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Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

The Pharmacogenomics Journal volume 5, pages 173–182 (2005)Cite this article

A Corrigendum to this article was published on 25 July 2005

Abstract

Cytochrome P4502D6 (CYP2D6) genotyping reliably predicts poor metabolizer phenotype in Caucasians, but is less accurate in African Americans. To evaluate discordance we have observed in phenotype to genotype correlation studies, select African American subjects were chosen for complete resequencing of the CYP2D6 gene including 4.2 kb of the CYP2D7-2D6 intergenic region. Comparisons were made to a CYP2D6*1 reference sequence revealing novel SNPs in the upstream, coding and intervening sequences. These sequence variations, defining four functional alleles (CYP2D6*41B, *45A and B and *46), were characterized for their ability to influence splice site strength, transcription level or catalytic protein activity. Furthermore, their frequency was determined in a population of 251 African Americans. A −692TGTG deletion (CYP2D6*45B) did not significantly decrease gene expression, nor could any other upstream SNP explain a genotype-discordant case. CYP2D6*45 and *46 have a combined frequency of 4% and can be identified by a common SNP. Carriers are predicted to exhibit an extensive or intermediate CYP2D6 phenotype.

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Acknowledgements

We thank Roger Gaedigk, PhD and Peter K Rogan, PhD for continuous support and advice and Darren W Baker, BS for technical support. We further express our gratitude to Rachel F Tyndale, PhD for her generous gift of IMR-32 cells and to John T Wilson, MD and Gregory L Kearns, PharmD, PhD who served as the Principal Investigators for the pediatric studies of tramadol. This project was supported in part by intramural grants from the Katherine B Richardson Associates Endowment Fund (AG and SWA) and the National Institute of Child Health Human Development (Pediatric Pharmacology Research Unit Network) and RO1ES10855-04 from the National Institute of Environmental Health Sciences.

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Authors and Affiliations

  1. Division of Clinical Pharmacology and Experimental Therapeutics, Children's Mercy Hospital & Clinics, Kansas City, MO, USA

    A Gaedigk, A Bhathena, L Ndjountché, R E Pearce, S M Abdel-Rahman, S W Alander & J Steven Leeder

  2. Morehouse School of Medicine, Atlanta, GA, USA

    L DiAnne Bradford

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  1. A Gaedigk
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Correspondence to A Gaedigk.

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Gaedigk, A., Bhathena, A., Ndjountché, L. et al. Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans. Pharmacogenomics J 5, 173–182 (2005). https://doi.org/10.1038/sj.tpj.6500305

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