CYP2C9 promoter region single-nucleotide polymorphisms linked to the R150H polymorphism are functional suggesting their role in CYP2C9*8-mediated effects

摘要

Cytochrome P450 2C9 (CYP2C9) c.449GA (*8) is common in African Americans and is associated with decreased warfarin clearance. We examined the effect of promoter region variants inherited with 449GA on warfarin clearance, dose requirements, and CYP2C9 expression. In an African American cohort, 449GA was in linkage disequilibrium with c.-1766TC (r 2=0.89) and c.-1188TC (D??=1). The combination of the-1766C and 449A alleles with the-1188CC genotype was associated with lower S-warfarin clearance (0.86??0.22 vs. 1.66??0.75 ml/min/m; n=48; P0.01) and dose requirements [33 (25-49) vs. 43 (35-56) mg/week; n=243; P=0.03] compared with other genotypes. In liver tissue, alleles with the-1766C/-1188C/449A haplotype showed two-fold decreased mRNA expression compared with reference alleles. In a promoter reporter assay, the-1766C/-1188C haplotype decreased CYP2C9 promoter activity. These data suggest that promoter region polymorphisms inherited with 449GA decrease CYP2C9 expression and contribute to CYP2C9*8 effects on warfarin clearance and dose requirements. ? 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.