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Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6-Mediated Metabolic Activity.
- Source :
-
Clinical and translational science [Clin Transl Sci] 2020 Jan; Vol. 13 (1), pp. 147-156. Date of Electronic Publication: 2019 Oct 25. - Publication Year :
- 2020
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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.<br /> (© 2019 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- Alleles
Cytochrome P-450 CYP2D6 metabolism
Dextromethorphan pharmacokinetics
Dextrorphan analysis
Dextrorphan metabolism
Genetic Association Studies
Genetic Loci genetics
Haplotypes
High-Throughput Nucleotide Sequencing
Humans
Metoprolol analogs & derivatives
Metoprolol analysis
Metoprolol metabolism
Metoprolol pharmacokinetics
Microsomes, Liver metabolism
Pharmacogenomic Testing standards
Polymorphism, Genetic
Practice Guidelines as Topic
Computational Biology
Cytochrome P-450 CYP2D6 genetics
Pharmacogenomic Testing methods
Subjects
Details
- Language :
- English
- ISSN :
- 1752-8062
- Volume :
- 13
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Clinical and translational science
- Publication Type :
- Academic Journal
- Accession number :
- 31536170
- Full Text :
- https://doi.org/10.1111/cts.12695