Genetic Polymorphisms in Antioxidant Enzymes Modulate the Susceptibility of Idiosyncratic Antituberculous Drug-Induced Liver Injury and Treatment Outcomes in Patients with Tuberculosis.

Background: The pathogenic mechanism of antituberculous drug-induced liver injury (ATDILI) is associated with antioxidant enzymes. The objective of the present study was to investigate the associations of ATDILI susceptibility with genetic polymorphisms of antioxidant enzyme genes including nitric oxide synthase 2 (NOS2), thioredoxin reductase 1 (TXNRD1), superoxide dismutase 2 (SOD2), BTB domain and CNC homolog 1 (BACH1), and MAF bZIP transcription factor K (MAFK).

Methods: Thirty tag single nucleotide polymorphisms (tag-SNPs) from the all candidate genes were genotyped in a 2-stage cohort study including an initial discovery stage with 461 ATDILI patients and 466 controls and a replication stage with 216 ATDILI patients and 432 controls. The frequencies and distributions of genotypes and haplotypes were compared between the case and control groups. Three different genetic models including dominant, recessive, and additive models were used to determine the associations with susceptibility to ATDILI.

Results: The SNPs rs9906835, rs944725, and rs3794764 of the NOS2 gene were significantly associated with an increased risk of ATDILI. The MAFK rs3735656 SNP was significantly associated with a decreased risk for ATDILI. The AAA haplotype of the NOS2 gene was associated with susceptibility to ATDILI. The treatment outcomes of patients with tuberculosis were further affected by genetic variants of the NOS2 and MAFK genes.

Conclusions: Genetic polymorphisms of NOS2 and MAFK are associated with ATDILI susceptibility in Chinese patients with tuberculosis. The variants in NOS2 and MAFK affect treatment outcomes of tuberculosis patients. Further studies are needed to better understand the molecular mechanisms of ATDILI susceptibility via regulation of the expression of ATDILI-susceptibility genes and proteins.