Frequency of Undetected <i>CYP2D6</i> Hybrid Genes in Clinical Samples: Impact on Phenotype Prediction

Black, John L.; Walker, Denise L.; O’Kane, Dennis J.; Harmandayan, Maria

doi:10.1124/dmd.111.040832

Cited by 47 publications

(59 citation statements)

References 25 publications

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“…We also detected a number of hybrid tandem structures: CYP2D6*4N+*4 , *68 + *4 , *36 + *10 , and *13 + *2 (previously known as *77 + *2 ). Because CYP2D6*4N , *68 , *36 , and * 13 are nonfunctional, their inclusion did not change the AS assignment …”

Section: Resultsmentioning

confidence: 99%

“…Additionally, the presence ofso‐called hybrid genes ( CYP2D6‐2D7 and CYP2D7‐2D6 ) may lead to false positive or negative calls using traditional approaches. For instance, polymerase chain reaction (PCR)‐based CYP2D6 copy number assays may produce erroneous results in the presence of hybrid genes that lack PCR probe binding sites . Overestimation or underestimation of CYP2D6 activity is possible if undetected structural variation leads to a default allele assignment of CYP2D6*1 .…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

mentioning

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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“…While the majority of these interfering variations are usually rare, they can severely alter accurate prediction of the metabolizing phenotype within a particular individual. As there is no clear governance regarding how many methodologies analytical laboratories are required to perform for a given genetic variation, it is conceivable that there are apparent gaps between genotype and predicted phenotype that consequently hamper PGx guided therapy [8]. …”

Section: Discussionmentioning

confidence: 99%

Allele Drop Out Conferred by a Frequent CYP2D6 Genetic Variation For Commonly Used CYP2D6*3 Genotyping Assays

Scantamburlo¹,

Tziolia

Zopf³

et al. 2017

Cell Physiol Biochem

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Background/Aim: Accurate genotyping of CYP2D6 is challenging due to its inherent genetic variation, copy number variation (duplications and deletions) and hybrid formation with highly homologous pseudogenes. Because a relatively high percentage (∼25%) of clinically prescribed drugs are substrates for this enzyme, accurate determination of its genotype for phenotype prediction is essential. Methods: A cohort of 365 patient samples was genotyped for CYP2D6 using Sanger sequencing (as the gold standard), hydrolysis probe assays or pyrosequencing. Results: A discrepant result between the three genotyping methods for the loss of function CYP2D6*3 (g.2549delA, rs35742686) genetic variant was found in one of the samples. This sample also contained the CYP2D6 g.2470T>C (rs17002852) variation, which had an allele frequency of 2.47% in our cohort. Redesign of the CYP2D6*3 pyrosequencing and hydrolysis probe assays to avoid CYP2D6 g.2470 corrected the anomaly. Conclusion: To evidence allele drop out and increase the accuracy of genotyping, intra-patient validation of the same genetic variation with at least two separate methods should be considered.

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“…It is recommended that patients with a "possible" phenotype status that could be high risk be treated the same as those with a definitive highrisk result (eg, avoid codeine in patients who are "possible CYP2D6 ultra-rapid metabolizers"). Cases for which the genotyping assay detected a complex CYP2D6 hybrid structure of indeterminate function 43 do not have an assigned phenotype. These results are placed in the EHR and assigned a CYP2D6 phenotype of "indeterminate."…”

Section: Assigning Cyp2d6 Phenotype Based On Genotypementioning

confidence: 99%

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease

et al. 2016

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After postoperative deaths in children who were prescribed codeine, several pediatric hospitals have removed it from their formularies. These deaths were attributed to atypical cytochrome P450 2D6 (CYP2D6) pharmacogenetics, which is also implicated in poor analgesic response. Because codeine is often prescribed to patients with sickle cell disease and is now the only Schedule III opioid analgesic in the United States, we implemented a precision medicine approach to safely maintain codeine as an option for pain control. Here we describe the implementation of pharmacogenetics-based codeine prescribing that accounts for CYP2D6 metabolizer status. Clinical decision support was implemented within the electronic health record to guide prescribing of codeine with the goal of preventing its use after tonsillectomy or adenoidectomy and in CYP2D6 ultra-rapid and poor metabolizer (high-risk) genotypes. As of June 2015, CYP2D6 genotype results had been reported for 2468 unique patients. Of the 830 patients with sickle cell disease, 621 (75%) had a CYP2D6 genotype result; 7.1% were ultra-rapid or possible ultra-rapid metabolizers, and 1.4% were poor metabolizers. Interruptive alerts recommended against codeine for patients with high-risk CYP2D6 status. None of the patients with an ultra-rapid or poor metabolizer genotype were prescribed codeine. Using genetics to tailor analgesic prescribing retained an important therapeutic option by limiting codeine use to patients who could safely receive and benefit from it. Our efforts represent an evidence-based, innovative medication safety strategy to prevent adverse drug events, which is a model for the use of pharmacogenetics to optimize drug therapy in specialized pediatric populations. abstractDepartments of a Pharmaceutical Sciences, b Hematology, and c Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee; and d Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin Dr Gammal collected data, carried out the initial analyses, and drafted the initial manuscript; Drs Crews, Haidar, and Hoffman are coinvestigators on the PG4KDS study; they supervised the collection and analysis of data and critically reviewed and revised the manuscript; Dr Baker created the clinical decision support alerts, collected data, and critically reviewed the manuscript; Drs Barker, Estepp, Wang, and Weiss critically reviewed and revised the manuscript; Ms Pei designed and conducted the statistical analysis; Dr Broeckel supervises all PG4KDS-related genotyping; Dr Relling conceptualized and designed the PG4KDS study, supervised the collection and analysis of data, and critically reviewed and revised the manuscript; Dr Hankins conceptualized and designed the study and critically reviewed and revised the manuscript; and all authors approved the fi nal manuscript as submitted. The use of codeine in pediatric medicine has been questioned following reports of postoperative deaths in children who were prescribed codeine and the subsequent US Food and Drug Admin...

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Frequency of Undetected CYP2D6 Hybrid Genes in Clinical Samples: Impact on Phenotype Prediction

Cited by 47 publications

References 25 publications

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

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

Allele Drop Out Conferred by a Frequent CYP2D6 Genetic Variation For Commonly Used CYP2D6*3 Genotyping Assays

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease

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