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

Cytochrome P450 2C9 (CYP2C9) c.449G>A (*8) is common in African Americans and is associated with decreased warfarin clearance. We examined the effect of promoter region variants inherited with 449G>A on warfarin clearance, dose requirements, and CYP2C9 expression. In an African American cohort, 449G>A was in linkage disequilibrium with c. -1766T>C (r(2) = 0.89) and c.-1188T>C (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(2); n=48; P<0.01) 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 449G>A decrease CYP2C9 expression and contribute to CYP2C9*8 effects on warfarin clearance and dose requirements. Pharmacogenetics and Genomics 23:228-231 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. Pharmacogenetics and Genomics 2013, 23:228-231