Wattanapokayakit S, Mushiroda T, Yanai H, Wichukchinda N, Chuchottawon C, Nedsuwan S, Rojanawiwat A, Denjanta S, Kantima T, Wongyai J, Suwankesawong W, Rungapiromnan W, Kidkeukarun R, Bamrungram W, Chaiwong A, Suvichapanich S, Mahasirimongkol S, Tokunaga K
Medical Genetics Center, Medical Life Sciences Institute, Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand; Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Int J Tuberc Lung Dis. 2016 Oct;20(10):1364-1369. doi: 10.5588/ijtld.15.0310.
Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the most common forms of drug-induced liver injury (DILI) in high tuberculosis (TB) burden countries. Among anti-tuberculosis drugs, isoniazid is the main cause of hepatotoxicity in patients with AT-DILI.
To investigate the association of AT-DILI with N-acetyltransferase 2 (NAT2) genotype status in Thai TB patients.
We enrolled 53 patients diagnosed with AT-DILI and 85 patients who tolerated anti-tuberculosis treatment as controls. Acetylator status was determined based on the inferred NAT2 haplotypes from four common single-nucleotide polymorphisms (SNPs) in Thais using Sanger sequencing.
Phenotype frequencies of the NAT2 acetylator in AT-DILI patients were respectively 71.7%, 22.6% and 5.7% for slow, intermediate and rapid acetylators. Among slow, intermediate, and rapid acetylators in treatment tolerant controls, phenotype frequencies were respectively 22.4%, 62.4% and 15.3%. Slow NAT2 acetylators demonstrated a significant association with risk of AT-DILI. The odds ratio of comparing slow NAT2 acetylator in DILI patients and tolerance was 8.80 (95%CI 4.01-19.31, P = 1.53 × 10).
Slow acetylator status in the NAT2 genotype is a significant risk factor for DILI in Thai patients with TB. This evidence provides confirmatory data in support of the role of NAT2 in AT-DILI in the Thai population.
在结核病负担较高的国家，抗结核药物性肝损伤（AT-DILI）是药物性肝损伤（DILI）最常见的形式之一。在抗结核药物中，异烟肼是AT-DILI患者肝毒性的主要原因。
调查泰国结核病患者中AT-DILI与N-乙酰转移酶2（NAT2）基因型状态的关联。
我们纳入了53例被诊断为AT-DILI的患者和85例耐受抗结核治疗的患者作为对照。使用桑格测序法，根据泰国人四个常见单核苷酸多态性（SNP）推断的NAT2单倍型确定乙酰化状态。
AT-DILI患者中NAT2乙酰化酶的表型频率，慢乙酰化酶、中间乙酰化酶和快乙酰化酶分别为71.7%、22.6%和5.7%。在治疗耐受对照的慢、中和快乙酰化酶中，表型频率分别为22.4%、62.4%和15.3%。慢NAT2乙酰化酶与AT-DILI风险显著相关。DILI患者与耐受患者中慢NAT2乙酰化酶比较的比值比为8.80（95%CI 4.01-19.31，P = 1.53×10）。
NAT2基因型中的慢乙酰化状态是泰国结核病患者发生DILI的重要危险因素。这一证据提供了确证数据，支持NAT2在泰国人群AT-DILI中的作用。
