Graduate Institute of Life Sciences, Tri-Service General Hospital, College of Medicine, Kaohsiung Medical University, Taiwan, ROC.
Pharmacogenet Genomics. 2013 Apr;23(4):200-7. doi: 10.1097/FPC.0b013e32835e95e1.
Earlier studies have demonstrated an association between N-acetyltransferase 2 (NAT2) catalytic activity and the genotype of a recently published tag single nucleotide polymorphism (SNP), rs1495741. There have been no reports on the relationship between the rs1495741 genotype and antituberculosis drug-induced hepatotoxicity (ATDIH) to date.
The aim of the present study was to determine the frequency of the NAT2 tag SNP (rs1495741) in the Taiwanese and its relation to the incidence of ATDIH.
A total of 348 tuberculosis patients were enrolled to determine the frequency of NAT2 tag SNP rs1495741 and its relation to the incidence of ATDIH. The conventional NAT2 variants alleles have also been investigated. Furthermore, to evaluate the correlation of NAT2 activity and rs1495741 genotypes, a pharmacokinetic study of isoniazid was also conducted in healthy volunteers.
Among the 348 tuberculosis patients, 20 (5.7%) were diagnosed with ATDIH. The frequencies of the three rs1495741 genotypes, viz., AA, AG, and GG, were 24.7, 52.3, and 23.0%, respectively. Significant differences among rs1495741 genotypes and susceptibility to hepatotoxicity were noted (odds ratio=14.068, P<0.05). Moreover, the rs1495741 genotypes showed an association with the isoniazid dosage required for induction of hepatotoxicity. In the pharmacokinetic study, NAT2 activity was strongly associated with genotype categories (P<0.001).
The present study demonstrated that the three genotypes according to rs1495741 were in good accordance with conventional NAT2 alleles-inferred phenotypes and the tag SNP could be used as a proxy to determine the susceptibility to ATDIH.
早期的研究表明，N-乙酰转移酶 2（NAT2）催化活性与最近发表的标签单核苷酸多态性（SNP）rs1495741 的基因型之间存在关联。迄今为止，尚未有关于 rs1495741 基因型与抗结核药物性肝损伤（ATDIH）之间关系的报道。
本研究旨在确定台湾人群中 NAT2 标签 SNP（rs1495741）的频率及其与 ATDIH 发生率的关系。
共纳入 348 例结核病患者，以确定 NAT2 标签 SNP rs1495741 的频率及其与 ATDIH 发生率的关系。还研究了常规 NAT2 变体等位基因。此外，为了评估 NAT2 活性与 rs1495741 基因型的相关性，还在健康志愿者中进行了异烟肼的药代动力学研究。
在 348 例结核病患者中，有 20 例（5.7%）被诊断为 ATDIH。rs1495741 的三种基因型 AA、AG 和 GG 的频率分别为 24.7%、52.3%和 23.0%。rs1495741 基因型与肝毒性易感性之间存在显著差异（比值比=14.068，P<0.05）。此外，rs1495741 基因型与导致肝毒性的异烟肼剂量有关。在药代动力学研究中，NAT2 活性与基因型类别密切相关（P<0.001）。
本研究表明，根据 rs1495741 确定的三种基因型与常规 NAT2 等位基因推断的表型非常一致，该标签 SNP 可作为确定 ATDIH 易感性的替代指标。
