Drug-induced liver injury (DILI) is the most common adverse drug reaction in the treatment of tuberculosis (TB). Several studies showed that patients with TB and the slow-acetylator phenotype caused by NAT2 variants are highly susceptible to DILI caused by anti-TB drugs, hereafter designated AT-DILI. However, the role of NAT2 variants in AT-DILI has never been assessed for an Indonesian population. We recruited 50 patients with TB and AT-DILI and 191 patients with TB but without AT-DILI; we then used direct DNA sequencing to assess single-nucleotide polymorphisms in the coding region of NAT2. NAT2*6A was significantly associated with susceptibility to AT-DILI (P=7.7 × 10−4, odds ratio (OR)=4.75 (1.8–12.55)). Moreover, patients with TB and the NAT2-associated slow-acetylator phenotype showed higher risk of AT-DILI than patients with the rapid- or intermediate-acetylator phenotypes (P=1.7 × 10−4, OR=3.45 (1.79–6.67)). In conclusion, this study confirms the significance of the association between slow-acetylator NAT2 variants and susceptibility to AT-DILI in an Indonesian population.
Subscribe to Journal
Get full journal access for 1 year
only $37.50 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
WHO Global Tuberculosis Report 2014, (World Health Organization, Geneva, Switzerland, 2014).
WHO. Treatment of Tuberculosis: Guidelines, (World Health Organization, Geneva, Switzerland, 2010).
Tostmann, A., Boeree, M. J., Aarnoutse, R. E., de Lange, W. C., van der Ven, A. J. & Dekhuijzen, R. Antituberculosis drug-induced hepatotoxicity: concise up-to-date review. J. Gastroen. Hepatol. 23, 192–202 (2008).
Bénichou, C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J. Hepatol. 11, 272–276 (1990).
Saukkonen, J. J., Cohn, D. L., Jasmer, R. M., Schenker, S., Jereb, J. A., Nolan, C. M. et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am. J. Resp. Crit. Med. 174, 935–952 (2006).
Daly, A. K., Donaldson, P. T., Bhatnagar, P., Shen, Y., Pe'er, I., Floratos, A. et al. HLA-B* 5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat. Genet. 41, 816–819 (2009).
Huang, Y. S., Chern, H. D., Su, W. J., Wu, J. C., Chang, S. C., Chiang, C. H. et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug‐induced hepatitis. Hepatology 37, 924–930 (2003).
Vuilleumier, N., Rossier, M. F., Chiappe, A., Degoumois, F., Dayer, P., Mermillod, B. et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur. J. Clin. Pharmacol. 62, 423–429 (2006).
Huang, Y.-S., Su, W.-J., Huang, Y.-H., Chen, C.-Y., Chang, F.-Y., Lin, H.-C. et al. Genetic polymorphisms of manganese superoxide dismutase, NAD (P) H: quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury. J. Hepatol. 47, 128–134 (2007).
Li, C., Long, J., Hu, X. & Zhou, Y. GSTM1 and GSTT1 genetic polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity: an updated meta-analysis. Eur. J. Clin. Microbiol. 32, 859–868 (2013).
Roy, B., Chowdhury, A., Kundu, S., Santra, A., Dey, B., Chakraborty, M. et al. Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 'null' mutation. J. Gastroen. Hepatol. 16, 1033–1037 (2001).
Tang, N., Deng, R., Wang, Y., Lin, M., Li, H., Qiu, Y. et al. GSTM1 and GSTT1 null polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury: a meta-analysis. Int. J. Tuberc. Lung Dis. 17, 17–25 (2013).
Ambreen, K., Sharma, R., Singh, K. P., Abbas, M. & Kumar, S. Association of GSTM1, GSTT1 and CYP2E1 Gene Polymorphisms with Antituberculosis Drug Induced Hepatotoxicity in North Indian Population. IJHSR 4, 149–160 (2014).
Sharma, S. K., Balamurugan, A., Saha, P. K., Pandey, R. M. & Mehra, N. K. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am. J. Respir. Crit. CAre Med. 166, 916–919 (2002).
Huang, Y.S., Chern, H. D., Su, W. J., Wu, J. C., Lai, S. L., Yang, S. Y. et al. Polymorphism of the N‐acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug–induced hepatitis. Hepatology 35, 883–889 (2002).
Ohno, M., Yamaguchi, I., Yamamoto, I., Fukuda, T., Yokota, S., Maekura, R. et al. Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. Int. J. Tuberc. Lung Dis. 4, 256–261 (2000).
Sim, E., Payton, M., Noble, M. & Minchin, R. An update on genetic, structural and functional studies of arylamine N-acetyltransferases in eucaryotes and procaryotes. Hum. Mol. Genet 9, 2435–2441 (2000).
Stanley, L. A. & Sim, E. Update on the pharmacogenetics of NATs: structural considerations. Pharmacogenomics 9, 1673–1693 (2008).
Cho, H.-J., Koh, W.-J., Ryu, Y.-J., Ki, C.-S., Nam, M.-H., Kim, J.-W. et al. Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis 87, 551–556 (2007).
Khalili, H., Fouladdel, S., Sistanizad, M., Hajiabdolbaghi, M. & Azizi, E. Association of N-acetyltransferase-2 genotypes and anti-tuberculosis induced liver injury; first case-controlled study from Iran. Curr. Drug Saf. 6, 17–22 (2011).
Lee, S., Chung, L., Huang, H., Chuang, T., Liou, Y. & Wu, L. NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis. Int. J. Tuberc. Lung Dis. 14, 622–626 (2010).
