The association between N-acetyltransferase 2 gene polymorphisms and the risk of antituberculosis drug-induced liver injury: a Meta-analysis_West China Medical Journal

Authors：

YANG Xue ¹ ^* , YANG Xin ² ^* , XU Li ¹ , TONG Xiang ¹ , BAI Min ¹ , WANG Dongguang ¹ ,  FAN Hong ¹

1. Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Respiratory and Critical Care Medicine, Gansu Provincial Hosptial, Lanzhou, Gansu 730000, P. R. China;

Corresponding author：

FAN Hong, Email: fanhongfan@qq.com

Keywords：

Antituberculosis drug-induced liver injury; N-acetyltransferase 2; Gene polymorphisms; Meta-analysis

DOI：

10.7507/1002-0179.201709118

Video：

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Objective To evaluate the association between N-acetyltransferase 2 (NAT2) gene polymorphisms and the risk of antituberculosis drug-induced liver injury (ATDILI). Methods We searched the PubMed, Embase, Wanfang, China National Knowledge Internet and VIP databases to find case-control studies, with the last updated search being performed on June 2017. Odds ratio (OR) with 95% confidence interval (CI) was calculated to evaluate the strength of association. Results A total of 29 studies, involving 1 382 cases and 5 967 controls were included. The results of the Meta-analysis indicated that NAT2 slow acetylators were associated with increased risk of ATDILI compared with fast and intermediate acetylators [OR=3.08, 95%CI (2.44, 3.88), P<0.000 01]. Similar results were also found in subgroup analysis when stratified by ethnicity, isoniazid dosage and diagnostic criteria of ATDILI. Conclusion Individuals with NAT2 slow acetylators may have increased risk of ATDILI.

Citation： YANG Xue, YANG Xin, XU Li, TONG Xiang, BAI Min, WANG Dongguang, FAN Hong. The association between N-acetyltransferase 2 gene polymorphisms and the risk of antituberculosis drug-induced liver injury: a Meta-analysis. West China Medical Journal, 2018, 33(1): 67-75. doi: 10.7507/1002-0179.201709118 Copy

