TY - JOUR
T1 - Establishment of CYP2D6 reference samples by multiple validated genotyping platforms
AU - Fang, H.
AU - Liu, X.
AU - Ramírez, J.
AU - Choudhury, N.
AU - Kubo, M.
AU - Im, H. K.
AU - Konkashbaev, A.
AU - Cox, N. J.
AU - Ratain, M. J.
AU - Nakamura, Y.
AU - O'Donnell, P. H.
N1 - Funding Information:
We acknowledge the help of Dr R Stephanie Huang and Bonnie LaCroix from the Pharmacogenomics of Anticancer Agents Cell Core and the kind remarks from Dr Kazuma Kiyotani. We also thank the Liver Tissue Procurement and Distribution System (NIH contract 3N01-DK-9-2310) and the Cooperative Human Tissue Network for providing the liver samples. This work is supported by NIH U01GM061393 (Pharmacogenomics of Anticancer Agents Research Group; to YN, MJR and NJC) and NIH K12 CA139160 and K23 GM100288-01A1 (to PHO). HF is supported by a NIH T32 GM007019 training grant in Clinical Pharmacology and Pharmacogenomics. MJR is a recipient of a Conquer Cancer Foundation of ASCO Translational Research Professorship, in memory of Merrill J Egorin, MD. Any opinions, findings and conclusions expressed in this material are those of the authors and do not necessarily reflect those of the American Society of Clinical Oncology or the Conquer Cancer Foundation.
Publisher Copyright:
© 2014 Macmillan Publishers Limited All rights reserved.
PY - 2014/12/11
Y1 - 2014/12/11
N2 - 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.
AB - 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.
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U2 - 10.1038/tpj.2014.27
DO - 10.1038/tpj.2014.27
M3 - Article
C2 - 24980783
AN - SCOPUS:84927178203
SN - 1470-269X
VL - 14
SP - 564
EP - 572
JO - Pharmacogenomics Journal
JF - Pharmacogenomics Journal
IS - 6
ER -