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.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 (r² = 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/m²; 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.