NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis

J Hum Genet. 2016 Jun;61(6):533-7. doi: 10.1038/jhg.2016.10. Epub 2016 Feb 25.

Abstract

Drug-induced liver injury (DILI) is the most common adverse drug reaction in the treatment of tuberculosis (TB). Several studies showed that patients with TB and the slow-acetylator phenotype caused by NAT2 variants are highly susceptible to DILI caused by anti-TB drugs, hereafter designated AT-DILI. However, the role of NAT2 variants in AT-DILI has never been assessed for an Indonesian population. We recruited 50 patients with TB and AT-DILI and 191 patients with TB but without AT-DILI; we then used direct DNA sequencing to assess single-nucleotide polymorphisms in the coding region of NAT2. NAT2*6A was significantly associated with susceptibility to AT-DILI (P=7.7 × 10(-4), odds ratio (OR)=4.75 (1.8-12.55)). Moreover, patients with TB and the NAT2-associated slow-acetylator phenotype showed higher risk of AT-DILI than patients with the rapid- or intermediate-acetylator phenotypes (P=1.7 × 10(-4), OR=3.45 (1.79-6.67)). In conclusion, this study confirms the significance of the association between slow-acetylator NAT2 variants and susceptibility to AT-DILI in an Indonesian population.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Antitubercular Agents / adverse effects*
  • Antitubercular Agents / therapeutic use
  • Arylamine N-Acetyltransferase / genetics*
  • Case-Control Studies
  • Chemical and Drug Induced Liver Injury / diagnosis
  • Chemical and Drug Induced Liver Injury / etiology*
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genotype
  • Haplotypes
  • Humans
  • Indonesia
  • Male
  • Middle Aged
  • Odds Ratio
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Tuberculosis / complications*
  • Tuberculosis / drug therapy
  • Tuberculosis / genetics*
  • Young Adult

Substances

  • Antitubercular Agents
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human