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

Research output: Contribution to journalArticle

39 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

Fingerprint

5' Flanking Region
Warfarin
Polymorphism
Metabolism
Linkage Disequilibrium
Genetic Promoter Regions
Single Nucleotide Polymorphism
Cytochrome P-450 CYP2C9
Nucleotides
Alleles
Genotype
Enzymes
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

5′-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients. / Takahashi, Harumi; Ieiri, Ichiro; Wilkinson, Grant R.; Mayo, Gail; Kashima, Toshitaka; Kimura, Sosuke; Otsubo, Kenji; Echizen, Hirotoshi.

In: Blood, Vol. 103, No. 8, 15.04.2004, p. 3055-3057.

Research output: Contribution to journalArticle

Takahashi, H, Ieiri, I, Wilkinson, GR, 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, vol. 103, no. 8, pp. 3055-3057. https://doi.org/10.1182/blood-2003-07-2521
Takahashi, Harumi ; Ieiri, Ichiro ; Wilkinson, Grant R. ; Mayo, Gail ; Kashima, Toshitaka ; Kimura, Sosuke ; Otsubo, Kenji ; Echizen, Hirotoshi. / 5′-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients. In: Blood. 2004 ; Vol. 103, No. 8. pp. 3055-3057.
@article{a8442aa4d5c74ac09ce07e99212de9ca,
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.",
author = "Harumi Takahashi and Ichiro Ieiri and Wilkinson, {Grant R.} and Gail Mayo and Toshitaka Kashima and Sosuke Kimura and Kenji Otsubo and Hirotoshi Echizen",
year = "2004",
month = "4",
day = "15",
doi = "10.1182/blood-2003-07-2521",
language = "English",
volume = "103",
pages = "3055--3057",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "8",

}

TY - JOUR

T1 - 5′-Flanking region polymorphisms of CYP2C9 and their relationship to S-warfarin metabolism in white and Japanese patients

AU - Takahashi, Harumi

AU - Ieiri, Ichiro

AU - Wilkinson, Grant R.

AU - Mayo, Gail

AU - Kashima, Toshitaka

AU - Kimura, Sosuke

AU - Otsubo, Kenji

AU - Echizen, Hirotoshi

PY - 2004/4/15

Y1 - 2004/4/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=1842526962&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=1842526962&partnerID=8YFLogxK

U2 - 10.1182/blood-2003-07-2521

DO - 10.1182/blood-2003-07-2521

M3 - Article

C2 - 15070684

AN - SCOPUS:1842526962

VL - 103

SP - 3055

EP - 3057

JO - Blood

JF - Blood

SN - 0006-4971

IS - 8

ER -