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Clin Pharmacol Ther. 2007 Feb;81(2):242-51.

Cytochrome P4502D6 (CYP2D6) gene locus heterogeneity: characterization of gene duplication events.

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1
Section of Developmental Pharmacology & Experimental Therapeutics, The Children's Mercy Hospital and Clinics, Kansas City, Missouri, USA. agaedigk@cmh.edu

Abstract

Duplications and multiplications of active CYP2D6 genes can cause ultrarapid drug metabolism and lead to therapeutic failure. Multiple functional and non-functional duplication alleles have been further characterized. Duplications were detected by long-range polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism, and sequence analysis. A PCR fragment encompassing the entire duplicated gene was utilized for detailed characterization. Duplications occurred at 1.3, 5.75, and 2.0% in Caucasian, African American, and racially mixed populations, respectively (n=887 total). Of those 28, 47, and 17% were non-functional CYP2D6*4 x N. Twelve unique duplication alleles were detected: *1 x N, *2 x N, *4 x N, *6 x N, *10 x N, *17 x N, *17 x N[spacer], *29 x N, *35 x N, *43 x N, *45 x N, and a novel non-functional tandem arrangement of a chimeric 2D7/2D6 and *1 gene. All novel duplications except *35 x N were found in African Americans. Accurate identification of gene duplication events is essential to avoid false-positive ultrarapid metabolism assignments and thus, overestimation of predicted activity and increased risk for unwanted adverse events.

PMID:
17259947
DOI:
10.1038/sj.clpt.6100033
[Indexed for MEDLINE]
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