Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for <i>CYP2D6</i> genotype and use of ondansetron and tropisetron

Bell, Gillian C.; Caudle, Kelly E.; Whirl‐Carrillo, Michelle; Gordon, R. J.; Hikino, Keiko; Prows, Cynthia A.; Gaedigk, Andrea; Agúndez, José A.G.; Sadhasivam, Senthilkumar; Klein, Teri E.; Schwab, Matthias

doi:10.1002/cpt.598

Cited by 175 publications

(141 citation statements)

References 24 publications

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“…The “A” allele of rs1065852 is the defining SNP of the cytochrome P450 2D6 (CYP2D6) *10 haplotype and is also found in combination with other variants in multiple CYP2D6 haplotypes. Haplotypes containing this SNP are associated with decreased CYP2D6 activity, which has important implications for drugs that are CYP2D6 substrates, including codeine, selective serotonin reuptake inhibitors, ondansetron, and tricyclic antidepressants . The CYP2C9 alleles *2 (defined by rs1799853), *3 (defined by rs1057910), and *8 (defined by rs7900194) are associated with reduced enzyme function and, therefore, are associated with recommended changes to the dosing of warfarin and phenytoin, which are substrates of CYP2C9 .…”

Section: Resultsmentioning

confidence: 99%

Standardized Biogeographic Grouping System for Annotating Populations in Pharmacogenetic Research

Huddart

Fohner

Whirl‐Carrillo

et al. 2019

Clin Pharma and Therapeutics

117

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The varying frequencies of pharmacogenetic alleles among populations have important implications for the impact of these alleles in different populations. Current population grouping methods to communicate these patterns are insufficient as they are inconsistent and fail to reflect the global distribution of genetic variability. To facilitate and standardize the reporting of variability in pharmacogenetic allele frequencies, we present seven geographically defined groups: American, Central/South Asian, East Asian, European, Near Eastern, Oceanian, and Sub‐Saharan African, and two admixed groups: African American/Afro‐Caribbean and Latino. These nine groups are defined by global autosomal genetic structure and based on data from large‐scale sequencing initiatives. We recognize that broadly grouping global populations is an oversimplification of human diversity and does not capture complex social and cultural identity. However, these groups meet a key need in pharmacogenetics research by enabling consistent communication of the scale of variability in global allele frequencies and are now used by Pharmacogenomics Knowledgebase (PharmGKB).

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Section: Resultsmentioning

confidence: 99%

Standardized Biogeographic Grouping System for Annotating Populations in Pharmacogenetic Research

Huddart

Fohner

Whirl‐Carrillo

et al. 2019

Clin Pharma and Therapeutics

117

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“…The Stargazer algorithm was then used to detect CYP2D6 structural variation from the next‐generation sequencing data and the star allele diplotype assignments determined manually were corrected accordingly . Values for AS calculations were assigned to each allele based on CPIC criteria …”

Section: Methodsmentioning

confidence: 99%

Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6‐Mediated Metabolic Activity

Dalton

Lee

Claw

et al. 2019

Clinical Translational Sci

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The cytochrome P450 2D6 (CYP2D6) gene locus is challenging to accurately genotype due to numerous single nucleotide variants and complex structural variation. Our goal was to determine whether the CYP2D6 genotype‐phenotype correlation is improved when diplotype assignments incorporate structural variation, identified by the bioinformatics tool Stargazer, with next‐generation sequencing data. Using CYP2D6 activity measured with substrates dextromethorphan and metoprolol, activity score explained 40% and 34% of variability in metabolite formation rates, respectively, when diplotype calls incorporated structural variation, increasing from 36% and 31%, respectively, when diplotypes did not incorporate structural variation. We also investigated whether the revised Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations for translating genotype to phenotype improve CYP2D6 activity predictions over the current system. Although the revised recommendations do not improve the correlation between activity score and CYP2D6 activity, perhaps because of low frequency of the CYP2D6*10 allele, the correlation with metabolizer phenotype group was significantly improved for both substrates. We also measured the function of seven rare coding variants: one (A449D) exhibited decreased (44%) and another (R474Q) increased (127%) activity compared with reference CYP2D6.1 protein. Allele‐specific analysis found that A449D is part of a novel CYP2D6*4 suballele, CYP2D6*4.028. The novel haplotype containing R474Q was designated CYP2D6*138 by PharmVar; another novel haplotype containing R365H was designated CYP2D6*139. Accuracy of CYP2D6 phenotype prediction is improved when the CYP2D6 gene locus is interrogated using next‐generation sequencing coupled with structural variation analysis. Additionally, revised CPIC genotype to phenotype translation recommendations provides an improvement in assigning CYP2D6 activity.

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“…Cytochrome P450 2D6 (CYP2D6) is directly involved in the metabolism of ~ 20% of currently approved medications, and genetic variation in the CYP2D6 gene has been implicated in the efficacy and/or toxicity of many drugs. Consequently, the highly polymorphic CYP2D6 gene is the focus of several Clinical Pharmacogenetics Implementation Consortium (CPIC) and/or Dutch Pharmacogenetics Working Group (DPWG) clinical practice guidelines on 15 widely used medications, including selective serotonin reuptake inhibitors, tricyclic antidepressants, atomoxetine, codeine, tramadol, tamoxifen, ondansetron, and tropisetron . Recently, the CPIC and DPWG reported some discrepancies in their guidelines, primarily related to how certain CYP2D6 genotypes or diplotypes (from here on referred to as “genotype”) were translated into metabolizer phenotype or metabolizer status (from here on referred to as “phenotype”) .…”

Section: Comparison Of Systems Used For Cyp2d6 Genotype To Phenotype mentioning

confidence: 99%

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

Caudle

Sangkuhl

Whirl‐Carrillo

et al. 2019

Clinical Translational Sci

400

502

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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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Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and use of ondansetron and tropisetron

Cited by 175 publications

References 24 publications

Standardized Biogeographic Grouping System for Annotating Populations in Pharmacogenetic Research

Standardized Biogeographic Grouping System for Annotating Populations in Pharmacogenetic Research

Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6‐Mediated Metabolic Activity

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

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