Genetic variants in antioxidant pathway: Risk factors for hepatotoxicity in tuberculosis patients

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

Anti-Macrophage Migration Inhibitory Factor Antibody Suppresses Chronic Rejection of Heterotopically Transplanted Trachea in Rats

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine essential for delayed hypersensitivity in vivo, and is involved in bronchiolitis obliterans and late rejection in lung transplantation. We tested here whether neutralization of MIF using anti-MIF antibody prevents such a response. We examined the MIF mRNA expression level and changes in allograft tracheal epithelium and intraluminal obstruction in a rat allograft model. Lewis rat (RT1l) underwent heterotopic tracheal transplantation from Brown Norway rats (RT1n) in the omentum. Anti-MIF antibody was injected in the peritoneum. Rats were divided into three groups (non-treated allograft, allograft treated with normal rabbit IgG and allograft treated with anti-MIF antibody). Implants were harvested on days 7 or 21 for histological analysis. MIF mRNA expression was higher in the allograft at days 7 and 21 than in the isograft. The epithelium in non-treated allograft was almost absent at day 7. The epithelial height in the anti-MIF-treated graft was higher than that in normal IgG-treated grafts. The intraluminal space was mostly replaced by granulation tissue at day 21 in the untreated group. The proportion of obliterans was lowest in the anti-MIF group, the second lowest in the untreated group and the third lowest in the normal IgG-treated grafts, and the difference was significant (p<0.001) between the first two groups. Our results indicate that anti-MIF antibody suppresses allogenic tracheal rejection