CYP2D7-2D6 hybrid tandems: identification of novel CYP2D6 duplication arrangements and implications for phenotype prediction.
OBJECTIVE
Allelic variants of cytochrome P450 CYP2D6 (CYP2D6), such as gene deletion, duplication, multiplication and conversion, contribute to the wide range of CYP2D6 activity. Novel gene arrangements were discovered and characterized.


METHODS
DNA from 32 Caucasian and 59 African-American duplication-positive subjects were analyzed by long-range PCR and genotyping to detect CYP2D7-2D6 hybrid tandem alleles. Novel allelic variants were sequenced and a strategy for the detection and analysis of hybrid genes was refined.


RESULTS
CYP2D7-2D6 hybrid tandem alleles were identified in one African-American and four Caucasian subjects. Three novel hybrid genes were found on CYP2D6*1 and CYP2D6*2 duplication backgrounds and designated CYP2D6*76, *77 and *78. CYP2D7 to 2D6 conversion occurred in introns 1 and 4, and exon 9. All carried a T-insertion in exon 1 abolishing activity. In Caucasians, four out of 33 (12%) of the duplication-positive alleles were hybrid tandems, three CYP2D6*77 + *2 and one CYP2D6*78 + *2. By contrast, in African-Americans only one of 60 duplication-positive alleles was identified as a hybrid tandem. This allele was designated CYP2D6*76 + *1.


CONCLUSIONS
Hybrid tandem alleles occur infrequently (<0.25%) in Caucasians, but may explain why not every subject with a CYP2D6 duplication presents with an ultrarapid metabolizer phenotype.
Gaedigk
Andrea
A
Section of Developmental Pharmacology & Experimental Therapeutics, The Children's Mercy Hospital and Clinics, 2401 Gillham Road, Kansas City, MO 62108, USA. agaedigk@cmh.edu
Fuhr
Uwe
U
Johnson
Charlene
C
Bérard
L Anick
LA
Bradford
Dianne
D
Leeder
J Steven
JS
D001741:Black or African American / Q000235:genetics; D000483:Alleles; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D020440:Gene Duplication; D005787:Gene Frequency; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D006824:Hybridization, Genetic / Q000235:genetics; D008969:Molecular Sequence Data; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D020080:Tandem Repeat Sequences / Q000235:genetics*; D044465:White People / Q000235:genetics
D003577:Cytochrome P-450 Enzyme System; C509164:CYP2D7 protein, human; D019389:Cytochrome P-450 CYP2D6