title: 5'-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients.
abstract: White and Japanese patients require different warfarin dosages to achieve therapeutic anticoagulation, but this can be only partly explained by genetic variability in the coding region of CYP2C9-a critical enzyme in the drug's metabolism. Accordingly, analysis of the -2.1-kb 5'-flanking region of CYP2C9 was undertaken in 22 white and 38 Japanese patients whose unbound oral clearance of S-warfarin had been previously determined. Thirteen single nucleotide polymorphisms (SNPs) were identified, some of which were in linkage disequilibrium with functionally defective coding region variants. Those 5'-flanking patterns linked with at least one CYP2C9*3 allele or CYP2C9*2/*3 were associated with reduced CYP2C9 activity and warfarin dose. Japanese patients possessing the wild-type promoter and coding sequences had significantly (P <.01) greater CYP2C9 activity than white patients with the corresponding genotype. In conclusion, either unidentified polymorphisms further upstream in the promoter region or environmental factor(s) account for the differences in the warfarin doses between whites and Japanese.
authors.affiliation: Department of Pharmacotherapy, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
authors.forename: Grant R
authors.initials: GR
authors.lastname: Wilkinson
authors.forename: Gail
authors.initials: G
authors.lastname: Mayo
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kashima
authors.forename: Sosuke
authors.initials: S
authors.lastname: Kimura
authors.forename: Kenji
authors.initials: K
authors.lastname: Otsubo
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Echizen
mesh_terms: D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014859:Warfarin / Q000008:administration & dosage / Q000378:metabolism*; D044465:White People / Q000235:genetics*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases