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Cytochrome P450 2C9 (CYP2C9) c.449G&gt;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&gt;A on warfarin clearance, dose requirements, and CYP2C9 expression. In an African American cohort, 449G&gt;A was in linkage disequilibrium with c.-1766T&gt;C (r(2) = 0.89) and c.-1188T&gt;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 &lt; 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&gt;A decrease CYP2C9 expression and contribute to CYP2C9*8 effects on warfarin clearance and dose requirements.

pharmacogenetics and genomics

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