Polymorphism of PXR gene associated with the increased risk of drug-induced liver injury in Indonesian pulmonary tuberculosis patients

J Clin Pharm Ther. 2015 Dec;40(6):680-4. doi: 10.1111/jcpt.12325. Epub 2015 Sep 29.

Abstract

What is known and objective: Tuberculosis is still a major infectious disease in Indonesia. Patients are treated mostly using fixed-dose combination treatment in primary public health facilities. The incidence of antituberculosis drug-induced liver injury (AT-DILI) is approximately 10% among Indonesian tuberculosis patients who used standard fixed combination regimens during the intensive phase of treatment. However, information regarding genetic polymorphism associated with the increase risk of drug-induced liver injury is still limited. The aim of this study was to investigate pregnane X receptor (PXR) gene polymorphisms as one of the risk factors of AT-DILI.

Methods: In this prospective cohort study, we recruited 106 adult patients diagnosed with pulmonary tuberculosis and treated with category I FDC (fixed-dose combination). The identification of SNP -25385C>T (rs3814055) was conducted by ARMS (amplification refractory mutation system). Hepatotoxicity was defined as ALT and/or AST levels above the normal threshold on the second, fourth and sixth months of monitoring during tuberculosis treatment.

Results and discussion: The logistic regression analysis showed that patients with the TT genotype of PXR gene (rs3814055) significantly had a greater risk of AT-DILI (OR 8·89; 95% CI 1·36-57·93, P < 0·05), compared with those of wild-type CC genotype.

What is new and conclusion: The result suggests that in Indonesian patients with tuberculosis, the risk of having AT-DILI was associated with TT genotype of the PXR gene.

Keywords: PXR; antituberculosis drugs; drug-induced hepatotoxicity; drug-induced liver injury; polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antitubercular Agents / adverse effects*
  • Antitubercular Agents / therapeutic use
  • Chemical and Drug Induced Liver Injury / genetics*
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Indonesia
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics*
  • Pregnane X Receptor
  • Prospective Studies
  • Receptors, Steroid / genetics*
  • Receptors, Steroid / therapeutic use
  • Risk Factors
  • Tuberculosis, Pulmonary / drug therapy
  • Tuberculosis, Pulmonary / genetics*
  • Young Adult

Substances

  • Antitubercular Agents
  • Pregnane X Receptor
  • Receptors, Steroid