title: CYP2C9 promoter region single-nucleotide polymorphisms linked to the R150H polymorphism are functional suggesting their role in CYP2C9*8-mediated effects.
abstract: 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.
authors: Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Illinois 60612, USA.
authors: Larisa H
authors: LH
authors: Cavallari
authors: David
authors: D
authors: Vaynshteyn
authors: Kimberly M
authors: KM
authors: Freeman
authors: Danxin
authors: D
authors: Wang
authors: Minoli A
authors: MA
authors: Perera
authors: Harumi
authors: H
authors: Takahashi
authors: Katrzyna
authors: K
authors: Drozda
authors: Shitalben R
authors: SR
authors: Patel
authors: Hyunyoung
authors: H
authors: Jeong
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases
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