Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients.
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.
Mushiroda
Taisei
T
Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Ohnishi
Yozo
Y
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Saito
Susumu
S
Laboratory for SNP Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Takahashi
Atsushi
A
Laboratory of Statistical Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Kikuchi
Yuka
Y
Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Saito
Shigeru
S
Tokushukai Hospital Group, Tokyo, Japan.
Shimomura
Hideki
H
Tokushukai Hospital Group, Tokyo, Japan.
Wanibuchi
Yasuhiko
Y
Tokushukai Hospital Group, Tokyo, Japan.
Suzuki
Takao
T
Tokushukai Hospital Group, Tokyo, Japan.
Kamatani
Naoyuki
N
Laboratory of Statistical Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Nakamura
Yusuke
Y
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.
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*
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