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Research ArticleArticle

CYP2D6*36 GENE ARRANGEMENTS WITHIN THE CYP2D6 LOCUS: ASSOCIATION OF CYP2D6*36 WITH POOR METABOLIZER STATUS

Andrea Gaedigk, L. DiAnne Bradford, Sarah W. Alander and J. Steven Leeder
Drug Metabolism and Disposition April 2006, 34 (4) 563-569; DOI: https://doi.org/10.1124/dmd.105.008292
Andrea Gaedigk
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L. DiAnne Bradford
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Sarah W. Alander
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J. Steven Leeder
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Abstract

Unexplained cases of CYP2D6 genotype/phenotype discordance continue to be discovered. In previous studies, several African Americans with a poor metabolizer phenotype carried the reduced function CYP2D6*10 allele in combination with a nonfunctional allele. We pursued the possibility that these alleles harbor either a known sequence variation (i.e., CYP2D6*36 carrying a gene conversion in exon 9 along the CYP2D6*10-defining 100C>T single-nucleotide polymorphism) or novel sequences variation(s). Discordant cases were evaluated by long-range polymerase chain reaction (PCR) to test for gene rearrangement events, and a 6.6-kilobase pair PCR product encompassing the CYP2D6 gene was cloned and entirely sequenced. Thereafter, allele frequencies were determined in different study populations comprising whites, African Americans, and Asians. Analyses covering the CYP2D7 to 2D6 gene region established that CYP2D6*36 did not only exist as a gene duplication (CYP2D6*36x2) or in tandem with *10 (CYP2D6*36+*10), as previously reported, but also by itself. This “single” CYP2D6*36 allele was found in nine African Americans and one Asian, but was absent in the whites tested. Ultimately, the presence of CYP2D6*36 resolved genotype/phenotype discordance in three cases. We also discovered an exon 9 conversion-positive CYP2D6*4 gene in a duplication arrangement (CYP2D6*4Nx2) and a CYP2D6*4 allele lacking 100C>T (CYP2D6*4M) in two white subjects. The discovery of an allele that carries only one CYP2D6*36 gene copy provides unequivocal evidence that both CYP2D6*36 and *36x2 are associated with a poor metabolizer phenotype. Given a combined frequency of between 0.5 and 3% in African Americans and Asians, genotyping for CYP2D6*36 should improve the accuracy of genotype-based phenotype prediction in these populations.

Footnotes

  • Supported by R01 ES10855-05 from the National Institute of Environmental Health Sciences and in part by an intramural grant from the Katherine B. Richardson Associates Endowment Fund.

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

  • doi:10.1124/dmd.105.008292.

  • ABBREVIATIONS: IM, intermediate metabolizer; PM, poor metabolizer; kb, kilobase pair(s); PCR, polymerase chain reaction; SNP, single-nucleotide polymorphism; bp, base pair(s); DM/DX ratio, dextromethorphan to dextrorphan ratio; UTR, untranslated region.

    • Received November 9, 2005.
    • Accepted January 12, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (4)
Drug Metabolism and Disposition
Vol. 34, Issue 4
1 Apr 2006
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Research ArticleArticle

CYP2D6*36 GENE ARRANGEMENTS WITHIN THE CYP2D6 LOCUS: ASSOCIATION OF CYP2D6*36 WITH POOR METABOLIZER STATUS

Andrea Gaedigk, L. DiAnne Bradford, Sarah W. Alander and J. Steven Leeder
Drug Metabolism and Disposition April 1, 2006, 34 (4) 563-569; DOI: https://doi.org/10.1124/dmd.105.008292

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Research ArticleArticle

CYP2D6*36 GENE ARRANGEMENTS WITHIN THE CYP2D6 LOCUS: ASSOCIATION OF CYP2D6*36 WITH POOR METABOLIZER STATUS

Andrea Gaedigk, L. DiAnne Bradford, Sarah W. Alander and J. Steven Leeder
Drug Metabolism and Disposition April 1, 2006, 34 (4) 563-569; DOI: https://doi.org/10.1124/dmd.105.008292
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