REGULAR ARTICLE Genotypes of vitamin K epoxide reductase, γ-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients Rina Kimura a , Kotaro Miyashita b , Yoshihiro Kokubo c , Yasuhisa Akaiwa b , Ryoichi Otsubo b , Kazuyuki Nagatsuka b , Toshiho Otsuki b , Akira Okayama c , Kazuo Minematsu b , Hiroaki Naritomi b , Shigenori Honda a , Hitonobu Tomoike c , Toshiyuki Miyata a, ⁎ a Research Institute, Japan b Cerebrovascular Division, Department of Medicine, Japan c Department of Preventive Cardiology, National Cardiovascular Center, Osaka, Japan Received 21 March 2006; received in revised form 13 September 2006; accepted 13 September 2006 Available online 17 October 2006 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), γ-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 42613ANC SNP in CYP2C9, known as CYP2C9⁎3, 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 - 1639GNA(p = 0.004) and 3730GNA genotypes (p = 0.006) in VKORC1, the 8016GNA genotype in GGCX (p = 0.022), and the 42613ANC 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 - 1639GNA, 5.2% for CYP2C9 ⁎ Corresponding author.Tel.: +81 6 6833 5012x2512; fax: +81 6 6835 1176. E-mail address: miyata@ri.ncvc.go.jp (T. Miyata). intl.elsevierhealth.com/journals/thre KEYWORDS Genetic polymorphisms; Warfarin; VKORC1; GGCX; CYP2C9 0049-3848/$ - see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2006.09.007 Thrombosis Research (2007) 120, 181–186