title: Establishment of CYP2D6 reference samples by multiple validated genotyping platforms.
abstract: 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.
authors: 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.
authors: H
authors: H
authors: Fang
authors: Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.
authors: X
authors: X
authors: Liu
authors: Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.
authors: J
authors: J
authors: Ramírez
authors: Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.
authors: N
authors: N
authors: Choudhury
authors: RIKEN Center for Genomic Medicine, Yokohama, Japan.
authors: M
authors: M
authors: Kubo
authors: Department of Health Studies, The University of Chicago, Chicago, IL, USA.
authors: H K
authors: HK
authors: Im
authors: Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA.
authors: A
authors: A
authors: Konkashbaev
authors: 1] Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA [2] Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA [3] Center for Personalized Therapeutics, The University of Chicago, Chicago, IL, USA.
authors: N J
authors: NJ
authors: Cox
authors: 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 [3] Center for Personalized Therapeutics, The University of Chicago, Chicago, IL, USA.
authors: M J
authors: MJ
authors: Ratain
authors: 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 [3] Center for Personalized Therapeutics, The University of Chicago, Chicago, IL, USA [4] Department of Surgery, The University of Chicago, Chicago, IL, USA.
authors: Y
authors: Y
authors: Nakamura
authors: 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 [3] Center for Personalized Therapeutics, The University of Chicago, Chicago, IL, USA.
authors: P H
authors: PH
authors: O'Donnell
mesh_terms: D000483:Alleles; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D060005:Genotyping Techniques / Q000592:standards*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D012015:Reference Standards; D015203:Reproducibility of Results
chemical_list: D019389:Cytochrome P-450 CYP2D6