A Combination Polymorphism of the Glutathione Synthesis Genes Can Be a Predictive Biomarker for Anti-Tuberculosis Drug-Induced Hepatotoxicity in Japanese Patients with Pulmonary Tuberculosis

Abstract

Background: To identify certain genes related to anti-tuberculosis drug-induced hepatotoxicity (ATDH) for Japanese patients with pulmonary tuberculosis (TB), we examined an association study of single nucleotide polymorphisms (SNPs) in candidate genes in glutathione synthesis with susceptibility to ATDH. Method: We studied 100 TB patients treated with anti-TB drugs. The frequencies of alleles and genotypes of 17 tag SNPs in 3 genes between TB patients with and without ATDH were compared by chi-square test or Fisher's exact test in three different inheritance models. A genetic testing was carried out using a single or combination of the associated SNP(s) as a biomarker. Results: Statistical analyses indicated that a C/C genotype of rs553822 in glutamate cysteine ligase, catalytic subunit (GCLC) and an A/T or T/T genotype of rs12140446 in glutamate cysteine ligase, modifier subunit (GCLM) independently contributed to susceptibility to ATDH. Genetic testing showed that the TB patients without these polymorphisms of GCLC and GCLM could safely be treated with anti-TB drugs on the basis of the higher value for the specificity and negative predictive value. Conclusion: GCLC and GCLM are ATDH-related genes and may be useful as a new biomarker to predict the high-risk TB patients susceptible to ATDH.