The association of genetic polymorphisms of N-acetyltransferase 2 gene with hepatotoxicity and efficacy in Chinese Han patients with tuberculosis

Abstract

Objective To investigate the association of the polymorphism of the N-acetyltransferase 2 (NAT2) gene with isoniazid-induced hepatotoxicity and anti-tuberculous treatment efficacy in Chinese Han patients with tuberculosis(TB). Methods A total of 108 TB patients who received initial anti-TB treatment were followed up prospectively. A polymerase chain reaction direct sequencing approach was used to detect genetic polymorphisms of the NAT2 gene. Associations between NAT2 genotype and isoniazid-induced hepatitis/early treatment were analyzed. Chi-square test was used for statistical analysis. Results Among the 108 TB patients, intermediate-acetylators(IA) was the most frequent NAT2 genotype with the proportion of 54.63%(59/108). The proportion of rapid-acetylators(RA) was 33.33%(36/108), slow-acetylators (SA) was 10.19%(11/108) and super-rapid acetylators was 1.85% (2/108). Among the 20 patients who developed drug-induced hepatitis, 2 were RA, 5 were SA and 13 were IA. Regarding NAT2 genotype, RA patients had a lower incidence of hepatotoxicity (OR=0.176, 95%CI: 0.038-0.809, P=0.014) and SA patients were more likely to developed drug-induced hepatic injury (OR=4.556, 95%CI: 1.231-16.854, P=0.044). Statistical analysis revealed that the frequency of variant diplotypes, NAT2*4/*6A (OR=7.741, 95%CI: 2.653-22.586, P<0.01) and NAT2*6A/*6A (OR=15.353, 95%CI: 1.506-156.552, P=0.020) were significantly increased in TB patients with hepatotoxicity. NAT2*4/*4 was less likely to developed hepatic injury (OR=0.176, 95%CI: 0.038-0.809, P=0.014). Among the 58 culture-positive patients, 12(31.03%) were persistent culture positive after 2 months standard therapy. Early treatment failure was observed with significantly higher incidence rate in RA than other genotypes (OR=7.200, 95%CI: 1.794-28.900, P=0.008). Conclusions In Chinese Han TB patients, IA is the most frequent NAT2 genotype. The SA status of NAT2 is a risk factor of isoniazid-induced hepatotoxicity. The diplotype of NAT2*6A has clearly high risk of isoniazid-induced hepatotoxicity. In contrast, NAT2*4/*4 is protective diplotype. RA is associated with early treatment failure in culture-positive patients. Key words: N-acetyltransferase 2; Isoniazid; Genetic polymorphism; Drug-induced liver injury; Efficacy; Han population