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

Abstract

1. 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 N-acetyltransferase 2 (NAT2) genotype, rs3814055 in nuclear receptor subfamily 1, group I, member 2 (NR1I2) has been demonstrated to be associated with anti-tuberculosis drug-induced hepatotoxicity (ATDH), but previous results have been inconsistent.

2. 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, NR1I2, UDP-glucuronosyltransferase 1A1, NAT2, superoxide dismutase 1, superoxide dismutase 2, and glutathione S-transferases (GSTT1, GSTM1, GSTP1) 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.

3. Conditional logistic regression demonstrated that the NAT2 slow acetylation genotype and the T allele of rs3814055 in NR1I2 may contribute to susceptibility to ATDH.

4. Stratified association analysis demonstrated that in NAT2 non-slow acetylators, the T allele of rs3814055 was a risk factor for ATDH, whereas the T allele did not increase the susceptibility to ATDH in slow acetylators.

Keywords:

• NAT2
• rs3814055
• NR1I2
• anti-tuberculosis
• hepatotoxicity

Author contributions

Ning Wang, Shaochen Guo, Haiting Liu, and Yangming Ding extracted the genome DNA. Rong Yao, Zhongquan Liu, Hui Zhu, Xi Chen, and Xinting Yang retrieved information for each blood sample and enrolled the patients. Ning Wang and Yangming Ding conducted the data processing.

Xiaoyou Chen and Yu Lu conceived the study and designed the methodology. Ning Wang drafted the manuscript. All authors approved the final version of the manuscript and authorship list.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data that support the findings and conclusions of this study are included within this article.

Additional information

Funding

The work was funded by the Beijing Municipal Science and Technology Commission [grant number: Z191100006619090].