Rana, S. V., Ola, R. P., Sharma, S. K., Arora, S. K., Sinha, S. K., Pandhi, P. et al. Comparison between acetylator phenotype and genotype polymorphism of n-acetyltransferase-2 in tuberculosis patients. Hepatol. Int. 6, 397–402 (2012).
Yuliwulandari, R., Sachrowardi, Q., Nishida, N., Takasu, M., Batubara, L., Susmiarsih, T. P. et al. Polymorphisms of promoter and coding regions of the arylamine N-acetyltransferase 2 (NAT2) gene in the Indonesian population: proposal for a new nomenclature. J. Hum. Genet. 53, 201–209 (2008).
Weckx, S., Del-Favero, J., Rademakers, R., Claes, L., Cruts, M., De Jonghe, P. et al. novoSNP, a novel computational tool for sequence variation discovery. Genome Res. 15, 436–442 (2005).
Stephens, M. & Scheet, P. Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am. J. Hum. Genet. 76, 449–462 (2005).
Stephens, M., Smith, N. J. & Donnelly, P. A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet. 68, 978–989 (2001).
Barrett, J. C., Fry, B., Maller, J. & Daly, M. J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).
Rabstein, S., Unfried, K., Ranft, U., Illig, T., Kolz, M., Rihs, H. P. et al. Variation of the N-acetyltransferase 2 gene in a Romanian and a Kyrgyz population. Cancer Epidemiol. Biomarkers Prev. 15, 138–141 (2006).
Sabbagh, A., Langaney, A., Darlu, P., Gérard, N., Krishnamoorthy, R. & Poloni, E. S. Worldwide distribution of NAT2 diversity: implications for NAT2 evolutionary history. BMC Genet. 9, 21 (2008).
Hein, D. W., Doll, M. A., Rustan, T. D. & Ferguson, R. J. Metabolic activation of N-hydroxyarylamines and N-hydroxyarylamides by 16 recombinant human NAT2 allozymes: effects of 7 specific NAT2 nucleic acid substitutions. Cancer Res. 55, 3531–3536 (1995).
Higuchi, N., Tahara, N., Yanagihara, K., Fukushima, K., Suyama, N., Inoue, Y. et al. NAT2 6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis. World J. Gastroenterol. 13, 6003–6008 (2007).
An, H. R., Wu, X. Q., Wang, Z. Y., Zhang, J. X. & Liang, Y. NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug-induced hepatotoxicity in Chinese patients. Clin. Exp. Pharmacol. Physiol. 39, 535–543 (2002).
Cai, Y., Yi, J. Y., Zhou, C. H. & Shen, X. Z. Pharmacogenetic study of drug metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis. PLoS ONE 7, e47769 (2012).
Wang, P. Y., Xie, S. Y., Hao, Q., Zhang, C & Jiang, B. F. NAT2 polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury: a meta-analysis. Int. J. Tuberc. Lung Dis. 16, 589–595 (2012).
Du, H., Chen, X., Fang, Y., Yan, O., Xu, H., Li, L. et al. Slow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis. Mol. Biol. Rep. 40, 3591–3596 (2013).
Zhang, Y., Doll, M. A., Zhao, S., States, J.C. & Hein, D. W. Functional characterization of single-nucleotide polymorphism and haplotypes of human N-acetyltransferase 2. Carcinogenesis 28, 1665–1671 (2007).
Zhang, Y., Doll, M. A., Zhao, S., States, J. C. & Hein, D. W. Functional Characterization of the A411T (L137F) and G364A (D122N) genetic polymorphism in human N-acetyltransferase 2. Pharmacogent. Genomics 1, 37–45 (2007).
Kementrian Kesehatan Republik Indonesia: Direktorat Jendral Pengendalian Penyakit dan Penyehatan Lingkungan. Pedoman Pengendalian Tuberkulosis, (Kementrian Kesehatan Republik Indonesia, Jakarta, Indonesia, 1994).
Azuma, J., Ohno, M., Kubota, R., Yokota, S., Nagai, T., Tsuyuguchi, K. et al. NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: a randomized controlled trial for pharmacogenetics-based therapy. Eur. J. Pharmacol. 69, 1091–1101 (2013).
Stephens, C., Lucena, M. I. & Andrade, R. J. Genetic variations in drug-induced liver injury (DILI): resolving the puzzle. Front. Genet. 3, 253 (2012).
Ma, Q. & Lu, A. Y. H. Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol. Rev. 63, 437–459 (2011).
Urban, T. J., Goldstein, D. B. & Watkins, P. B. Genetic basis of susceptibility to drug-induced liver injury: what have we learned and where do we go from here? Pharmacogenomics 13, 735–738 (2012).
This project was funded by a grant from the Indonesian Directorate General of Higher Education (DIKTI) of the Ministry of Higher Education, Research and Technology of the Republic of Indonesia. We are also thankful to the following institutions/organizations for their support in this project: YARSI Foundation, Pasar Rebo General Hospital, and YARSI Genomic Medicine Research Group. Last, special appreciation goes to our TB collaborators under JSPS (Japan Society for the Promotion of Science) core-to-core program and all TB patients who participated in this study.
The authors declare no conflict of interest.
About this article
Relevance of NAT2 genotype to anti‐tuberculosis drug‐induced hepatotoxicity in a Chinese Han population
The Journal of Gene Medicine (2019)
Pharmacogenetic association between NAT2 gene polymorphisms and isoniazid induced hepatotoxicity: trial sequence meta-analysis as evidence
Bioscience Reports (2019)
Glutathione S-transferase M1 and T1 null allele frequencies among Indonesian ethnics toward improved disease risk assessment
Environmental Toxicology and Pharmacology (2019)
Annals of Human Genetics (2019)
Current Pharmacology Reports (2018)