RESUMO
Tuberculosis (TB) treatment can cause serious sequelae including adverse effects such as anti-TB drug-induced hepatotoxicity (ATDH). We performed a candidate gene-based association study between single nucleotide polymorphisms (SNPs) in 10 genes in the antioxidant pathway and ATDH susceptibility. The subjects comprised 100 Japanese patients with pulmonary TB who received a treatment regimen including isoniazid and rifampicin. Out of them, 18 patients had ATDH. Thirty-four tag SNPs in 10 genes were analyzed by PCR-restriction fragment length polymorphism or PCR-direct DNA sequencing. The frequencies of alleles and genotypes between patients with and without ATDH were compared in three different genetic models. Statistical analyses revealed that a C/C genotype at rs11080344 in NOS2A, a C/C genotype at rs2070401 in BACH1, and a G/A or A/A genotype at rs4720833 in MAFK independently conferred ATDH susceptibility. Remarkably, the association of the latter two tag SNPs with ATDH susceptibility was highly statistically significant (P = 0.0006) with an odds ratio of 9.730. This study is the first report to demonstrate that NOS2A, BACH1, and MAFK appear to be genetic determinants of ATDH in Japanese patients with TB. Furthermore, a combination of BACH1 and MAFK polymorphisms may be useful as new biomarkers to identify high-risk Japanese TB patients for ATDH.
Assuntos
Antituberculosos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Tuberculose Pulmonar/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/uso terapêutico , Fatores de Transcrição de Zíper de Leucina Básica/genética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Quimioterapia Combinada , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Isoniazida/efeitos adversos , Fator de Transcrição MafK/genética , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/genética , Oxirredução , Polimorfismo de Nucleotídeo Único , Rifampina/efeitos adversos , Fatores de Risco , Adulto JovemRESUMO
AIM: To investigate an association between N-acetyltransferase 2 (NAT2)-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression analysis. RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2 6A, was significantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2 4", was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia. CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2 4 and NAT2 6A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.
