, Venkatesan, Radha, Eapen, Chundamannil E., Grove, Jane I., Zafer, Samreen, Bjornsson, Einar, Lucena, M. Isabel, Andrade, Raul J., Pirmohamed, Munir, Wadelius, Mia, Larrey, Dominique, Maitland‐van der Zee, Anke‐Hilse, Ibanez, Luisa, Watkins, Paul B, Daly, Ann K., Aithal, Guruprasad P.·2021·Clinical Pharmacology & Therapeutics
DOI 10.1002/cpt.2100
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Abstract

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.

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  • Genetic polymorphisms may be associated with an increased risk of AT-DILI in people carrying the HLA-B*52:01 allele and in ultraslow metabolizers carrying NAT2*6 or NAT2*7 variants.

    “Genetic polymorphisms may be associated with an increased risk of AT-DILI in people carrying the HLA-B*52:01 allele and in ultraslow metabolizers carrying NAT2*6 or NAT2*7 variants [140].”

    From Chinese guideline for the diagnosis and treatment of drug-induced liver injury: an update (2024) · cites this paper as [140]

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Metadata

Authors
Nicoletti, P., Devarbhavi, H., Goel, A., Venkatesan, R., Eapen, C. E., Grove, J. I., Zafer, S., Bjornsson, E., Lucena, M. I., Andrade, R. J., Pirmohamed, M., Wadelius, M., Larrey, D., Maitland‐van der Zee, A., Ibanez, L., Watkins, P. B., Daly, A. K., & Aithal, G. P.
Venue
Clinical Pharmacology & Therapeutics
Publisher
Wiley
Published
2020-12-05
Volume
109
Issue
4
Pages
1125-1135
ISSN
  • 0009-9236
  • 1532-6535
DOI
10.1002/cpt.2100
Cited by
61
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Svenska Läkaresällskapet (2008‐21619)
  • Innovative Medicines Initiative (821283)
  • National Institute for Health Research (BRC‐121520003)
  • Instituto de Salud Carlos III
  • Vetenskapsrådet (521‐2011‐2440, 251‐2014‐3370, 2017‐00641)
  • European Regional Development Fund (P10‐CTS‐6470, FISPI12/00378, PI16/01748)

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