Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis

PLoS One. 2012;7(10):e47769. doi: 10.1371/journal.pone.0047769. Epub 2012 Oct 17.

Abstract

Background: Three first-line antituberculosis drugs, isoniazid, rifampicin and pyrazinamide, may induce liver injury, especially isoniazid. This antituberculosis drug-induced liver injury (ATLI) ranges from a mild to severe form, and the associated mortality cases are not rare. In the past decade, many investigations have focused the association between drug-metabolising enzyme (DME) gene polymorphisms and risk for ATLI; however, these studies have yielded contradictory results.

Methods: PubMed, EMBASE, ISI web of science and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between polymorphisms from 4 DME genes (NAT2, CYP2E1, GSTM1 and GSTT1) and susceptibility to ATLI. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Heterogeneity among articles and their publication bias were also tested.

Results: 38 studies involving 2,225 patients and 4,906 controls were included. Overall, significantly increased ATLI risk was associated with slow NAT2 genotype and GSTM1 null genotype when all studies were pooled into the meta-analysis. Significantly increased risk was also found for CYP2E1*1A in East Asians when stratified by ethnicity. However, no significant results were observed for GSTT1.

Conclusions: Our results demonstrated that slow NAT2 genotype, CYP2E1*1A and GSTM1 null have a modest effect on genetic susceptibility to ATLI.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / adverse effects*
  • Arylamine N-Acetyltransferase / genetics
  • Chemical and Drug Induced Liver Injury / enzymology*
  • Chemical and Drug Induced Liver Injury / genetics*
  • Cytochrome P-450 CYP2E1 / genetics
  • Genetic Predisposition to Disease*
  • Glutathione Transferase / genetics
  • Humans
  • Inactivation, Metabolic / genetics*
  • Pharmacogenetics
  • Polymorphism, Genetic*
  • Publication Bias
  • Risk Factors

Substances

  • Antitubercular Agents
  • Cytochrome P-450 CYP2E1
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human
  • glutathione S-transferase T1
  • Glutathione Transferase
  • glutathione S-transferase M1

Grant support

This work was supported by Shanghai Natural Science Foundation (12ZR1405300) and Shanghai Science and Technology Commission (10410709400; 10411950100). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.