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      Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group

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          Abstract

          Translating CYP2D6 genotype to metabolizer phenotype is not standardized across clinical laboratories offering pharmacogenetic (PGx) testing and PGx clinical practice guidelines, such as the Clinical Pharmacogenetics Implementation Consortium ( CPIC) and the Dutch Pharmacogenetics Working Group ( DPWG). The genotype to phenotype translation discordance between laboratories and guidelines can cause discordant cytochrome P450 2D6 (CYP2D6) phenotype assignments and, thus lead to inconsistent therapeutic recommendations and confusion among patients and clinicians. A modified‐Delphi method was used to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts. Experts with diverse involvement in CYP2D6 interpretation (clinicians, researchers, genetic testing laboratorians, and PGx implementers; n = 37) participated in conference calls and surveys. After completion of 7 surveys, a consensus (> 70%) was reached with 82% of the CYP2D6 experts agreeing to the final CYP2D6 genotype to phenotype translation method. Broad adoption of the proposed CYP2D6 genotype to phenotype translation method by guideline developers, such as CPIC and DPWG, and clinical laboratories as well as researchers will result in more consistent interpretation of CYP2D6 genotype.

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          Most cited references25

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          The Delphi method as a research tool: an example, design considerations and applications

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            Pharmacogenetics: from bench to byte--an update of guidelines.

            Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics-based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-S-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL).
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              The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype.

              Inferring CYP2D6 phenotype from genotype is increasingly challenging, considering the growing number of alleles and their range of activity. This complexity poses a challenge in translational research where genotyping is being considered as a tool to personalize drug therapy. To simplify genotype interpretation and improve phenotype prediction, we evaluated the utility of an "activity score" (AS) system. Over 25 CYP2D6 allelic variants were genotyped in 672 subjects of primarily Caucasian and African-American heritage. The ability of genotype and AS to accurately predict phenotype using the CYP2D6 probe substrate dextromethorphan was evaluated using linear regression and clustering methods. Phenotype prediction, given as a probability for each AS group, was most accurate if ethnicity was considered; among subjects with genotypes containing a CYP2D6*2 allele, CYP2D6 activity was significantly slower in African Americans compared to Caucasians. The AS tool warrants further prospective evaluation for CYP2D6 substrates and in additional ethnic populations.
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                Author and article information

                Contributors
                Kelly.caudle@stjude.org
                Journal
                Clin Transl Sci
                Clin Transl Sci
                10.1111/(ISSN)1752-8062
                CTS
                Clinical and Translational Science
                John Wiley and Sons Inc. (Hoboken )
                1752-8054
                1752-8062
                24 October 2019
                January 2020
                : 13
                : 1 ( doiID: 10.1111/cts.v13.1 )
                : 116-124
                Affiliations
                [ 1 ] Department of Pharmaceutical Sciences St. Jude Children's Research Hospital Memphis Tennessee USA
                [ 2 ] Department of Biomedical Data Science Stanford University Stanford California USA
                [ 3 ] Department of Clinical Pharmacy & Toxicology Leiden University Medical Center Leiden The Netherlands
                [ 4 ] Department of Pharmacy Practice MCPHS University School of Pharmacy Boston Massachusetts USA
                [ 5 ] Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York USA
                [ 6 ] Sema4, a Mount Sinai venture Stamford Connecticut USA
                [ 7 ] Department of Clinical Pharmacy University of Michigan College of Pharmacy Ann Arbor Michigan USA
                [ 8 ] Division of Clinical Pharmacology, Toxicology, & Therapeutic Innovation Children's Mercy Kansas City Kansas City Missouri USA
                [ 9 ] School of Medicine University of Missouri‐Kansas City Kansas City Missouri USA
                Author notes
                [*] [* ]Correspondence: Kelly E. Caudle ( Kelly.caudle@ 123456stjude.org )
                Article
                CTS12692
                10.1111/cts.12692
                6951851
                31647186
                c677df4b-f7ee-4fd2-b928-27a527c0e977
                © 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 21 June 2019
                : 05 August 2019
                Page count
                Figures: 3, Tables: 4, Pages: 9, Words: 7691
                Funding
                Funded by: National Institutes of Health (NIH)
                Award ID: R24GM115264
                Award ID: U24HG010135‐01
                Funded by: PharmGKB
                Award ID: R24GM61374
                Funded by: PharmVar
                Award ID: R24GM123930
                Funded by: European Union's Horizon 2020
                Award ID: U‐PGx: 668353
                Categories
                Article
                Research
                Articles
                Custom metadata
                2.0
                January 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.4 mode:remove_FC converted:09.01.2020

                Medicine
                Medicine

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