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

Overview

Journal Clin Transl Sci

Specialties Biomedical Engineering
General Medicine

Date 2019 Oct 25

PMID 31647186

Citations 232

Authors

Kelly E Caudle

Katrin Sangkuhl

Michelle Whirl-Carrillo

Jesse J Swen

Cyrine E Haidar

Teri E Klein

Roseann S Gammal

Mary V Relling

Stuart A Scott

Daniel L Hertz

Henk-Jan Guchelaar

Andrea Gaedigk

Affiliations

Soon will be listed here.

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.

Citing Articles

The CYP2D6 phenotyping performance of single-point saliva metabolic ratio in a healthy Chinese Han population.

Huang Y, He Z, Guan X, Hu P, Chen R Front Pharmacol. 2025; 16:1438760.

PMID: 40061957 PMC: 11885511. DOI: 10.3389/fphar.2025.1438760.

Nanopore sequencing-based genotyping suggested an association between CYP2D6 function and susceptibility to anxiety and depression.

Chua E, Karunanathie H, Yanasegaran K, Maggo S, Kee P, Kennedy M BMC Res Notes. 2025; 18(1):88.

PMID: 40016731 PMC: 11869584. DOI: 10.1186/s13104-025-07156-9.

The impact of coadministration of venlafaxine, citalopram or gabapentin on the metabolic activation of tamoxifen.

Safgren S, Suman V, Leon Ferre R, Kosel M, Stearns V, Henry N Breast Cancer Res Treat. 2025; .

PMID: 40011368 DOI: 10.1007/s10549-025-07644-3.

A Randomized Hybrid-Effectiveness Trial Comparing Pharmacogenomics (PGx) to Standard Care: The PGx Applied to Chronic Pain Treatment in Primary Care (PGx-ACT) Trial.

Smith D, Beyene R, Kolm P, Young T, Zifa S, Natividad V Clin Transl Sci. 2025; 18(2):e70154.

PMID: 39921243 PMC: 11805805. DOI: 10.1111/cts.70154.

Effect of metoprolol exposure following myocardial infarction on future cardiovascular events: a Mendelian randomization study.

Bruun L, Andersen G, Kringen M, Myhre P, Halvorsen S, Hansen C Eur J Clin Pharmacol. 2025; .

PMID: 39900827 DOI: 10.1007/s00228-025-03806-w.

References

Pratt V, Del Tredici A, Hachad H, Ji Y, Kalman L, Scott S . Recommendations for Clinical CYP2C19 Genotyping Allele Selection: A Report of the Association for Molecular Pathology. J Mol Diagn. 2018; 20(3):269-276. DOI: 10.1016/j.jmoldx.2018.01.011. View

Hicks J, Swen J, Gaedigk A . Challenges in CYP2D6 phenotype assignment from genotype data: a critical assessment and call for standardization. Curr Drug Metab. 2014; 15(2):218-32. DOI: 10.2174/1389200215666140202215316. View

Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Twist G, Klein T, Miller N . The Evolution of PharmVar. Clin Pharmacol Ther. 2018; 105(1):29-32. PMC: 6312487. DOI: 10.1002/cpt.1275. View

Swen J, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee A, Mulder H . Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther. 2011; 89(5):662-73. DOI: 10.1038/clpt.2011.34. View

Beretta R . A critical review of the Delphi technique. Nurse Res. 2016; 3(4):79-89. DOI: 10.7748/nr.3.4.79.s8. View

Saravanakumar A, Sadighi A, Ryu R, Akhlaghi F . Physicochemical Properties, Biotransformation, and Transport Pathways of Established and Newly Approved Medications: A Systematic Review of the Top 200 Most Prescribed Drugs vs. the FDA-Approved Drugs Between 2005 and 2016. Clin Pharmacokinet. 2019; 58(10):1281-1294. PMC: 6773482. DOI: 10.1007/s40262-019-00750-8. View

Hicks J, Bishop J, Sangkuhl K, Muller D, Ji Y, Leckband S . Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015; 98(2):127-34. PMC: 4512908. DOI: 10.1002/cpt.147. View

Hasson F, Keeney S, McKenna H . Research guidelines for the Delphi survey technique. J Adv Nurs. 2000; 32(4):1008-15. View

Henderson E, Rubin G . Development of a community-based model for respiratory care services. BMC Health Serv Res. 2012; 12:193. PMC: 3474150. DOI: 10.1186/1472-6963-12-193. View

10.

Goetz M, Sangkuhl K, Guchelaar H, Schwab M, Province M, Whirl-Carrillo M . Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. Clin Pharmacol Ther. 2018; 103(5):770-777. PMC: 5931215. DOI: 10.1002/cpt.1007. View

11.

Caudle K, Dunnenberger H, Freimuth R, Peterson J, Burlison J, Whirl-Carrillo M . Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet Med. 2016; 19(2):215-223. PMC: 5253119. DOI: 10.1038/gim.2016.87. View

12.

Hicks J, Sangkuhl K, Swen J, Ellingrod V, Muller D, Shimoda K . Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther. 2016; 102(1):37-44. PMC: 5478479. DOI: 10.1002/cpt.597. View

13.

Green B, Jones M, Hughes D, Williams A . Applying the Delphi technique in a study of GPs' information requirements. Health Soc Care Community. 2001; 7(3):198-205. DOI: 10.1046/j.1365-2524.1999.00176.x. View

14.

Bousman C, Zierhut H, Muller D . Navigating the Labyrinth of Pharmacogenetic Testing: A Guide to Test Selection. Clin Pharmacol Ther. 2019; 106(2):309-312. DOI: 10.1002/cpt.1432. View

15.

Montane Jaime L, Lalla A, Steimer W, Gaedigk A . Characterization of the CYP2D6 gene locus and metabolic activity in Indo- and Afro-Trinidadians: discovery of novel allelic variants. Pharmacogenomics. 2013; 14(3):261-76. DOI: 10.2217/pgs.12.207. View

16.

Wu A . Genotype and phenotype concordance for pharmacogenetic tests through proficiency survey testing. Arch Pathol Lab Med. 2013; 137(9):1232-6. DOI: 10.5858/arpa.2012-0261-CP. View

17.

Crews K, Gaedigk A, Dunnenberger H, Leeder J, Klein T, Caudle K . Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014; 95(4):376-82. PMC: 3975212. DOI: 10.1038/clpt.2013.254. View

18.

Slade S, Dionne C, Underwood M, Buchbinder R . Standardised method for reporting exercise programmes: protocol for a modified Delphi study. BMJ Open. 2015; 4(12):e006682. PMC: 4281530. DOI: 10.1136/bmjopen-2014-006682. View

19.

Caudle K, Keeling N, Klein T, Whirl-Carrillo M, Pratt V, Hoffman J . Standardization can accelerate the adoption of pharmacogenomics: current status and the path forward. Pharmacogenomics. 2018; 19(10):847-860. PMC: 6123879. DOI: 10.2217/pgs-2018-0028. View

20.

Kalman L, Agundez J, Appell M, Black J, Bell G, Boukouvala S . Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting. Clin Pharmacol Ther. 2015; 99(2):172-85. PMC: 4724253. DOI: 10.1002/cpt.280. View