Standardizing <i><scp>CYP</scp>2D6</i> Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group

Caudle, Kelly E.; Sangkuhl, Katrin; Whirl‐Carrillo, Michelle; Swen, Jesse J.; Haidar, Cyrine E.; Klein, Teri E.; Gammal, Roseann S.; Relling, Mary V.; Scott, Stuart A.; Hertz, Daniel L.; Guchelaar, Henk‐Jan; Gaedigk, Andrea

doi:10.1111/cts.12692

Cited by 365 publications

(453 citation statements)

References 30 publications

(71 reference statements)

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“…Work is ongoing that may lead to increased standardization of CYP2D6 genotype to phenotype translations. 36 The CPIC guidelines for other genes often include straightforward recommendations for genotype-to-pheno-type translation, which may be reflected in the overall high degree of concordance identified in our study.…”

Section: Efforts Underway To Improve Standardizationmentioning

confidence: 61%

Genotype and Phenotype Concordance for Pharmacogenetic Tests Through Proficiency Survey Testing

Moyer

McMillin

Long

et al. 2020

Archives of Pathology &Amp; Laboratory Medicine

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Context.-As pharmacogenetic testing is incorporated into routine care, it is essential for laboratories to provide accurate and consistent results. Certified laboratories must successfully complete proficiency testing.Objectives.-To understand and examine trends in participation and performance of laboratories participating in the College of American Pathologists pharmacogenetic proficiency testing surveys.Design.-Results from College of American Pathologists pharmacogenetic proficiency testing challenges from 2012 through 2017 were reviewed for concordance with expected genotype and phenotype for each sample (intended responses).Results.-Laboratories correctly reported results for 96.7% to 100% of samples with no variants. Excluding CYP2D6, laboratories correctly detected and reported variant alleles for each gene (93.7%-99.2% correct).CYP2D6 showed lower concordance, with 83.1% of laboratories reporting the intended genotype across all samples; however, in many cases, the laboratories that did not report a variant allele did not test for that allele. Among laboratories reporting the intended genotype, most successfully reported the intended phenotype (85.9%-99.0%).Conclusions.-Although laboratories are generally performing well, there is room for additional improvement, particularly for challenging genes, such as CYP2D6. Efforts in the field of pharmacogenomics to recommend alleles that should be included in clinical tests, identify reference materials, and standardize translation from genotype to phenotype may address some of the remaining variability in results.(Arch Pathol Lab Med.

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Section: Efforts Underway To Improve Standardizationmentioning

confidence: 61%

Genotype and Phenotype Concordance for Pharmacogenetic Tests Through Proficiency Survey Testing

Moyer

McMillin

Long

et al. 2020

Archives of Pathology &Amp; Laboratory Medicine

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“…32 The CPIC recently completed the CYP2D6 Genotype to Phenotype Standardization Project, which proposes several changes to CYP2D6 phenotype transla tion. 33 Analyses within this report were conducted using the new activity score definitions and phenotype assignments.…”

Section: Phenotype Assignment and Definition Of Actionable Resultsmentioning

confidence: 99%

Pharmacogenetics in Practice: Estimating the Clinical Actionability of Pharmacogenetic Testing in Perioperative and Ambulatory Settings

Smith

Peshkin

Springfield

et al. 2020

Clinical Translational Sci

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Most literature describing pharmacogenetic implementations are within academic medical centers and use single‐gene tests. Our objective was to describe the results and lessons learned from a multisite pharmacogenetic pilot that utilized panel‐based testing in academic and nonacademic settings. This was a retrospective analysis of 667 patients from a pilot in 4 perioperative and 5 outpatient cardiology clinics. Recommendations related to 12 genes and 65 drugs were classified as actionable or not actionable. They were ascertained from Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and US Food and Drug Administration (FDA) labeling. Patients displayed a high prevalence of actionable results (88%, 99%) and use of medications (28%, 46%) with FDA or CPIC recommendations, respectively. Sixteen percent of patients had an actionable result for a current medication per CPIC compared with 5% per FDA labeling. A systematic approach by a health system may be beneficial given the quantity and diversity of patients affected.

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“…To date, direct prediction method based on CYP2D6 locus mutation polymorphism, which was summarized by Zanger et al [27] and indirect prediction method of genotype scoring, which was recommended by Gaedigk et al [28] and Caudle et al [31], are applied to predict CYP2D6 enzyme activity based on genetic information. Since the genotype scoring method can quantify the degree of gene mutation and abides by more abundant genotypic criteria, this method was used in the study.…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphism of human CYP2D6 gene coding region from vivax malaria cases in Yunnan Province, China

Huang

Duan²,

et al. 2020

Preprint

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Background: Primaquine is one of two medications able to effectively eliminate the hypnozoites of P. vivax, and therefore has been recommended by World Health Organization (WHO) as the anti-relapsing drug for the treatment of vivax patients. However, 5-hydroxy-primaquine, the presumed active component, must be generated by CYP2D6 enzyme in human hepatocytes and reduced CYP2D6 enzyme activity caused by gene mutations has been considered cause of primaquine failure. Based on the analysis of CYP2D6 gene polymorphisms in suspected relapsed vivax malaria patients, the current study aims to determine the association between human CYP2D6 genotype and the efficacy of primaquine. Methods: Blood samples from vivax patients in Yunnan Province who received "chloroquine/primaquine eight-day therapy" and experienced suspected relapses were collected from 2014 to 2018. Human genomic DNA was extracted, and 9 exons of CYP2D6 gene were amplified by polymerase chain reaction (PCR) and were then sequenced. The mutation types of CDS and their association with CYP2D6 enzyme activity changes were analyzed. Results: A total of 156 blood samples from 75 relapsed cases of vivax malaria and 75 non-relapsed cases were collected and two nested-PCR products, the CYP2D6 gene fragments containing exon1-4 and exon5-9 (2411bp and 2388bp), were obtained from the sample. After splicing and combining these two amplification products, we found that the CDS of CYP2D6 gene in each sample was 1491bp in length. Moreover, we identified 24 haplotypes (Hap_1~Hap_24) in the Clustered CYP2D6 full-CDS of 150 patients, including 17 haplotypes in relapsed patients and 15 haplotypes in non-relapsed patients (8 haplotypes co-existed in two groups of patients). In addition, we identified 33 diplotypes (A_1~A_33) in 150 patients. The A_10 and A_12 diplotypes showed higher frequency in suspected relapsed group.Conclusion: Among the numerous mutations of CYP2D6 gene， Hap_2 accounted for the largest proportion in 24 haplotypes. And the combined homozygous mutations at c. 408, c. 1457, especially the two loci combined mutations with c. 886, may be related to the poor efficacy of primaquine in the radical cure P. vivax in Yunnan, however, greater sample size is required confirm these findings.

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

Cited by 365 publications

References 30 publications

Genotype and Phenotype Concordance for Pharmacogenetic Tests Through Proficiency Survey Testing

Genotype and Phenotype Concordance for Pharmacogenetic Tests Through Proficiency Survey Testing

Pharmacogenetics in Practice: Estimating the Clinical Actionability of Pharmacogenetic Testing in Perioperative and Ambulatory Settings

Genetic Polymorphism of human CYP2D6 gene coding region from vivax malaria cases in Yunnan Province, China

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