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

The Pharmacogenomics Journal volume 13, pages 558–566 (2013)Cite this article

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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.

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Acknowledgements

This research was supported in part by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), through Grant KL2TR000069 (SAS). The Cytochrome P-450 MLPA kit reagents used in this study were generously provided by MRC-Holland (Amsterdam, The Netherlands). We thank Dr Sarah Sim, Karolinska Institutet, Stockholm, Sweden, for critical reading of the manuscript; Ms Edith Gould, formerly of the Mount Sinai School of Medicine, New York, for her technical assistance with the MLPA assays; and Dr Minjie Luo, Mount Sinai School of Medicine, for assistance with the long-range PCR assays.

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  1. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA

    S Martis, H Mei, L Edelmann, R J Desnick & S A Scott

  2. MRC-Holland, Amsterdam, The Netherlands

    R Vijzelaar

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Correspondence to S A Scott.

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One of the authors (RV) is an employee of MRC-Holland, Amsterdam, The Netherlands. The remaining authors declare no conflict of interest.

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Martis, S., Mei, H., Vijzelaar, R. et al. Multi-ethnic cytochrome-P450 copy number profiling: novel pharmacogenetic alleles and mechanism of copy number variation formation. Pharmacogenomics J 13, 558–566 (2013). https://doi.org/10.1038/tpj.2012.48

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