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Pharmacogenetics: CYP2D6 Genetic Polymorphisms

  • GENETIC POLYMORPHISMS OF CYTOCHROME P450 (CYP) 2D6
     Allele Population
    Single Nucleotide
    Polymorphism

    Location
    CYP2D6
    Activity

    Notes
     CYP2D6*1
     General Population Wild-type; 5,139bp
    22q13.1
    normal
    Extensive metabolizer
    CYP2D6*2xn Ethiopians/Saudi
    Arabian 10-16%
    Caucasians 1-5%
      Asians 0-2%
    Gene duplication
    C2983T (R296C)
    G4268C (S486T)
    Exon 6
    Exon 9


    Ultra-rapid or extensive
    metabolizer

     CYP2D6*3 Asians 0%
    1-bp deletion 2637A
    or (aka., 2549A)
    Exon 5
    absent
    Poor metabolizer due
    to frame shift mutation
     CYP2D6*4 African Americans 2%
    G1934A Junction
    of Intron 3
    & Exon 4
     absent Poor to no metabolic
    activity due to a
    splicing defect
     CYP2D6*5 Caucasians 0.04%
    African Americans 4%
    11.5-kb deletion
    on gene
    On allele absent
    No 2D6 enzyme
    present in liver
     CYP2D6*6
    Caucasians 1.8%
    Deletion of T-1795
    causing a premature
    stop codon
    Exon 3
    absent

    Poor metabolizer non-
    functioning variant

     CYP2D6*9
     NR AGA deletion at
    2613-2615 (K281)
    -
    ↓/↔
    Poor metabolizer
     CYP2D6*10
     Asians 39-51%
    African American 6%
    Caucasians 1-2%
    C188T; also seen as
    C100T (P34S)
    Exon 1

    Intermediate metabolizer
     CYP2D6*14
     Asian 2.2%
    P34S
    G169R
    R296C
    S486T
    Exon 3
    absent
    Poor metabolizer; non-
    functional enzyme
     CYP2D6*17
     African Americans
    20-35%
    C111T (T107I)
    C2938T (R296S)
    G4268C (S486T)
    Intron 1

    Altered affinity for
    substrates of 2D6
     CYP2D6*29
     Black Africans 20%
    G3183A
    -

    Poor metabolizer
     CYP2D6*41
     Caucasians 8-10%
    African American 11%
    Japanese 2.6%
    G2988A
    Intron 6

    Intermediate metabolizer
    due to aberrant splicing

    The letters  before and after the numbers represent the single nucleotides that make up the DNA sequence and codons to code for an amino acid (A = adenine, C = cytosine, G = guanine, T = thymine). Amino acids represented:(C = cysteine, G = glycine, K = lysine, P = proline, R = arginine, S = serine, T = threonine, V = valine). NR = not reported.


    References:

    1. Gough AC, Smith C A, Howell S M et al. Localization of the CYP2D gene locus to human chromosome 22q13.1 by polymerase chain reaction, in situ hybridization, and linkage analysis.  Genomics 1993;15:430-432.  PubMed
    2. Kimura S, Umeno M, Skoda R C et al. The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene.  Am J Hum Genet 1989;45:889-904.  PubMed   
    3. Griese EU, Asante-Poku S, Ofori-Adjei D et al.  Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population.  Pharmacogenetics 1999;9:715-23.  PubMed
    4. Kubota T, Yamaura Y, Ohkawa N et al.  Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O-demethylation in different CYP2D6 genotypes.  Br J Clin Pharmacol  2000;50:31-4.  PubMed
    5. Johansson I, Lundqvist E, Bertilsson L et al. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine.  Proc Nat Acad Sci 1993;90:11825-11829.  PubMed
    6. Gough AC, Miles JS, Spurr NK et al. Identification of the primary gene defect at the cytochrome P450 CYP2D locus.  Nature 1990;347:773-776.  PubMed
    7. Hanioka N, Kimura S, Meyer UA et al. The human CYP2D locus associated with a common genetic defect in drug oxidation: a G(1934)-to-A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3-prime splice recognition site.  Am J Hum Genet. 1990;47:994-1001.  PubMed
    8. Gaedigk A, Blum M, Gaedigk R et al. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism.  Am J Hum Genet 1991;48:943-950.  PubMed
    9. Nelson DR, Koymans L, Kamataki T et al. Cytochrome P450 superfamily: update on new sequences, gene mapping, accession numbers, and nomenclature.  Pharmacogenetics 1996;6:1-42.  PubMed
    10. Steen VM, Molven A, Aarskog NK et al.  Homologous unequal cross-over involving a 2.8 kb direct repeat as a mechanism for the generation of allelic variants of the human cytochrome P450 CYP2D6 gene.  Hum Molec Genet  1995;4:2251-2257.  PubMed
    11. Saxena R, Shaw GL, Relling MV et al. Identification of a new variant CYP2D6 allele with a single base deletion in exon 3 and its association with the poor metabolizer phenotype.  Hum Molec Genet 1994;3:923-926.  PubMed
    12. Tyndale R, Aoyama T, Broly F et al.  Identification of a new variant CYP2D6 allele lacking the codon encoding Lys-281: possible association with the poor metabolizer phenotype.  Pharmacogenetics 1991;1:26-32.  PubMed
    13. Kagimoto M, Heim M, Kagimoto K et al. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine: study of the functional significance of individual mutations by expression of chimeric genes.  J Biol Chem 1990;265:17209-17214.  PubMed
    14. Wang SL, Lai MD, Huang JD.  G169R mutation diminishes the metabolic activity of CYP2D6 in chinese.  Drug Metab Dispos 1999;27:385-8.  PubMed
    15. Masimirembwa C, Persson I, Bertilsson L et al.  A novel mutant variant of the CYP2D6 gene (CYP2D6*17) common in a black African population: association with diminished debrisoquine hydroxylase activity.  Br J Clin Pharmacol  1996;42:713-9.  PubMed
    16. Wennerholm A, Johansson I, Hidestrand M et al.  Characterization of the CYP2D6*29 allele commonly present in a black Tanzanian population causing reduced catalytic activity.  Pharmacogenetics  2001;11:417-27.  PubMed
    17. Ikenaga Y, Fukuda T, Fukuda K et al.  The frequency of candidate alleles for CYP2D6 genotyping in the Japanese population with an additional respect to the -1584C to G substitution.  Drug Metab Pharmacokinet 2005;20:113-6.  PubMed
    18. Raimundo S, Toscano C, Klein K et al.  A novel intronic mutation, 2988G>A, with predictivity for impaired function of cytochrome P450 2D6 in white subjects.  Clin Pharmacol Ther  2004;76:128-38.  PubMed

Editors & Reviewers

  • Editors:  Anthony J. Busti, MD, PharmD, FNLA, FAHA
    Last Reviewed:  June 2015

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