Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin

Thromb Haemost. 2006 Feb;95(2):205-11. doi: 10.1160/TH05-06-0446.

Abstract

We examined the influence of combined genotypes on interindividual variability in warfarin dose-response. In 100 anticoagulated patients we quantified the effects of polymorphisms in: CYP2C9, VKORC1, calumenin (CALU), gamma-glutamyl carboxylase (GGCX) and microsomal epoxide hydrolase (EPHX1) on warfarin dose requirements. The G(1542)C VKORC1 polymorphism was associated with decreased warfarin doses in the hetero- and homozygous mutant patients (21% and 50% lower, respectively; p < 0.0001). Warfarin daily dose was predominantly determined by VKORC1 and CYP2C9 genotypes (partial r(2) = 0.21; 0.20, respectively). Together with age and body weight, these two genotypes explained 63% of the dose variance. A single patient, homozygous for G(11)A CALU mutant allele, required an exceptionally high warfarin dose (20 mg/day) and the prevalence of heterozygous (11)A allele carriers in the upper 10(th) dose percentile was significantly higher (0.27 vs. 0.18, p < 0.02). Combined genotype analysis revealed that CYP2C9 andVKORC1 wild type and CALU mutant patients required the highest warfarin doses (7.8 +/- 1.5mg/day; n = 9) as compared to the CYP2C9 and VKORC1 mutant and CALU wild type genotypes (2.8 +/- 0.3 mg/day; n = 18; p < 0.01). The odds ratio for doses <3mg/day was 5.9 (1.9-18.4) for this genotype. Compound genetic profiles comprising VKORC1, CALU and CYP2C9 improve categorization of individual warfarin dose requirements in more than 25% of patients at steady-state anticoagulation.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Calcium-Binding Proteins / genetics
  • Carbon-Carbon Ligases / genetics
  • Cytochrome P-450 CYP2C9
  • Dose-Response Relationship, Drug
  • Drug Resistance / genetics
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Mixed Function Oxygenases / genetics
  • Pharmacogenetics*
  • Polymorphism, Genetic*
  • Vitamin K / metabolism*
  • Vitamin K Epoxide Reductases
  • Warfarin / administration & dosage
  • Warfarin / pharmacokinetics*

Substances

  • CALU protein, human
  • Calcium-Binding Proteins
  • Vitamin K
  • 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