Abstract
CYP2C19 is a principal enzyme involved in the bioactivation of the antiplatelet prodrug clopidogrel and common CYP2C19 loss-of-function alleles are associated with adverse cardiovascular events. To assess the impact of the CYP2C19*17 increased activity allele in the Ashkenazi Jewish (AJ) and Sephardi Jewish (SJ) populations and to determine the frequencies of additional variant alleles, 250 AJ and 135 SJ individuals were genotyped for CYP2C19*2–*10, *12–*17, *22 and P-glycoprotein (ABCB1) c.3435C>T. Importantly, CYP2C19*4, a loss-of-function allele, was identified in linkage disequilibrium with *17. This novel haplotype, designated CYP2C19*4B, significantly alters the interpretation of CYP2C19 genotyping when testing *17. Moreover, genotyping CYP2C19*17 changed the frequency of extensive metabolizers from ∼70 to ∼40%, reclassifying ∼30% as ultrarapid metabolizers. Combining CYP2C19 and ABCB1 identified ∼1 in 3 AJ and ∼1 in 2 SJ individuals at increased risk for adverse responses to clopidogrel. These data underscore the importance of including *4B and *17 when clinically genotyping CYP2C19.
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Acknowledgements
We thank Dr Joseph M Sweeny, Mount Sinai Medical Center, New York, and Dr Sarah Sim, Karolinska Institutet, Stockholm, Sweden, for critical reading of the manuscript. This research was supported in part by a research training grant (5 T32 GM082773) and a grant (UL1RR029887) for the Mount Sinai Institutes for Clinical and Translational Sciences from the National Center for Research Resources, National Institutes of Health. eSensor 2C19 Test reagents for this study were supplied by GenMark Diagnostics (Carlsbad, CA, USA).
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Scott, S., Martis, S., Peter, I. et al. Identification of CYP2C19*4B: pharmacogenetic implications for drug metabolism including clopidogrel responsiveness. Pharmacogenomics J 12, 297–305 (2012). https://doi.org/10.1038/tpj.2011.5
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DOI: https://doi.org/10.1038/tpj.2011.5
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