Identification of CYP2C19*4B: pharmacogenetic implications for drug metabolism including clopidogrel responsiveness.

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 CYP2C1917 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 CYP2C192-*10, *12-*17, 22 and P-glycoprotein (ABCB1) c.3435C>T. Importantly, CYP2C194, a loss-of-function allele, was identified in linkage disequilibrium with 17. This novel haplotype, designated CYP2C194B, significantly alters the interpretation of CYP2C19 genotyping when testing 17. Moreover, genotyping CYP2C1917 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.