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VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients
Author(s) -
Obayashi Kyoko,
Nakamura Katsunori,
Kawana Junichi,
Ogata Hiroyasu,
Hanada Kazuhiko,
Kurabayashi Masahiko,
Hasegawa Akira,
Yamamoto Koujirou,
Horiuchi Ryuya
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2006.04.010
Subject(s) - vkorc1 , cyp2c9 , warfarin , medicine , cyp2c19 , maintenance dose , linkage disequilibrium , vitamin k epoxide reductase , pharmacodynamics , gastroenterology , pharmacology , genotype , biology , pharmacokinetics , single nucleotide polymorphism , genetics , gene , atrial fibrillation , cytochrome p450 , metabolism
Objectives To compare the genetic and clinical factors that cause large interpatient variability and ethnic differences in warfarin efficacy, we investigated variations of the VKORC1 , CYP2C9 , and CYP2C19 genes in Japanese subjects. Furthermore, we evaluated the genetic variations and clinical data as contributors of variation in warfarin maintenance dose. Methods Gene variations of VKORC1 , CYP2C9 , and CYP2C19 in 125 patients treated with warfarin and 114 healthy subjects were analyzed. The daily dose of warfarin, concentrations of S ‐ and R ‐warfarin in plasma, and prothrombin time expressed as the international normalized ratio were used as the pharmacokinetic and pharmacodynamic indices. Data were evaluated by a multivariate analysis method. Results Three missense mutations (47 G>C, 113 A>C, and 1338 A>G) in VKORC1 were newly identified in the Japanese population. The 113 A>C (Asp38Ser) variant decreased the warfarin dose requirement from 3.33 ± 1.54 mg/d (n = 122) to 1.5 mg/d (n = 1). The variants −1639 G>A in the 5′‐upstream region, 1173 C>T in intron 1, and 1542 G>C in intron 2 were in complete linkage disequilibrium, and the frequency of the −1639 G>A variation was only 0.8%, which contrasts with the frequency (39.8%‐45.8%) reported previously for white persons. The dose of warfarin was larger in the VKORC1 −1639 GA genotype group (4.55 ± 1.75 mg/d, P < .001) than in the −1639 AA group (2.94 ± 1.15 mg/d). The mean daily dose of warfarin was lower in subjects with CYP2C9*1/*3 (1.86 ± 0.80 mg/d, P = .007) than in subjects with CYP2C9*1/*1 (3.36 ± 1.43 mg/d). When the relative contributions of the VKORC1 variants, CYP2C9*2 , CYP2C9*3 , CYP2C19*2 , and CYP2C19*3 , as well as the clinical characteristics of the patients, diagnoses, and concurrent medications, were compared, the VKORC1 −1639 GA genotype group accounted for 16.5% and CYP2C9 variants accounted for 13.4% of variation in warfarin dose. Conclusion The ethnic difference in warfarin maintenance dose was mainly dependent on the linked VKORC1 variants. Genotyping of −1639 G>A of the VKORC1 gene could be clinically important for predicting individual variability in anticoagulant responses to warfarin. Clinical Pharmacology & Therapeutics (2006) 80 , 169–178; doi: 10.1016/j.clpt.2006.04.010