Cytochrome P4502D6 (CYP2D6) Gene Locus Heterogeneity: Characterization of Gene Duplication Events
2007; Wiley; Volume: 81; Issue: 2 Linguagem: Inglês
10.1038/sj.clpt.6100033
ISSN1532-6535
AutoresAndrea Gaedigk, Liliane Ndjountché, Karthika Divakaran, L. DiAnne Bradford, Issam Zineh, Tim F. Oberlander, David C. Brousseau, D. Gail McCarver, J A Johnson, Sarah W. Alander, K. Wayne Riggs, J. Steven Leeder,
Tópico(s)Pharmaceutical studies and practices
ResumoDuplications 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
Referência(s)