Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients

J Hum Genet. 2011 Apr;56(4):290-5. doi: 10.1038/jhg.2011.4. Epub 2011 Feb 17.

Abstract

Warfarin is a commonly prescribed anticoagulant drug for the prevention of thromboembolic disorders. We investigated the contribution of genetic variations of four genes and clinical factors to warfarin dose requirement and provided a warfarin-dosing algorithm based on genetic and clinical variables in Korean patients. We recruited 564 Korean patients on stable anticoagulation. Single nucleotide polymorphisms (SNPs) for the VKORC1, CYP2C9, CYP4F2 and GGCX were analyzed. Using multiple regression analysis, we developed a model to predict the warfarin requirement. The SNPs of VKORC1, CYP2C9, CYP4F2 and GGCX showed significant correlation with warfarin dose. Patients with the 3730AA genotype received significantly higher doses of warfarin than those with the 3730GG (P=0.0001). For CYP2C9, the highest maintenance dose was observed in the patients with wild-type genotype compared with the variant allele carriers (P<0.0001). The multiple regression model including age, gender, body surface area (BSA), international normalized ratio (INR) and four genetic polymorphisms accounted for 35% of total variations in warfarin dose (R(2)=0.3499; P<0.0001). This study shows that age, gender, BSA, INR and VKORC1, CYP2C9 and CYP4F2 polymorphism affect warfarin dose requirements in Koreans. Translation of this knowledge into clinical guidelines for warfarin prescription may contribute to improve the efficacy and safety of warfarin treatment for Korean patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aged
  • Algorithms*
  • Analysis of Variance
  • Anticoagulants / administration & dosage*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Asian People / genetics*
  • Body Size
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P450 Family 4
  • Dose-Response Relationship, Drug
  • Female
  • Gene Frequency
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Mixed Function Oxygenases / genetics
  • Models, Biological*
  • Pharmacogenetics / methods*
  • Polymorphism, Single Nucleotide / genetics
  • Regression Analysis
  • Sex Factors
  • Vitamin K Epoxide Reductases
  • Warfarin / administration & dosage*

Substances

  • Anticoagulants
  • Warfarin
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P450 Family 4
  • CYP4F2 protein, human
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases