title: Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients.
abstract: The dose required for the anticoagulant effect of warfarin exhibits large inter-individual variations. This study sought to determine the contribution of four genes, vitamin K epoxide reductase (VKORC1), gamma-glutamyl carboxylase (GGCX), calumenin (CALU), and cytochrome P450 2C9 (CYP2C9) to the warfarin maintenance dose required in Japanese patients following ischemic stroke. We recruited 93 patients on stable anticoagulation with a target International Normalized Ratio (INR) of 1.6-2.6. We genotyped eleven representative single nucleotide polymorphisms (SNPs) in the three genes involved in vitamin K cycle and the 42613A>C SNP in CYP2C9, known as CYP2C93, and then examined an association of these genotypes with warfarin maintenance doses (mean+/-SD=2.96+/-1.06 mg/day). We found an association of effective warfarin dose with the -1639G>A (p=0.004) and 3730G>A genotypes (p=0.006) in VKORC1, the 8016G>A genotype in GGCX (p=0.022), and the 42613A>C genotype in CYP2C9 (p=0.015). The model using the multiple regression analysis including age, sex, weight, and three genetic polymorphisms accounted for 33.3% of total variations in warfarin dose. The contribution to inter-individual variation in warfarin dose was 5.9% for VKORC1 -1639G>A, 5.2% for CYP2C9 42613A>C, and 4.6% for GGCX 8016G>A. In addition to polymorphisms in VKORC1 and CYP2C9, we identified GGCX 8016G>A, resulting in the missense mutation R325Q, as a genetic determinant of warfarin maintenance dose in Japanese patients.
authors.affiliation: Research Institute, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Kimura
authors.forename: Kotaro
authors.initials: K
authors.lastname: Miyashita
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kokubo
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Akaiwa
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Otsubo
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nagatsuka
authors.forename: Toshiho
authors.initials: T
authors.lastname: Otsuki
authors.forename: Akira
authors.initials: A
authors.lastname: Okayama
authors.forename: Kazuo
authors.initials: K
authors.lastname: Minematsu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Naritomi
authors.forename: Shigenori
authors.initials: S
authors.lastname: Honda
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D019735:Carbon-Carbon Ligases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008954:Models, Biological; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D020521:Stroke / Q000188:drug therapy / Q000235:genetics; 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; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase