NAT2 Polymorphism and Clinical Factors that Increase Antituberculosis Drug-Induced Hepatotoxicity

Abstract

Aim: Hepatotoxicity is a known adverse effect of antituberculosis drugs. The NAT2 gene polymorphism has been associated with an increased risk of antituberculosis drug-induced hepatotoxicity (ATDIH). Materials and methods: This study investigates the association of NAT2 polymorphism and clinical risk factors that may contribute to the development of ATDIH. The authors sequenced the NAT2 region of 33 tuberculosis patients who developed ATDIH and 100 tuberculosis patients who did not develop ATDIH during tuberculosis treatment. NAT2 haplotypes were inferred and NAT2 acetylator status was predicted from the combination of the inferred haplotypes. Multiple logistic regression was performed to identify possible factors that are associated with ATDIH. Results: The TT genotype of NAT2*13A and the AA genotype of NAT2*6B were found to be substantially linked with the risk of ATDIH, with odds ratios of 3.09 (95% CI: 1.37–6.95) and 3.07 (95% CI: 1.23–7.69), respectively. NAT2 slow acetylators are 3.39-times more likely to develop ATDIH. Factors that were associated with ATDIH include underlying diabetes mellitus (adjusted odds ratio [AOR] 2.96; 95% CI: 1.05–8.37), pre-treatment serum bilirubin (AOR 1.09; 95% CI: 1.02–1.16) and NAT2 slow acetylator (AOR 3.77; 95% CI: 1.51–9.44). Conclusion: Underlying diabetes mellitus, having a higher baseline bilirubin and being a slow acetylator are identified as the risk factors associated with ATDIH among patients in Malaysia.

Advancing tuberculosis management: the role of predictive, preventive, and personalized medicine

“…Previous studies on genotyping the NAT2 as a pharmacogenetic biomarker for the personalization of isoniazid therapeutic dosage revealed a direct correlation between the plasmatic concentration and the NAT2 allele ( Kinzig-Schippers et al, 2005 ; Fukino et al, 2008 ). In addition, the gene polymorphisms in NAT2 have consistently demonstrated an association with an elevated risk of isoniazid-induced hepatotoxicity in various studies ( Jaramillo-Valverde et al, 2022 ; Masiphephethu et al, 2022 ; Mohamed Noor et al, 2022 ). On the contrary, the study conducted by Kim et al yielded results indicating that severe cutaneous adverse reactions associated with first-line anti-tuberculosis drugs are not linked to polymorphisms in NAT2 or CYP2E1 genes.…”