Cytochrome P4502D6 (CYP2D6) Gene Locus Heterogeneity: Characterization of Gene Duplication Events

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 × N. Twelve unique duplication alleles were detected: *1 × N, *2 × N, *4 × N, *6 × N, *10 × N, *17 × N, *17 × N[spacer], *29 × N, *35 × N, *43 × N, *45 × N, and a novel non-functional tandem arrangement of a chimeric 2D7/2D6 and *1 gene. All novel duplications except *35 × 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. Clinical Pharmacology & Therapeutics (2007) 81, 242–251. doi:10.1038/sj.clpt.6100033