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Association between genetic polymorphisms of NRF2, KEAP1, MAFF, MAFK and anti-tuberculosis drug-induced liver injury:

Shixian Chen1, Hongqiu Pan2, Yongzhong Chen2

  • 1Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.

Scientific Reports
|October 6, 2019
PubMed

Insights

Genetic variations in NRF2, MAFF, and MAFK influence anti-tuberculosis drug-induced liver injury (ATLI) risk. Specific genotypes increase susceptibility, while others offer protection in the Chinese population.

Area of Science:

  • Pharmacogenomics
  • Hepatology
  • Tuberculosis Research

Background:

  • Reactive metabolites of anti-tuberculosis (anti-TB) drugs generate reactive oxygen species (ROS), leading to drug-induced liver injury (DILI).
  • The Nrf2-ARE signaling pathway is vital for cellular defense against ROS by inducing antioxidant and phase II metabolizing enzymes.

Purpose of the Study:

  • To investigate the association between genetic polymorphisms in the Nrf2-ARE pathway genes (NRF2, KEAP1, MAFF, MAFK) and the risk of anti-TB drug-induced liver injury (ATLI).
  • To identify specific tag single-nucleotide polymorphisms (tagSNPs) and haplotypes that predict ATLI susceptibility in a Chinese anti-TB treatment cohort.

Main Methods:

  • A nested case-control study involving 314 ATLI cases and 628 controls from a Chinese anti-TB treatment cohort.
  • Analysis of 13 tagSNPs in NRF2, KEAP1, MAFF, and MAFK genes using conditional logistic regression, adjusting for weight and hepatoprotectant use.

Main Results:

  • Carriage of the TC genotype at rs4243387 in NRF2 or the C-C haplotype (rs2001350-rs6726395) was associated with an increased risk of ATLI.
  • Carriage of the TC genotype at rs2267373 in MAFF or the C-G-C haplotype (rs2267373-rs4444637-rs4821767) was associated with a reduced risk of ATLI.
  • Subgroup analyses revealed significant associations between specific tagSNPs in MAFF and MAFK and distinct clinical patterns of liver injury.

Conclusions:

  • Genetic polymorphisms in NRF2, MAFF, and MAFK genes are significant contributors to ATLI susceptibility in the Chinese population undergoing anti-TB treatment.
  • These findings highlight the potential of pharmacogenomic approaches for predicting and potentially preventing ATLI in TB patients.

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