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N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to antituberculosis drug treatment in a mixed-ethnicity patient group

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

This study aims to assess whether NAT2 genotype affects susceptibility to moderate to severe liver injury in patients undergoing drug treatment for tuberculosis with isoniazid-containing regimens.

Methods

Twenty-six patients of European or South Asian ethnicity, who had suffered liver injury during treatment with isoniazid-containing drug regimens and 101 ethnically matched controls were genotyped for the NAT2*5, NAT2*6, and NAT2*7 alleles. Genotyping for additional polymorphisms in the NAT gene region was also performed on 20 of the 26 cases. NAT2 genotype frequency between cases and controls was compared.

Results

NAT2 genotypes predicting a slow acetylator phenotype were found to be associated with an increased risk of isoniazid-related liver injury (odds ratio (OR) = 4.25 (95 % confidence interval (CI), 1.36–13.22); p = 0.012) with 85 % of the cases being slow acetylators compared with 56 % of the controls. There was no evidence for an increased risk for the slow acetylator genotype in patients with the most severe cases of liver injury, who underwent liver transplantation.

Conclusions

The NAT2 slow acetylator genotype appears to be a significant risk factor for moderate and severe drug- induced liver injury. However, the overall effect size is modest and generally in line with effects described previously for this genotype in milder drug-induced liver injury. Additional genetic risk factors may also contribute.

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Acknowledgments

Sample collection and genotyping was funded by the UK Department of Health (ref PHGX10A) with additional support from UK NIHR funding to the Nottingham Digestive Diseases Centre and from the International Serious Adverse Events Consortium. Special thanks to Julia Patch for technical assistance. C-SN acknowledges a studentship from University of Malaya and AH a Commonwealth Fellowship.

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Authors and Affiliations

  1. Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

    Ching-Soon Ng, Christopher P. Day & Ann K. Daly

  2. Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

    Ching-Soon Ng

  3. Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh

    Abul Hasnat, Abdullah Al Maruf & Maizbha Uddin Ahmed

  4. Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK

    Munir Pirmohamed

  5. NIHR Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK

    Guruprasad P. Aithal

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  1. Ching-Soon Ng
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Correspondence to Ann K. Daly.

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Ng, CS., Hasnat, A., Al Maruf, A. et al. N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to antituberculosis drug treatment in a mixed-ethnicity patient group. Eur J Clin Pharmacol 70, 1079–1086 (2014). https://doi.org/10.1007/s00228-014-1703-0

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