Cytochrome P4502D6 (CYP2D6) gene locus heterogeneity: characterization of gene duplication events. Clin Pharmacol Ther 2007 Feb;81(2):242-51
Date
01/30/2007Pubmed ID
17259947DOI
10.1038/sj.clpt.6100033Scopus ID
2-s2.0-33846643134 (requires institutional sign-in at Scopus site) 145 CitationsAbstract
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.
Author List
Gaedigk A, Ndjountché L, Divakaran K, Dianne Bradford L, Zineh I, Oberlander TF, Brousseau DC, McCarver DG, Johnson JA, Alander SW, Wayne Riggs K, Steven Leeder JMESH terms used to index this publication - Major topics in bold
AllelesCytochrome P-450 CYP2D6
Gene Amplification
Gene Duplication
Gene Frequency
Genetic Heterogeneity
Genotype
Humans
Models, Genetic
Polymerase Chain Reaction
Predictive Value of Tests
