title: Genetic variants in antioxidant pathway: risk factors for hepatotoxicity in tuberculosis patients.
abstract: 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.
authors.affiliation: Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Nanashima
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Mawatari
authors.forename: Naoko
authors.initials: N
authors.lastname: Tahara
authors.forename: Norihide
authors.initials: N
authors.lastname: Higuchi
authors.forename: Ayano
authors.initials: A
authors.lastname: Nakaura
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Inamine
authors.forename: Shinji
authors.initials: S
authors.lastname: Kondo
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Kiyoyasu
authors.initials: K
authors.lastname: Fukushima
authors.forename: Naofumi
authors.initials: N
authors.lastname: Suyama
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsukamoto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000627:therapeutic use; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics*; D004359:Drug Therapy, Combination; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects; D050985:MafK Transcription Factor / Q000235:genetics; D008297:Male; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D010084:Oxidation-Reduction; D020641:Polymorphism, Single Nucleotide; D012293:Rifampin / Q000009:adverse effects; D012307:Risk Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; C494695:MAFK protein, human; D050985:MafK Transcription Factor; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D007538:Isoniazid; D012293:Rifampin