NAT2 Involed in the Susceptibility to Antituberculosis Drug-Induced Liver Injury

Donglin Zhu (Department of Laboratory Medicine, The Third Affliated Hospital of Sun Yat-sen University)
Changzhi Xu (Department of Laboratory Medicine, The Third Affliated Hospital of Sun Yat-sen University)
Zhizhi Xie (Department of Laboratory Medicine, The Third Affliated Hospital of Sun Yat-sen University)
Gang Xiao (Department of Laboratory Medicine, The Third Affliated Hospital of South China Medical University)
Yun Xi (Department of Laboratory Medicine, The Third Affliated Hospital of Sun Yat-sen University)


Objective: To investigate whether the N-acetyltransferase 2 (NAT2) gene is involved in the development of susceptibility to antituberculosis drug-induced liver damage (ATDLI) in patients with pulmonary tuberculosis in the Han nationality. Methods: We retrospectively analyzed 300 cases of tuberculosis patients without liver damage (control group) and 221 cases of tuberculosis patients with liver damage after antituberculosis treatment (case group). After antituberculosis treatment, genetic polymorphisms of NAT2 were analyzed in those patients using MassARRAY method. Results: Of the 10 tagged SNPs selected, In the promoter area of NAT2, the frequencies of T allele in rs4646243 and A allele in rs4646246 were signifcantly higher in the patients with ATDLI than controls (0.569 vs. 0.483, p=0.0062 and 0.567 vs 0.487, p=0.0103). The A allele of rs1115784 in the intron area showed a significant association with the development of ATDLI (0.389 vs 0.305, p = 0.0043). The frequencies of the mutated genes T and A in rs1041983 and rs1799930 in the second exon region were significantly higher than those in the control group (0.491 vs 0.360, p<0.00001 and 0.336 vs 0.212, respectively; p<0.00001). Two monomer domains were found in the 10 tag SNP sites, haplotype ht [TGAA] in monomeric domain 1 and haplotype ht [TAG] in monomeric domain 2, both were signifcantly more likely to be detected in the liver injury group than in the control group(p=0.0038, p<0.001, respectively). Two haplotypes were also found on the NAT2 gene: haplotype ht [CGGG] in monomeric domain 1 and ht [CGG] in block 2, and their presence means a lower risk of liver damage. Conclusion: NAT2 genotypes might have signifcant association with the risk of ATDLI in the Chinese Han nationality. By detecting the NAT2 gene and its haplotype, we can screen patients with a higher risk of liver damage before anti-TB treatment and take measures for the protection of patients.


NAT2; MassARRAY; Tuberculosis; Liver injury; Genetic polymorphism

Full Text:



Dye C, Watt CJ, Bleed DM, et al.C. Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence, and deaths globally[J]. JAMA, 2005, 293(22):2790-2793.

Agal S, Baijal R, Pramanik S, et al. Monitoring and management of antituberculosis drug induced hepatotoxicity[J]. J Gastroenterol Hepatol, 2005, 20(11):1745-1752.

XUE Hong Yuan, HOU Yan Ning, LIU Hui Chen,et al. Study On the Mechanisms of Increased Hepatotoxicity of Rifampicin Plus Isoniazid in mice[J].Pharm J Chin PLA, 2002,18(6):330-333.

Sang-Heon Kim , Sang-Hoon Kim , Ho Joo Yoon, et al. GSTT1 and GSTM1 null mutations and adverse reactions induced by antituberculosis drugs in Koreans[J]. Tuberculosis, 2010, 90 (1): 39-43.

Bose PD, Sarma MP, Medhi S, et al. Role of polymorphic N-acetyl transferase2 and cytochrome P4502E1 gene in antituberculosis treatment-induced hepatitis[J]. J Gastroenterol Hepatol, 2011,26(2):312-318.

Saukkonen JJ, Cohn DL, Jasmer RM, et al. An offcial ATS statement: hepatotoxicity of antituberculosis therapy [J]. Am J Resp ir Crit.Care Med, 2006,174(8):935-952.