1.	Lee WM. Drug-induced hepatotoxicity. N Engl J Med, 1995, 333(17): 1118-1127.
2.	Wong WM, Wu PC, Yuen MF, et al. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology, 2000, 31(1): 201-206.
3.	Byrd RB, Horn BR, Solomon DA, et al. Toxic effects of isoniazid in tuberculosis chemoprophylaxis. Role of biochemical monitoring in 1,000 patients. JAMA, 1979, 241(12): 1239-1241.
4.	Huang YS. Recent progress in genetic variation and risk of antituberculosis drug-induced liver injury. J Chin Med Assoc, 2014, 77(4): 169-173.
5.	Tostmann A, Boeree MJ, Aarnoutse RE, et al. Antituberculosis drug-induced hepatotoxicity: concise up-to-date review. J Gastroenterol Hepatol, 2008, 23(2): 192-202.
6.	Huang YS, Chern HD, Su WJ, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology, 2002, 35(4): 883-889.
7.	Huang YS. Genetic polymorphisms of drug-metabolizing enzymes and the susceptibility to antituberculosis drug-induced liver injury. Expert Opin Drug Metab Toxicol, 2007, 3(1): 1-8.
8.	Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med, 2006, 174(8): 935-952.
9.	Little J, Bradley L, Bray MS, et al. Reporting, appraising, and integrating data on genotype prevalence and gene-disease associations. Am J Epidemiol, 2002, 156(4): 300-310.
10.	Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ, 1997, 315(719): 629-634.
11.	Ohno M, Yamaguchi I, Yamamoto I, et al. Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. Int J Tuberc Lung Dis, 2000, 4(3): 256-261.
12.	Shimizu Y, Dobashi K, Mita Y, et al. DNA microarray genotyping of N-acetyltransferase 2 polymorphism using carbodiimide as the linker for assessment of isoniazid hepatotoxicity. Tuberculosis, 2006, 86(5): 374-381.
13.	Vuilleumier N, Rossier MF, Chiappe A, et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol, 2006, 62(6): 423-429.
14.	Cho HJ, Koh WJ, Ryu YJ, et al. Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis (Edinb), 2007, 87(6): 551-556.
15.	Higuchi N, Tahara N, Yanagihara K, 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, 2007, 13(45): 6003-6008.
16.	Bozok Cetintaş V, Erer OF, Kosova B, et al. Determining the relation between N-acetyltransferase-2 acetylator phenotype and antituberculosis drug induced hepatitis by molecular biologic tests. Tuberk Toraks, 2008, 56(1): 81-86.
17.	Yamada S, Tang M, Richardson K, et al. Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population. Pharmacogenomics, 2009, 10(9): 1433-1445.
18.	郭梅, 孙永红, 李世明, 等. N-乙酰化转移酶 2 基因多态性与抗结核药物所致肝损伤的相关性. 中华传染病杂志, 2010, 28(2): 99-102.
19.	Lee SW, Chung LS, Huang HH, et al. NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis. Int J Tuberc Lung Dis, 2010, 14(5): 622-626.
20.	邬宇美, 骆子义, 张红梅, 等. NAT2 基因多态性与抗结核药物性肝炎的相关性. 中华肝脏病杂志, 2010, 18(6): 467-469.
21.	Bose PD, Sarma MP, Medhi S, et al. Role of polymorphic N-acetyl transferase2 and cytochrome P4502E1 gene in antituberculosis treatment-induced hepatitis. J Gastroenterol Hepatol, 2011, 26(2): 312-318.
22.	黄冬生, 邹永红, 何刚, 等. N-乙酰基转移酶 2 基因多态性与抗结核药所致肝损害的关系. 中华生物医学工程杂志, 2011, 17(5): 444-447.
23.	Khalili H, Fouladdel S, Sistanizad M, et al. Association of N-acetyltransferase-2 genotypes and anti-tuberculosis induced liver injury; first case-controlled study from Iran. Curr Drug Saf, 2011, 6(1): 17-22.
24.	Teixeira RL, Morato RG, Cabello PH, et al. Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients. Mem Inst Oswaldo Cruz, 2011, 106(6): 716-724.
25.	An HR, Wu XQ, Wang ZY, et al. NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug-induced hepatotoxicity in Chinese patients. Clin Exp Pharmacol Physiol, 2012, 39(6): 535-543.
26.	Ben Mahmoud L, Ghozzi H, Kamoun A, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis. Pathol Biol (Paris), 2012, 60(5): 324-330.
27.	Lv X, Tang S, Xia Y, et al. NAT2 genetic polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in Chinese community population. Ann Hepatol, 2012, 1(5): 700-707.
28.	Chamorro JG, Castagnino JP, Musella RM, et al. Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs. J Gastroenterol Hepatol, 2013, 28(2): 323-328.
29.	Forestiero FJ, Cecon L, Hirata MH, et al. Relationship of NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms with mild elevation of liver enzymes in Brazilian individuals under anti-tuberculosis drug therapy. Clin Chim Acta, 2013, 415: 215-219.
30.	Gupta VH, Amarapurkar DN, Singh M, et al. Association of N-acetyltransferase 2 and cytochrome P4502E1 gene polymorphisms with antituberculosis drug-induced hepatotoxicity in Western India. J Gastroenterol Hepatol, 2013, 28(8): 1368-1374.
31.	Ho HT, Wang TH, Hsiong CH, et al. The NAT2 tag SNP rs1495741 correlates with the susceptibility of antituberculosis drug-induced hepatotoxicity. Pharmacogenet Genomics, 2013, 23(4): 200-207.
32.	Rana SV, Sharma SK, Ola RP, et al. N-acetyltransferase 2, cytochrome P4502E1 and glutathione S-transferase genotypes in antitubercular treatment-induced hepatotoxicity in North Indians. J Clin Pharm Ther, 2014, 39(1): 91-96.
33.	Singla N, Gupta D, Birbian N, et al. Association of NAT2, GST and CYP2E1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity. Tuberculosis (Edinb), 2014, 94(3): 293-298.
34.	Xiang Y, Ma L, Wu W, et al. The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1. PLoS One, 2014, 9(1): e85905.
35.	沈婷婷, 张琴, 张文宏, 等. 中国汉族结核病患者 N-乙酰基转移酶 2 基因型与药物性肝损伤以及抗结核疗效的关系. 中华传染病杂志, 2015(6): 327-330.
36.	Mushiroda T, Yanai H, Yoshiyama T, et al. Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients. Hum Genome Var, 2016, 3: 16014.
37.	Yuliwulandari R, Susilowati RW, Wicaksono BD, et al. NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis. J Hum Genet, 2016, 61(6): 533-537.
38.	Yamamoto TS, Hirayama C. Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype. Hepatology, 1986, 6(2): 295-298.
39.	Mitchell JR, Thorgeirsson UP, Black M, et al. Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydranize metabolites. Clin Pharmacol Ther, 1975, 18(1): 70-79.
40.	Mitchell JR, Zimmerman HJ, Ishak KG, et al. Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis. Ann Intern Med, 1976, 84(2): 181-192.
41.	Sun F, Chen Y, Xiang Y, et al. Drug-metabolising enzyme polymorphisms and predisposition to anti-tuberculosis drug-induced liver injury: a meta-analysis. Int J Tuberc Lung Dis, 2008, 12(9): 994-1002.
42.	Cai Y, Yi J, Zhou C, et al. Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis. PLoS One, 2012, 7(10): e47769.
43.	Wang PY, Xie SY, Hao Q, et al. NAT2 polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury: a meta-analysis. Int J Tuberc Lung Dis, 2012, 16(5): 589-595.
44.	Du H, Chen X, Fang Y, et al. Slow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis. Mol Biol Rep, 2013, 40(5): 3591-3956.
45.	Shi J, Xie M, Wang JM, et al. Susceptibility of N-acetyltransferase 2 slow acetylators to antituberculosis drug-induced liver injury: a meta-analysis. Pharmacogenomics, 2015, 16(18): 2083-2097.
46.	Leiro-Fernandez V, Valverde D, Vazquez-Gallardo R, et al. N-acetyltransferase 2 polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity in Caucasians. Int J Tuberc Lung Dis, 2011, 15(10): 1403-1408.
47.	Azuma J, Ohno M, Kubota R, 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 Clin Pharmacol, 2013, 69(5): 1091-1101.

