中国汉族人群 CYP2C19 和 CYP2D6 的遗传多态性、连锁不平衡、单倍型结构和新等位基因分析。
Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese.
机构信息
Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
出版信息
Pharmacogenomics J. 2009 Dec;9(6):380-94. doi: 10.1038/tpj.2009.31. Epub 2009 Jul 28.
The cytochrome P450 2C19 and 2D6 enzymes are predominantly found in the human liver, and have important functions in the metabolism of many different classes of commonly used drugs. Their genetic polymorphisms give rise to both important interethnic variability in metabolism and the risk of treatment failure or dose-dependent drug toxicity. To investigate genetic polymorphisms in CYP2C19 and CYP2D6 genes in Han Chinese, we sequenced regions of the 5' flanking region, exon, intron and 3' UTR from these two genes using 100 unrelated healthy Chinese Hans. We detected 48 genetic variants in CYP2C19. A total of 15 of them are novel, including two polymorphisms in putative transcriptional factor-binding sites. The CYP2C19*1, *2, *3, *4, *17, *23, *24 and 25 alleles have frequencies of 67.5, 25.5, 2, 0.5, 3, 0.5, 0.5 and 0.5%, respectively. Based on computational predictions, three novel alleles (CYP2C1923, *24 and 25) are deleterious mutations of the CYP2C19 protein. In CYP2D6, we identified 84 different polymorphisms, including 18 novel single-nucleotide polymorphisms. One novel polymorphism is located in a potential cis-regulatory element of the gene. The allele frequencies of CYP2D61, *2, *4, *5, *6, *10, *14, *21, *36, *41, *43, *52 and 71 are 18.5, 14, 1, 7, 0.5, 49, 1.5, 0.5, 1, 4, 0.5, 1 and 1.5%, respectively. The occurrence of CYP2D6 duplication is 0.5%. The novel CYP2D671 is anticipated as a putative poor metabolizer allele. We also performed linkage disequilibrium analysis and observed strong linkage disequilibrium spanning of the CYP2C19 and CYP2D6 regions. In addition, network analysis showed that 15 haplotypes of CYP2C19 and 22 of CYP2D6 are classified into five and three groups, respectively. Comparisons of allele frequency distributions revealed significant interethnic and intraethnic differences in these two genes. In conclusion, this study revealed that CYP2C19 and CYP2D6 have a complicated allele composition and distinct frequency distribution in Han Chinese.
细胞色素 P450 2C19 和 2D6 酶主要存在于人类肝脏中，在许多不同类别的常用药物的代谢中具有重要功能。它们的遗传多态性导致了代谢的重要种族间变异性以及治疗失败或剂量依赖性药物毒性的风险。为了研究汉族人 CYP2C19 和 CYP2D6 基因的遗传多态性，我们使用 100 个无关的健康汉族人对这两个基因的 5'侧翼区、外显子、内含子和 3'UTR 进行了测序。我们在 CYP2C19 中检测到 48 种遗传变异。其中共有 15 种是新的，包括两个假定转录因子结合位点的多态性。CYP2C19*1、*2、*3、*4、17、23、24 和25 等位基因的频率分别为 67.5%、25.5%、2%、0.5%、3%、0.5%、0.5%和 0.5%。基于计算预测，三个新的等位基因（CYP2C1923、24 和25）是 CYP2C19 蛋白的有害突变。在 CYP2D6 中，我们鉴定了 84 种不同的多态性，包括 18 种新的单核苷酸多态性。一种新的多态性位于基因的潜在顺式调控元件中。CYP2D61、*2、*4、*5、*6、*10、*14、*21、*36、*41、43、52 和71 的等位基因频率分别为 18.5%、14%、1%、7%、0.5%、49%、1.5%、0.5%、1%、4%、0.5%、1%和 1.5%。CYP2D6 重复的发生率为 0.5%。新的 CYP2D671 预计为潜在的弱代谢等位基因。我们还进行了连锁不平衡分析，并观察到 CYP2C19 和 CYP2D6 区域的强连锁不平衡跨越。此外，网络分析显示，CYP2C19 有 15 种单倍型，CYP2D6 有 22 种单倍型，分别分为五组和三组。对等位基因频率分布的比较揭示了这两个基因在不同种族和同一种族内的显著差异。总之，本研究表明 CYP2C19 和 CYP2D6 在汉族人中具有复杂的等位基因组成和不同的频率分布。
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