Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis

Setting. - Antituberculosis drug-induced hepatitis attributed to isoniazide (INN) is one of the most prevalent drug-induced liver injuries. INN is metabolized by hepatic N-acetyltransferase 2 (NAT2) to form hepatotoxins. Aim. - To evaluate whether polymorphism of the NAT2 gene was associated with antituberculosis drug-induced hepatotoxicity in Tunisian patients. Methods. - A total of 66 patients with tuberculosis (TB) who received anti-TB treatment were followed prospectively. Their NAT2 genotype was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We identified three single nucleotide polymorphisms (SNPs); 481C to T (NAT2*5B), 590G to A (NAT2*6A) and 857G to A (NAT2*7B). Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. Results. - Fourteen patients (21.2%) were diagnosed with anti-TB drug-induced hepatitis. None of the rapid acetylators-type patients have expressed serum aminotransferase elevation. Among patients with hepatotoxicity, slow acetylators-type patients had a higher risk of hepatotoxicity than intermediate acetylators (21.4% vs. 78.6%, P = 0.01). Statistical analysis revealed that the frequency of a variant diplotypes, NAT2*513/513 and NAT2*6A/6A, were significantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity (P = 0.01, odds ratio [OR] = 7.6 and P = 0.029, OR = 15, respectively). By contrast, the frequency of the rapid acetylation NAT2*4 allele was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P = 0.02, OR = 0.18). Moreover, 590G/G genotype was associated with decreased hepatotoxicity (P = 0.01); by contrast, homozygous point mutation at position 481 and 590 were associated with a higher risk of hepatotoxicity (P = 0.01). Conclusion. - Our results suggest that the slow-acetylator status of NAT2 is risk factor for INN-induced hepatotoxicity. Moreover, diplotypes, NAT2*513/513, NAT2*6A/6A, 481T/T and 590A/A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity. (C) 2011 Elsevier Masson SAS. All rights reserved.