Fang H, Liu X, Ramírez J, Choudhury N, Kubo M, Im H K, Konkashbaev A, Cox N J, Ratain M J, Nakamura Y, O'Donnell P H
1] Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA [2] Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.
Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.
Pharmacogenomics J. 2014 Dec;14(6):564-72. doi: 10.1038/tpj.2014.27. Epub 2014 Jul 1.
Cytochrome P450 2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6)), a highly polymorphic drug-metabolizing enzyme, is involved in the metabolism of one-quarter of the most commonly prescribed medications. Here we have applied multiple genotyping methods and Sanger sequencing to assign precise and reproducible CYP2D6 genotypes, including copy numbers, for 48 HapMap samples. Furthermore, by analyzing a set of 50 human liver microsomes using endoxifen formation from N-desmethyl-tamoxifen as the phenotype of interest, we observed a significant positive correlation between CYP2D6 genotype-assigned activity score and endoxifen formation rate (rs = 0.68 by rank correlation test, P = 5.3 × 10(-8)), which corroborated the genotype-phenotype prediction derived from our genotyping methodologies. In the future, these 48 publicly available HapMap samples characterized by multiple substantiated CYP2D6 genotyping platforms could serve as a reference resource for assay development, validation, quality control and proficiency testing for other CYP2D6 genotyping projects and for programs pursuing clinical pharmacogenomic testing implementation.
细胞色素P450 2D6（细胞色素P450家族2亚家族D多肽6，CYP2D6）是一种高度多态的药物代谢酶，参与了四分之一最常用处方药的代谢。我们在此应用了多种基因分型方法和桑格测序法，为48个国际人类基因组单体型图（HapMap）样本确定精确且可重复的CYP2D6基因型，包括拷贝数。此外，通过以N-去甲基他莫昔芬生成的4-羟基他莫昔芬作为感兴趣的表型，分析一组50个人类肝微粒体，我们观察到CYP2D6基因型指定活性评分与4-羟基他莫昔芬生成率之间存在显著正相关（等级相关检验rs = 0.68，P = 5.3×10⁻⁸），这证实了我们基因分型方法得出的基因型-表型预测。未来，这48个通过多个经过验证的CYP基因分型平台表征的公开可用HapMap样本，可作为其他CYP2D6基因分型项目以及开展临床药物基因组学检测实施项目的分析方法开发、验证、质量控制和能力验证的参考资源。
