Multi-ethnic cytochrome-P450 copy number profiling: novel pharmacogenetic alleles and mechanism of copy number variation formation

Pharmacogenomics J. 2013 Dec;13(6):558-66. doi: 10.1038/tpj.2012.48. Epub 2012 Nov 20.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Comparative Genomic Hybridization
  • Cytochrome P-450 Enzyme System / genetics*
  • DNA Copy Number Variations*
  • Ethnic Groups*
  • Humans
  • Pharmacogenetics*
  • Real-Time Polymerase Chain Reaction

Substances

  • Cytochrome P-450 Enzyme System