1. Lee WM. Drug-induced hepatotoxicity. N Engl J Med, 1995, 333(17): 1118-1127.
2. Wong WM, Wu PC, Yuen MF, et al. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology, 2000, 31(1): 201-206.
3. Byrd RB, Horn BR, Solomon DA, et al. Toxic effects of isoniazid in tuberculosis chemoprophylaxis. Role of biochemical monitoring in 1,000 patients. JAMA, 1979, 241(12): 1239-1241.
4. Huang YS. Recent progress in genetic variation and risk of antituberculosis drug-induced liver injury. J Chin Med Assoc, 2014, 77(4): 169-173.
5. Tostmann A, Boeree MJ, Aarnoutse RE, et al. Antituberculosis drug-induced hepatotoxicity: concise up-to-date review. J Gastroenterol Hepatol, 2008, 23(2): 192-202.
6. Huang YS, Chern HD, Su WJ, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology, 2002, 35(4): 883-889.
7. Huang YS. Genetic polymorphisms of drug-metabolizing enzymes and the susceptibility to antituberculosis drug-induced liver injury. Expert Opin Drug Metab Toxicol, 2007, 3(1): 1-8.
8. Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med, 2006, 174(8): 935-952.
9. Little J, Bradley L, Bray MS, et al. Reporting, appraising, and integrating data on genotype prevalence and gene-disease associations. Am J Epidemiol, 2002, 156(4): 300-310.
10. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ, 1997, 315(719): 629-634.
11. Ohno M, Yamaguchi I, Yamamoto I, et al. Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. Int J Tuberc Lung Dis, 2000, 4(3): 256-261.
12. Shimizu Y, Dobashi K, Mita Y, et al. DNA microarray genotyping of N-acetyltransferase 2 polymorphism using carbodiimide as the linker for assessment of isoniazid hepatotoxicity. Tuberculosis, 2006, 86(5): 374-381.
13. Vuilleumier N, Rossier MF, Chiappe A, et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol, 2006, 62(6): 423-429.
14. Cho HJ, Koh WJ, Ryu YJ, et al. Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis (Edinb), 2007, 87(6): 551-556.
15. Higuchi N, Tahara N, Yanagihara K, 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, 2007, 13(45): 6003-6008.
16. Bozok Cetintaş V, Erer OF, Kosova B, et al. Determining the relation between N-acetyltransferase-2 acetylator phenotype and antituberculosis drug induced hepatitis by molecular biologic tests. Tuberk Toraks, 2008, 56(1): 81-86.
17. Yamada S, Tang M, Richardson K, et al. Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population. Pharmacogenomics, 2009, 10(9): 1433-1445.
18. 郭梅, 孙永红, 李世明, 等. N-乙酰化转移酶 2 基因多态性与抗结核药物所致肝损伤的相关性. 中华传染病杂志, 2010, 28(2): 99-102.
19. Lee SW, Chung LS, Huang HH, et al. NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis. Int J Tuberc Lung Dis, 2010, 14(5): 622-626.
20. 邬宇美, 骆子义, 张红梅, 等. NAT2 基因多态性与抗结核药物性肝炎的相关性. 中华肝脏病杂志, 2010, 18(6): 467-469.
21. Bose PD, Sarma MP, Medhi S, et al. Role of polymorphic N-acetyl transferase2 and cytochrome P4502E1 gene in antituberculosis treatment-induced hepatitis. J Gastroenterol Hepatol, 2011, 26(2): 312-318.
22. 黄冬生, 邹永红, 何刚, 等. N-乙酰基转移酶 2 基因多态性与抗结核药所致肝损害的关系. 中华生物医学工程杂志, 2011, 17(5): 444-447.
23. Khalili H, Fouladdel S, Sistanizad M, et al. Association of N-acetyltransferase-2 genotypes and anti-tuberculosis induced liver injury; first case-controlled study from Iran. Curr Drug Saf, 2011, 6(1): 17-22.
24. Teixeira RL, Morato RG, Cabello PH, et al. Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients. Mem Inst Oswaldo Cruz, 2011, 106(6): 716-724.
25. An HR, Wu XQ, Wang ZY, et al. NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug-induced hepatotoxicity in Chinese patients. Clin Exp Pharmacol Physiol, 2012, 39(6): 535-543.
26. Ben Mahmoud L, Ghozzi H, Kamoun A, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis. Pathol Biol (Paris), 2012, 60(5): 324-330.
