title: Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients.
abstract: Warfarin is the most commonly used oral anticoagulant for treatment of thromboembolism, but adjustment of the dose appropriate to each patient is not so easy because of the large inter-individual variation in dose requirement. We analyzed single nucleotide polymorphism (SNP) genotypes of the VKORC1 and CYP2C9 genes using DNA from 828 Japanese patients treated with warfarin, and investigated association between SNP genotype and warfarin-maintenance dose. Five SNPs in VKORC1, 5' flanking-1413A > G, intron 1-136T > C, intron 2+124C > G, intron 2+837T > C and exon 3 343G > A, were in absolute linkage disequilibrium, and showed a significant association with daily warfarin dose of these patients. The median warfarin dose of patients with homozygosity for the minor allele was 4.0 mg/day, which is significantly higher than those heterozygous for the minor allele (3.5 mg/day) or those homozygous for the major allele (2.5 mg/day; P = 5.1 x 10(-11) in the case of intron 1-136T > C SNP). We then genotyped the CYP2C9 gene for the Japanese common genetic variant, CYP2C9*3 and, based on the genotype of these two genes, classified patients into three categories, which we call "warfarin-responsive index." The median warfarin daily dose varied significantly in this classification according to the warfarin-responsive index (2.0 mg/day for index 0 group, 2.5 mg/day for index 1 group, and 3.5 mg/day for index 2 group; P = 4.4 x 10(-13)). Thus, analysis of the combination of VKORC1 and CYP2C9 genotypes should identify warfarin-sensitive patients who require a lower dose of drug, allowing personalized warfarin treatment.
authors.affiliation: Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Ohnishi
authors.affiliation: Laboratory for SNP Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Saito
authors.affiliation: Laboratory of Statistical Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kikuchi
authors.affiliation: Tokushukai Hospital Group, Tokyo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Saito
authors.affiliation: Tokushukai Hospital Group, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Shimomura
authors.affiliation: Tokushukai Hospital Group, Tokyo, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Wanibuchi
authors.affiliation: Tokushukai Hospital Group, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Laboratory of Statistical Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.affiliation: Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan. yusuke@ims.u-tokyo.ac.jp.|Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. yusuke@ims.u-tokyo.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D013923:Thromboembolism / Q000517:prevention & control; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases