Abstract
Reactive metabolites of anti-tuberculosis (anti-TB) drugs can result in excessive reactive oxygen species (ROS), which are responsible for drug-induced liver injury. The nuclear factor erythroid 2-related factor 2 (Nrf2) - antioxidant response elements (ARE) (Nrf2-ARE) signaling pathway plays a crucial role in protecting liver cells from ROS, inducing enzymes such as phase II metabolizing enzymes and antioxidant enzymes. Based on a Chinese anti-TB treatment cohort, a nested case-control study was performed to explore the association between 13 tag single-nucleotide polymorphisms (tagSNPs) in the NRF2, KEAP1, MAFF, MAFK genes in Nrf2-ARE signaling pathway and the risk of anti-TB drug-induced liver injury (ATLI) in 314 cases and 628 controls. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting weight and usage of hepatoprotectant. Patients carrying the TC genotype at rs4243387 or haplotype C-C (rs2001350-rs6726395) in NRF2 were at an increased risk of ATLI (adjusted OR = 1.362, 95% CI: 1.017–1.824, P = 0.038; adjusted OR = 2.503, 95% CI: 1.273–4.921, P = 0.008, respectively), whereas patients carrying TC genotype at rs2267373 or haplotype C-G-C (rs2267373-rs4444637-rs4821767) in MAFF were at a reduced risk of ATLI (adjusted OR = 0.712, 95% CI: 0.532–0.953, P = 0.022; adjusted OR = 0.753, 95% CI: 0.587–0.965, P = 0.025, respectively). Subgroup analysis also detected a significant association between multiple tagSNPs (rs4821767 and rs4444637 in MAFF, rs4720833 in MAFK) and specific clinical patterns of liver injury under different genetic models. This study shows that genetic polymorphisms of NRF2, MAFF and MAFK may contribute to the susceptibility to ATLI in the Chinese anti-TB treatment population.
Highlights
Tuberculosis (TB) has existed throughout human history and remains a serious public health conce[1]
The distribution of basic characteristics between anti-TB drug-induced liver injury (ATLI) cases and nonATLI controls are summarized in Table 1 (The basic characteristics in Table 1 has been reported in our previous study)[21]
The role of 13 tag single-nucleotide polymorphisms (tagSNPs) in NRF2, KEAP1, MAFF and MAFK in the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response elements (ARE) signaling pathway were examined among Chinese anti-TB treatment patients
Summary
Tuberculosis (TB) has existed throughout human history and remains a serious public health conce[1]. Www.nature.com/scientificreports non-adherence and treatment interruption, and they contribute to eventual treatment failure, relapse or the emergence of drug-resistance[4] Among these ADRs, the most serious adverse reaction is anti-TB drug-induced liver injury (ATLI), which is often fatal[5]. In a population-based study, the activity of glutathione was reduced and the level of MDA was increased in an ATLI group[15] All these studies suggest that the accumulation of ROS in the liver is a potential mechanism of drug-induced liver injury[16]. In present study, we hypothesized that the genetic polymorphisms in the Nrf2-ARE signaling pathway may play an important role in susceptibility to ATLI To test this hypothesis, 13 tag single-nucleotide polymorphisms (tagSNPs) in NRF2, KEAP1, MAFF, MAFK genes were analyzed to determine the role of tagSNPs in Chinese ATLI patients
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