[The associations of polymorphism of N-acetyltransferase 2 gene is associated with antituberculosis drug-induced hepatotoxicity in tuberculosis patients]

Hui-ru An, Xue-qiong Wu, Zhong-yuan Wang, Yan Liang, Jun-xian Zhang
Zhonghua Yu Fang Yi Xue za Zhi [Chinese Journal of Preventive Medicine] 2011, 45 (1): 36-40

OBJECTIVE: To study the possible relationship between polymorphic N-acetyltransferase 2 (NAT2) acetylator status and antituberculosis drug-induced hepatotoxicity and to elucidate the molecular mechanism of antituberculosis drug-induced hepatotoxicity.

METHODS: Blood samples from 101 tuberculosis cases with antituberculosis drug-induced hepatotoxicity and from 107 tuberculosis without antituberculosis drug-induced hepatotoxicity were collected for a case-control study. DNA of the subjects was extracted and amplified by polymerase chain reaction (PCR). The single nucleotide polymorphisms of NAT2 were determined by direct PCR sequencing. The genotype frequencies were compared between cases and controls by χ(2) test, using SPSS 12.0 software, and the association between the disease and genotypes was analyzed.

RESULTS: Among the 101 patients with antituberculosis drug-induced liver injury, 36 patients (35.6%) were found with 282 T/T, 12 (11.9%) with 590 A/A, and 48 (47.5%) with 857 G/A or A/A. However, among the 107 controls, 9 patients (8.4%) were found with 282 T/T, 3 (2.8%) with 590 A/A, and 33 (33.8%) with 857 G/A or A/A. The patients with 282 T/T, 590 A/A, or 857 G/A or A/A genotype had a higher risk of antituberculosis drug-induced hepatotoxicity than those with 282 C/C or C/T, 590 G/G or G/A, or 857 G/G, and the OR values were 6.03 (95%CI: 2.88 - 12.62; χ(2) = 22.73, P < 0.05), 4.67 (95%CI: 1.42 - 15.44; χ(2) = 6.40, P < 0.05) and 2.03 (95%CI: 1.16 - 3.57; χ(2) = 6.08, P < 0.05) respectively. There were 40 patients with slow acetylator (39.6%) in cases with hepatotoxicity and 13 with slow acetylator (12.2%) in controls without hepatotoxicity. Patients with slow acetylator genotype (OR = 4.74, 95% CI = 2.42 - 9.28; χ(2) = 20.62, P < 0.05) had a significantly higher risk of antituberculosis drug-induced hepatotoxicity than those with rapid or intermediate acetylator genotypes. Among the cases, 19.8% (20/101) were found with NAT2(*)6A/7B, and 11.9% (12/101) with NAT2(*)6A/6A, whereas among the controls, 2.8% (3/107) were found with NAT2(*)6A/7B, and 2.8% (3/107) with NAT2(*)6A/6A respectively, the patients with NAT2(*)6A/7B and NAT2(*)6A/6A had a much higher risk of antituberculosis drug-induced hepatotoxicity, and the OR values were 8.40 (95%CI: 2.85 - 24.73; χ(2) = 14.90, P < 0.05) and 4.67 (95%CI: 1.42 - 15.44; χ(2) = 6.40, P < 0.05) respectively.

CONCLUSION: Perhaps, the slow acetylation genotypes of NAT2 were the main risk factors of developing antituberculosis drug-induced hepatotoxicity.

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