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: Rina Kimura, Kotaro Miyashita, Yoshihiro Kokubo, Yasuhisa Akaiwa, Ryoichi Otsubo, Kazuyuki Nagatsuka, Toshiho Otsuki, Akira Okayama, Kazuo Minematsu, Hiroaki Naritomi, Shigenori Honda, Hitonobu Tomoike, Toshiyuki Miyata
• Journal: Thrombosis research (Thromb Res) Vol. 120 Issue 2 Pg. 181-6 ( 2007) ISSN: 0049-3848 [Print] United States
• PMID: 17049586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticoagulants
• Warfarin
• Mixed Function Oxygenases
• CYP2C9 protein, human
• Cytochrome P-450 CYP2C9
• Aryl Hydrocarbon Hydroxylases
• VKORC1 protein, human
• Vitamin K Epoxide Reductases
• Carbon-Carbon Ligases
• glutamyl carboxylase

Topics

• Aged
• Anticoagulants (administration & dosage)
• Aryl Hydrocarbon Hydroxylases (genetics)
• Carbon-Carbon Ligases (genetics)
• Cytochrome P-450 CYP2C9
• Female
• Genotype
• Humans
• Japan
• Male
• Middle Aged
• Mixed Function Oxygenases (genetics)
• Models, Biological
• Pharmacogenetics
• Polymorphism, Single Nucleotide
• Regression Analysis
• Stroke (drug therapy, genetics)
• Vitamin K Epoxide Reductases
• Warfarin (administration & dosage)