27. Lv X, Tang S, Xia Y, et al. NAT2 genetic polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in Chinese community population. Ann Hepatol, 2012, 1(5): 700-707.
28. Chamorro JG, Castagnino JP, Musella RM, et al. Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs. J Gastroenterol Hepatol, 2013, 28(2): 323-328.
29. Forestiero FJ, Cecon L, Hirata MH, et al. Relationship of NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms with mild elevation of liver enzymes in Brazilian individuals under anti-tuberculosis drug therapy. Clin Chim Acta, 2013, 415: 215-219.
30. Gupta VH, Amarapurkar DN, Singh M, et al. Association of N-acetyltransferase 2 and cytochrome P4502E1 gene polymorphisms with antituberculosis drug-induced hepatotoxicity in Western India. J Gastroenterol Hepatol, 2013, 28(8): 1368-1374.
31. Ho HT, Wang TH, Hsiong CH, et al. The NAT2 tag SNP rs1495741 correlates with the susceptibility of antituberculosis drug-induced hepatotoxicity. Pharmacogenet Genomics, 2013, 23(4): 200-207.
32. Rana SV, Sharma SK, Ola RP, et al. N-acetyltransferase 2, cytochrome P4502E1 and glutathione S-transferase genotypes in antitubercular treatment-induced hepatotoxicity in North Indians. J Clin Pharm Ther, 2014, 39(1): 91-96.
33. Singla N, Gupta D, Birbian N, et al. Association of NAT2, GST and CYP2E1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity. Tuberculosis (Edinb), 2014, 94(3): 293-298.
34. Xiang Y, Ma L, Wu W, et al. The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1. PLoS One, 2014, 9(1): e85905.
35. 沈婷婷, 张琴, 张文宏, 等. 中国汉族结核病患者 N-乙酰基转移酶 2 基因型与药物性肝损伤以及抗结核疗效的关系. 中华传染病杂志, 2015(6): 327-330.
36. Mushiroda T, Yanai H, Yoshiyama T, et al. Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients. Hum Genome Var, 2016, 3: 16014.
37. Yuliwulandari R, Susilowati RW, Wicaksono BD, et al. NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis. J Hum Genet, 2016, 61(6): 533-537.
38. Yamamoto TS, Hirayama C. Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype. Hepatology, 1986, 6(2): 295-298.
39. Mitchell JR, Thorgeirsson UP, Black M, et al. Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydranize metabolites. Clin Pharmacol Ther, 1975, 18(1): 70-79.
40. Mitchell JR, Zimmerman HJ, Ishak KG, et al. Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis. Ann Intern Med, 1976, 84(2): 181-192.
41. Sun F, Chen Y, Xiang Y, et al. Drug-metabolising enzyme polymorphisms and predisposition to anti-tuberculosis drug-induced liver injury: a meta-analysis. Int J Tuberc Lung Dis, 2008, 12(9): 994-1002.
42. Cai Y, Yi J, Zhou C, et al. Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis. PLoS One, 2012, 7(10): e47769.
43. Wang PY, Xie SY, Hao Q, et al. NAT2 polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury: a meta-analysis. Int J Tuberc Lung Dis, 2012, 16(5): 589-595.
44. Du H, Chen X, Fang Y, et al. Slow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis. Mol Biol Rep, 2013, 40(5): 3591-3956.
45. Shi J, Xie M, Wang JM, et al. Susceptibility of N-acetyltransferase 2 slow acetylators to antituberculosis drug-induced liver injury: a meta-analysis. Pharmacogenomics, 2015, 16(18): 2083-2097.
46. Leiro-Fernandez V, Valverde D, Vazquez-Gallardo R, et al. N-acetyltransferase 2 polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity in Caucasians. Int J Tuberc Lung Dis, 2011, 15(10): 1403-1408.
47. Azuma J, Ohno M, Kubota R, 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 Clin Pharmacol, 2013, 69(5): 1091-1101.

West China Medical Journal

The association between N-acetyltransferase 2 gene polymorphisms and the risk of antituberculosis drug-induced liver injury: a Meta-analysis

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