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Research ArticleArticle

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

John Logan Black III, Denise L. Walker, Dennis J. O'Kane and Maria Harmandayan
Drug Metabolism and Disposition January 2012, 40 (1) 111-119; DOI: https://doi.org/10.1124/dmd.111.040832
John Logan Black III
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Denise L. Walker
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Dennis J. O'Kane
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Maria Harmandayan
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This article has a correction. Please see:

  • Correction to “Frequency of Undetected CYP2D6 Hybrid Genes in Clinical Samples: Impact on Phenotype Prediction” - June 01, 2012

Abstract

Cytochrome P450 2D6 (CYP2D6) is highly polymorphic. CYP2D6-2D7 hybrid genes can be present in samples containing CYP2D6*4 and CYP2D6*10 alleles. CYP2D7-2D6 hybrid genes can be present in samples with duplication signals and in samples with homozygous genotyping results. The frequency of hybrid genes in clinical samples is unknown. We evaluated 1390 samples for undetected hybrid genes by polymerase chain reaction (PCR) amplification, PCR fragment analysis, TaqMan copy number assays, DNA sequencing, and allele-specific primer extension assay. Of 508 CYP2D6*4-containing samples, 109 (21.5%) harbored CYP2D6*68 + *4-like, whereas 9 (1.8%) harbored CYP2D6*4N + *4-like. Of 209 CYP2D6*10-containing samples, 44 (21.1%) were found to have CYP2D6*36 + *10. Of 332 homozygous samples, 4 (1.2%) harbored a single CYP2D7-2D6 hybrid, and of 341 samples with duplication signals, 25 (7.3%) harbored an undetected CYP2D7-2D6 hybrid. Phenotype before and after accurate genotyping was predicted using a method in clinical use. The presence of hybrid genes had no effect on the phenotype prediction of CYP2D6*4- and CYP2D6*10-containing samples. Four of four (100%) homozygous samples containing a CYP2D7-2D6 gene had a change in predicted phenotype, and 23 of 25 (92%) samples with a duplication signal and a CYP2D7-2D6 gene had a change in predicted phenotype. Four novel genes were identified (CYP2D6*13A1 variants 1 and 2, CYP2D6*13G1, and CYP2D6*13G2), and two novel hybrid tandem structures consisting of CYP2D6*13B + *68×2 + *4-like and CYP2D6*13A1 variant 2 + *1×N were observed.

Footnotes

  • This research was supported by National the Institutes of Health National Center for Research Resources [Clinical and Translational Science Award UL1-RR024150]; and the Mayo Clinic.

  • Drs. Black and O'Kane and the Mayo Clinic have licensed intellectual property to AssureRx.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.111.040832.

  • ABBREVIATIONS:

    SNP
    single nucleotide polymorphism
    ASPE
    allele-specific primer extension assay
    PCR
    polymerase chain reaction
    rt
    real-time
    UM
    ultrarapid metabolizer
    EM
    extensive metabolizer
    IM
    intermediate metabolizer
    kb
    kilobase
    CT
    the cycle number at which fluorescence crosses an arbitrary line in rtPCR.

  • Received May 23, 2011.
  • Accepted October 13, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (1)
Drug Metabolism and Disposition
Vol. 40, Issue 1
1 Jan 2012
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Research ArticleArticle

UNDETECTED CYP2D6 HYBRID GENES IN CLINICAL SAMPLES

John Logan Black, Denise L. Walker, Dennis J. O'Kane and Maria Harmandayan
Drug Metabolism and Disposition January 1, 2012, 40 (1) 111-119; DOI: https://doi.org/10.1124/dmd.111.040832

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Research ArticleArticle

UNDETECTED CYP2D6 HYBRID GENES IN CLINICAL SAMPLES

John Logan Black, Denise L. Walker, Dennis J. O'Kane and Maria Harmandayan
Drug Metabolism and Disposition January 1, 2012, 40 (1) 111-119; DOI: https://doi.org/10.1124/dmd.111.040832
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