Novel single nucleotide polymorphism in CYP2C9 is associated with changes in warfarin clearance and CYP2C9 expression levels in African Americans

摘要

Warfarin is a widely used anticoagulant whose active S-enantiomer is primarily metabolized by the CYP2C9 enzyme. The CYP2C9*2 and CYP2C9*3 alleles are associated with lower warfarin dose requirement and decreased enzyme activity. In contrast, we previously identified a novel single-nucleotide polymorphism (SNP) (rs7089580A > T) in CYP2C9 that is associated with higher warfarin dose requirement in African Americans (AAs). In this study, we examine the effect of rs7089580 on warfarin pharmacokinetics and CYP2C9 expression in 63 AA patients and 32 AA liver tissues, respectively. We found oral clearance of S-warfarin to be higher among carriers of the minor rs7089580 allele (T) compared with wild-type homozygotes (3.73 +/- 1.46 vs 2.95 +/- 1.39 mL/min; P = 0.04). CYP2C9 messenger RNA expression in liver tissue was also higher among A/T and T/T genotypes compared with A/A (P < 0.02). Our findings indicate that rs7089580 is associated with higher S-warfarin clearance and CYP2C9 expression and may help explain the higher dose requirement of warfarin in AAs. Furthermore, rs7089580 is in complete linkage disequilibrium with the promoter SNP rs12251841 in AAs, which may provide a biologically plausible explanation for the observed effect on CYP2C9 expression levels. Given the many clinically relevant substrates of CYP2C9, identifying polymorphisms that affect expression levels and metabolism across ethnicities is essential for individualization of doses with a narrow therapeutic index.