ArticleClinical and translational science2020
Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6-Mediated Metabolic Activity.
Article in Clinical and translational science, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- Does Next Generation Sequencing (NGS)-Based CYP2D6 Sequencing Improve Genotype-Phenotype Concordance in Tamoxifen-Treated Patients?Clinical pharmacology and therapeutics · 2026Article
- Very strong correlations of metoprolol- and solanidine-derived metabolic ratios in a real-world cohort with a stable metoprolol drug regimen.Frontiers in pharmacology · 2026Article
- Population Genetics of Pharmacogenetic Variants in a Greek Psychiatric Cohort of over 3000 Individuals.International journal of molecular sciences · 2025Article
- Exploring the Pharmacogenetic Landscape: Identification of Clinically Relevant Genotypes by a Nation-Wide Medical Testing Laboratory in Romania.Pharmaceuticals (Basel, Switzerland) · 2025Article
- The CYP2D6 phenotyping performance of single-point saliva metabolic ratio in a healthy Chinese Han population.Frontiers in pharmacology · 2025Article
- Structural and genetic diversity in the secreted mucins MUC5AC and MUC5B.American journal of human genetics · 2024Article
- Structural and genetic diversity in the secreted mucins,bioRxiv : the preprint server for biology · 2024Article
- Cytochrome P450 FamilyACS pharmacology & translational science · 2024Article
- The Utility of Mixed Effects Models in the Evaluation of Complex Genomic Traits In Vitro.Drug metabolism and disposition: the biological fate of chemicals · 2023Article
- Structural variation of the coding and non-coding human pharmacogenome.NPJ genomic medicine · 2023Article
- The genetic landscape of major drug metabolizing cytochrome P450 genes-an updated analysis of population-scale sequencing data.The pharmacogenomics journal · 2022Article
- From Croatian Roma to 1000 Genomes: The Story of theJournal of personalized medicine · 2022Article
- The feasibility and potential of pharmacogenetics to reduce adverse drug events in nursing home residents.Journal of the American Geriatrics Society · 2022Article
- Keeping pace withPharmacogenomics · 2022Review
- The Impact of the CYP2D6 "Enhancer" Single Nucleotide Polymorphism on CYP2D6 Activity.Clinical pharmacology and therapeutics · 2022Article
- The impact ofFrontiers in pharmacology · 2022Article
- ClinPharmSeq: A targeted sequencing panel for clinical pharmacogenetics implementation.PloS one · 2022Article
- Physiologically based pharmacokinetic (PBPK) modeling of the role of CYP2D6 polymorphism for metabolic phenotyping with dextromethorphan.Frontiers in pharmacology · 2022Article
- Comprehensive Allele Genotyping in Critical Pharmacogenes Reduces Residual Clinical Risk in Diverse Populations.Clinical pharmacology and therapeutics · 2021Article
- How to Integrate CYP2D6 Phenoconversion Into Clinical Pharmacogenetics: A Tutorial.Clinical pharmacology and therapeutics · 2021Review
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Authors and funding
18 authors.
Funding
Abstract
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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