Effect of the VKORC1 genotype on warfarin dose requirements in Japanese pediatric patients.

The primary aim of the present study was to evaluate the effect of the genotype of vitamin K epoxide reductase complex 1 (VKORC1) on warfarin dose requirements in Japanese pediatric patients. Forty-eight pediatric patients (0.42-19.25 years old) in whom stable anticoagulation was achieved by warfarin were enrolled in this study, and the polymorphic alleles of VKORC1 and CYP2C9 were determined for each subject. The relative impact of covariates on the anticoagulant effect of warfarin was evaluated by multiple regression analysis. It was found that VKORC1 genotype and age were major factors affecting the relationship between the weight-normalized warfarin dose and the therapeutic prothrombin time-international normalized ratio (PT-INR). Because only one patient had the CYP2C9*3 allele, we could not evaluate the effect of CYP2C9 polymorphisms on the anticoagulant effect of warfarin. In contrast, the anticoagulant effect of warfarin in patients with the VKORC1 1173CT or 1173CC genotype was 52.3% of that in patients with the 1173TT genotype. In addition, the anticoagulant effect of warfarin was shown to increase by 10.5% per year in Japanese pediatric patients. In conclusion, genotyping of VKORC1 will be useful in establishing individual anticoagulant therapy with warfarin, and it should be noted that a higher weight-normalized dose of warfarin is required in younger pediatric patients.

[1]  M. Pirmohamed,et al.  Effects of CYP4F2 genetic polymorphisms and haplotypes on clinical outcomes in patients initiated on warfarin therapy , 2009, Pharmacogenetics and genomics.

[2]  T. Miyawaki,et al.  Evaluation of phenytoin dosage regimens based on genotyping of CYP2C subfamily in routinely treated Japanese patients. , 2005, Drug metabolism and pharmacokinetics.

[3]  T. Aoyama,et al.  Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. , 1992, Chemical research in toxicology.

[4]  M. Ritchie,et al.  Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans , 2006, Pharmacogenetics and genomics.

[5]  S. Ishikawa,et al.  Developmental changes in pharmacokinetics and pharmacodynamics of warfarin enantiomers in Japanese children , 2000, Clinical pharmacology and therapeutics.

[6]  Yusuke Nakamura,et al.  Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese. , 2010, Human molecular genetics.

[7]  K. Kosaki,et al.  1173C>T Polymorphism in VKORC1 Modulates the Required Warfarin Dose , 2006, Pediatric Cardiology.

[8]  Y. Turpaz,et al.  CYP4F2 genetic variant alters required warfarin dose. , 2008, Blood.

[9]  M. Margaglione,et al.  A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. , 2005, Blood.

[10]  T. Ishizaki,et al.  Genetic analysis of CYP2C9 polymorphism in a Japanese population. , 1997, Pharmacogenetics.

[11]  大林 恭子.  VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients , 2006 .