Department of Pharmacological Research, National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul.
J Clin Pharm Ther. 2009 Dec;34(6):709-18. doi: 10.1111/j.1365-2710.2009.01065.x.
N-acetyltransferase 2 (NAT2) is responsible for the acetylation of numerous drugs and in the transformation of aromatic and heterocyclinc amines into carcinogenic intermediates. Polymorphism of NAT2 may contribute to interindividual variability in such acetylation. The aim of this study was to determine the allele frequencies of polymorphisms of the NAT2 gene, analyse linkage disequilibrium (LD) block and haplotypes in Koreans and compare them with those of other ethnic groups.
We analysed genetic polymorphisms in all functional promoter and exons of the NAT2 gene by direct sequencing of genomic DNA from 192 healthy Korean subjects. The LD and haplotype blocks of these subjects were constructed from genotype data using an expectation-maximization algorithm. We compared these allele frequencies, LD block and haplotype structure with those of other ethnic groups registered on the International HapMap database.
We identified 33 polymorphisms including six novel single nucleotide polymorphisms, -10778T>C, -10777A>G, -10351A>G, -10199C>T and -10104G>T in promoter and 578C>T in exon2 (T193M) in the Korean subjects tested. All allele frequencies reported in the Koreans were similar to those of Asians except for one allele (rs4345600, -9306A>G), whereas African and European groups had different frequencies in exon2. The haplotype structure and LD block among the five groups also revealed significant differences.
Ethnic differences in the NAT2 genotype frequencies may be one of the important factors explaining variability in cancer incidence and drug toxicity. Our observations could be useful in assessing the susceptibility of different populations to cancer and contribute to better predictions of the pharmacokinetics and pharmacodynamics of drugs that are metabolized by NAT2, in different populations.
N-乙酰基转移酶 2（NAT2）负责许多药物的乙酰化作用，并将芳香族和杂环胺转化为致癌中间体。NAT2 的多态性可能导致这种乙酰化作用的个体间变异性。本研究旨在确定 NAT2 基因多态性的等位基因频率，分析韩国人群中的连锁不平衡（LD）块和单倍型，并与其他种族进行比较。
我们通过对 192 名韩国健康受试者的基因组 DNA 进行直接测序，分析了 NAT2 基因所有功能启动子和外显子的遗传多态性。我们使用期望最大化算法从基因型数据构建这些受试者的 LD 和单倍型块。我们将这些等位基因频率、LD 块和单倍型结构与国际 HapMap 数据库中登记的其他种族进行比较。
我们在韩国受试者中鉴定出 33 种多态性，包括 6 种新的单核苷酸多态性，启动子中的-10778T>C、-10777A>G、-10351A>G、-10199C>T 和-10104G>T，以及外显子 2 中的 578C>T（T193M）。除一个等位基因（rs4345600，-9306A>G）外，报告的韩国人群中的所有等位基因频率与亚洲人群相似，而非洲和欧洲群体在外显子 2 中的频率不同。五个群体的单倍型结构和 LD 块也显示出显著差异。
NAT2 基因型频率的种族差异可能是解释癌症发病率和药物毒性变异性的重要因素之一。我们的观察结果可能有助于评估不同人群对癌症的易感性，并有助于更好地预测不同人群中由 NAT2 代谢的药物的药代动力学和药效学。
