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 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.
Gaedigk
A
A
Section of Developmental Pharmacology & Experimental Therapeutics, The Children's Mercy Hospital and Clinics, Kansas City, Missouri, USA. agaedigk@cmh.edu
Ndjountché
L
L
Divakaran
K
K
Dianne Bradford
L
L
Zineh
I
I
Oberlander
T F
TF
Brousseau
D C
DC
McCarver
D G
DG
Johnson
J A
JA
Alander
S W
SW
Wayne Riggs
K
K
Steven Leeder
J
J
D001741:Black or African American / Q000235:genetics; D000483:Alleles; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005784:Gene Amplification; D020440:Gene Duplication; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D044469:Racial Groups / Q000145:classification / Q000235:genetics; D044465:White People / Q000235:genetics
D019389:Cytochrome P-450 CYP2D6