5′-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients

Harumi Takahashi, Ichiro Ieiri, Grant R. Wilkinson, Gail Mayo, Toshitaka Kashima, Sosuke Kimura, Kenji Otsubo, Hirotoshi Echizen

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40 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3055-3057
Number of pages3
JournalBlood
Volume103
Issue number8
DOIs
Publication statusPublished - Apr 15 2004
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Takahashi, H., Ieiri, I., Wilkinson, G. R., Mayo, G., Kashima, T., Kimura, S., Otsubo, K., & Echizen, H. (2004). 5′-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients. Blood, 103(8), 3055-3057. https://doi.org/10.1182/blood-2003-07-2521