Relevance of gene polymorphisms of NAT2 and NR1I2 to anti-tuberculosis drug-induced hepatotoxicity

The recommended treatment regimen for tuberculosis is a combination of agents with antitubercular activity, during which hepatotoxicity is one of the most common side effects. In addition to the <i>N</i>-acetyltransferase 2 (<i>NAT2</i>) genotype, <i>rs3814055</i> in nuclear receptor subfamily 1, group I, member 2 (<i>NR1I2</i>) has been demonstrated to be associated with anti-tuberculosis drug-induced hepatotoxicity (ATDH), but previous results have been inconsistent.A retrospective nested hospital-based case–control study was performed to investigate the association between genetic polymorphisms and the risk of ATDH. Fifteen genetic variants (13 SNPs and two null genotypes) in cytochrome P450 2E1, <i>NR1I2</i>, UDP-glucuronosyltransferase 1A1, <i>NAT2</i>, superoxide dismutase 1, superoxide dismutase 2, and glutathione <i>S</i>-transferases (<i>GSTT1</i>, <i>GSTM1</i>, <i>GSTP1)</i> were genotyped. Odds ratios with 95% confidence intervals were calculated with drug doses, body mass index comorbidity of diabetes mellitus, and baseline alanine transaminase value as covariates.Conditional logistic regression demonstrated that the <i>NAT2</i> slow acetylation genotype and the <i>T</i> allele of <i>rs3814055</i> in <i>NR1I2</i> may contribute to susceptibility to ATDH.Stratified association analysis demonstrated that in <i>NAT2</i> non-slow acetylators, the <i>T</i> allele of <i>rs3814055</i> was a risk factor for ATDH, whereas the <i>T</i> allele did not increase the susceptibility to ATDH in slow acetylators. The recommended treatment regimen for tuberculosis is a combination of agents with antitubercular activity, during which hepatotoxicity is one of the most common side effects. In addition to the <i>N</i>-acetyltransferase 2 (<i>NAT2</i>) genotype, <i>rs3814055</i> in nuclear receptor subfamily 1, group I, member 2 (<i>NR1I2</i>) has been demonstrated to be associated with anti-tuberculosis drug-induced hepatotoxicity (ATDH), but previous results have been inconsistent. A retrospective nested hospital-based case–control study was performed to investigate the association between genetic polymorphisms and the risk of ATDH. Fifteen genetic variants (13 SNPs and two null genotypes) in cytochrome P450 2E1, <i>NR1I2</i>, UDP-glucuronosyltransferase 1A1, <i>NAT2</i>, superoxide dismutase 1, superoxide dismutase 2, and glutathione <i>S</i>-transferases (<i>GSTT1</i>, <i>GSTM1</i>, <i>GSTP1)</i> were genotyped. Odds ratios with 95% confidence intervals were calculated with drug doses, body mass index comorbidity of diabetes mellitus, and baseline alanine transaminase value as covariates. Conditional logistic regression demonstrated that the <i>NAT2</i> slow acetylation genotype and the <i>T</i> allele of <i>rs3814055</i> in <i>NR1I2</i> may contribute to susceptibility to ATDH. Stratified association analysis demonstrated that in <i>NAT2</i> non-slow acetylators, the <i>T</i> allele of <i>rs3814055</i> was a risk factor for ATDH, whereas the <i>T</i> allele did not increase the susceptibility to ATDH in slow acetylators.