title: Multi-ethnic cytochrome-P450 copy number profiling: novel pharmacogenetic alleles and mechanism of copy number variation formation.
abstract: To determine the role of CYP450 copy number variation (CNV) beyond CYP2D6, 11 CYP450 genes were interrogated by multiplex ligation-dependent probe amplification and quantitative PCR in 542 African-American, Asian, Caucasian, Hispanic and Ashkenazi Jewish individuals. The CYP2A6, CYP2B6 and CYP2E1 combined deletion/duplication allele frequencies ranged from 2 to 10% in these populations. High-resolution microarray-based comparative genomic hybridization (aCGH) localized CYP2A6, CYP2B6 and CYP2E1 breakpoints to directly oriented low-copy repeats. Sequencing localized the CYP2B6 breakpoint to a 529-bp intron 4 region with high homology to CYP2B7P1, resulting in the CYP2B6*29 partial deletion allele and the reciprocal, and novel, CYP2B6/2B7P1 duplicated fusion allele (CYP2B6*30). Together, these data identified novel CYP450 CNV alleles (CYP2B6*30 and CYP2E1*1Cx2) and indicate that common CYP450 CNV formation is likely mediated by non-allelic homologous recombination resulting in both full gene and gene-fusion copy number imbalances. Detection of these CNVs should be considered when interrogating these genes for pharmacogenetic drug selection and dosing.
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Martis
authors.forename: H
authors.initials: H
authors.lastname: Mei
authors.forename: R
authors.initials: R
authors.lastname: Vijzelaar
authors.forename: L
authors.initials: L
authors.lastname: Edelmann
authors.forename: R J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: S A
authors.initials: SA
authors.lastname: Scott
mesh_terms: D055028:Comparative Genomic Hybridization; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D056915:DNA Copy Number Variations; D005006:Ethnicity; D006801:Humans; D010597:Pharmacogenetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D003577:Cytochrome P-450 Enzyme System