Ng CS, Hasnat A, Al Maruf A, et al. N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to antituberculosis drug treatment in a mixed-ethnicity patient group[J].Eur J Clin Pharmacol, 2014, 70(9):1079-

Sharma SK, Balamurugan A, Saha PK,et al. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment[J]. Am. J. Respir. Crit. Care Med,2002, 166(7): 916-919.

Yee D, Valiquette C, Pelletier M, et al. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis[J]. Am. J. Respir. Crit. Care Med, 2003,


Mushiroda T, Yanai H, Yoshiyama T, et al. Development of a prediction system for antituberculosis drug-induced liver injury in Japanese patients [J].Hum Genome Var, 2016, 3:16014.

Shi J, Xie M, Wang J, et al. Susceptibility of N acetyltransferase 2 slow acetylators to antituberculosis

drug-induced liver injury: a meta-analysis[J].Pharmacogenomics, 2015 , 16(18):2083-97.

Wilke RA, Lin DW, Roden DM, et al. Identifying genetic risk factors for serious adverse drug reactions:current progress and challenges [J].Nat Rev Drug Discov, 2007, 6(11):904-916.

Stephens EA, Taylor JA, Kaplan N, et al. Ethnic variation in the CYP2E1 gene: polymorphism analysis of 695 African-Americans, European-Americans and Taiwanese [J]. Pharmacogenetics , 1994, 4(4):185-192.

Adrian J, Fretland, Mattew, et al. Functional characterization of human N-acetyltransferase(NAT2) single nucleotide polymorphisms [J]. Pharmacogenetics,2001, 11:207-215.

Bing Chen, Jin-Heng Li, Yi-Min Xu, et al. The influence of NAT2 genotypes on the plasma concentration of isoniazid and acetylisoniazid in Chinese pulmonary tuberculosis patients[J]. Clinica Chimica Acta,2006, 365:104-108.

Yu Zang, Mark A. Doll, Shuang Zhao, et al. Functional Characterization of Single Nucleotide Polymorphisms and Haplotypes of Human N-Acetyltransferase 2[J]. Carcinogenesis, 2007, 28(8):1665-1671.

Yi-Shin Huang, Herng-Der Chern, Wei-Juin al. Polymorphism of the N-Acetyltransferase 2 Gene as a Susceptibility Risk Factor for Antituberculosis Drug–Induced Hepatitis[J]. Hepatology, 2002,35(4):883-889.

Hyun-Jung Cho, Won-Jung Koh, Yon-Ju Ryub, et al. Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis[J]. Tuberculosis, 2007, 87(6): 551-556.

Khalili H, Fouladdel S, Sistanizad M, et al. Association of N-acetyltransferase-2 genotypes and antituberculosis induced liver injury; frst case-controlled study from Iran[J]. Curr Drug Saf. 2011, 6(1):17-22.

WANG Jin-he,LIU Jin-wei,WU Xue-qiong, et al. The study on the susceptible gene of isoniazid and rifampicin-induced hepatotoxicity of pulmonary tuberculosis patients[J]. Academic Journal of Pla Postgraduate Medical School, 2004,25(3):239-240.

Sharma SK, Jha BK, Sharma A, et al. Genetic polymorphisms of N-acetyltransferase 2 & susceptibility to antituberculosis drug-induced hepatotoxicity[J]. Indian J Med Res, 2016, 144(6):924-928.

Guaoua S, Ratbi I, El Bouazzi O, et al. NAT2 Genotypes in Moroccan Patients with Hepatotoxicity Due to Antituberculosis Drugs[J].Genet Test Mol Biomarkers. 2016, 20(11):680-684.

Sang-Heon Kim, Sang-Hoon Kim,Joon-Woo Bahn,et al.Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis[J].Pharmacogenomics, 2009, 10(11):1767-1779.

Possuelo LG, Castelan JA, de Brito TC, et al. Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil [J].Eur J Clin Pharmacol, 2008,64(7):673-681.



  • There are currently no refbacks.
Copyright © 2019 云 席 Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.