Association of genetic polymorphisms of CYP2E1, NAT2, GST and SLCO1B1 with the risk of anti-tuberculosis drug-induced liver injury: a systematic review and meta-analysis

BMJ Open. 2019 Aug 1;9(8):e027940. doi: 10.1136/bmjopen-2018-027940.

Abstract

Objectives: The objective of this study was to investigate the association between genetic polymorphisms of N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1), glutathione S-transferase (GST) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) and the risk of anti-tuberculosis drug-induced liver injury (ATDILI).

Design: Systematic review and meta-analysis.

Data sources: PubMed, Embase, Web of Science and Cochrane Reviews databases were searched through April 2019.

Eligibility criteria: We included case-control or cohort studies investigating an association between NAT2, CYP2E1, GST or SLCO1B1 polymorphisms and the ATDILI risk in patients with tuberculosis.

Data extraction and synthesis: Three authors screened articles, extracted data and assessed study quality. The strength of association was evaluated for each gene using the pooled OR with a 95% CI based on the fixed-effects or random-effects model. Sensitivity analysis was performed to confirm the reliability and robustness of the results.

Results: Fifty-four studies were included in this analysis (n=26 for CYP2E1, n=35 for NAT2, n=19 for GST, n=4 for SLCO1B1). The risk of ATDILI was significantly increased with the following genotypes: CYP2E1 RsaI/PstI c1/c1 (OR=1.39, 95% CI 1.06 to 1.83), NAT2 slow acetylator (OR=3.30, 95% CI 2.65 to 4.11) and GSTM1 null (OR=1.30, 95% CI 1.12 to 1.52). No significant association with ATDILI was found for the genetic polymorphisms of CYP2E1 DraI, GSTT1, GSTM1/GSTT1, SLCO1B1 388A>G and SLCO1B1 521T>C (p>0.05).

Conclusions: ATDILI is more likely to occur in patients with NAT2 slow acetylator genotype, CYP2E1 RsaI/PstI c1/c1 genotype and GSTM1 null genotype. Close monitoring may be warranted for patients with these genotypes.

Keywords: anti-tuberculosis drug-induced liver injury; drug transporter; drug-metabolizing enzyme; genetic polymorphisms; meta-analysis; tuberculosis.

Publication types

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

MeSH terms

  • Antitubercular Agents / adverse effects*
  • Arylamine N-Acetyltransferase / genetics*
  • Chemical and Drug Induced Liver Injury / genetics*
  • Cytochrome P-450 CYP2E1 / genetics*
  • Genotype
  • Glutathione Transferase / genetics*
  • Humans
  • Liver-Specific Organic Anion Transporter 1 / genetics*
  • Polymorphism, Genetic
  • Tuberculosis / drug therapy

Substances

  • Antitubercular Agents
  • Liver-Specific Organic Anion Transporter 1
  • SLCO1B1 protein, human
  • Cytochrome P-450 CYP2E1
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human
  • Glutathione Transferase
  • glutathione S-transferase M1