The genetic interaction between VKORC1 c1173t and calumenin a29809g modulates the anticoagulant response of acenocoumarol

J Thromb Haemost. 2007 Aug;5(8):1701-6. doi: 10.1111/j.1538-7836.2007.02630.x. Epub 2007 May 21.

Abstract

Background: The efficacy of oral anticoagulant therapy is largely conditioned by both environmental and genetic factors.

Objectives: To attempt to define the genetic profile involved in the response to this treatment.

Patients and methods: We selected 100 men younger than 75 years, with non-valvular atrial fibrillation, who started anticoagulation with acenocoumarol following the same protocol: 3 mg for three consecutive days. Then, doses were individually adjusted to achieve a steady International Normalized Ratio (INR). The basal plasma level and the level after 3 days were obtained, and the INR was determined. We studied five functional polymorphisms: FVII -323 Del/Ins, CYP2C*9, VKORC1 c1173t, calumenin (CALU) R4Q and CALU a29809g. The dose required for a steady INR was also recorded.

Results: Only the VKORC1 genotype had significant impact on the efficacy of therapy. Carriers of the 1173t allele were significantly more sensitive to therapy for 3 days [INR 2.07 (1.59-2.87) vs. 1.74 (1.30-2.09); P = 0.015] and they needed lower acenocoumarol doses to stabilize their INR (15.8 +/- 5.6 vs. 19.5 +/- 6.0 mg week(-1); P = 0.004). Its effect was exacerbated by combination with the CALU a29809g polymorphism. Carriers of both variants (27% of the sample) achieved the highest INR [2.26 (1.70-3.32)] and required the lowest dose (14.1 +/- 5.1 mg week(-1)). This genetic profile was particularly relevant in patients with INR >or= 3.5 at the start of therapy (P = 0.005; odds ratio = 6.67, 95% confidence interval = 1.32-37.43).

Conclusions: Our results suggest that CALU a29809g might be a new genetic factor involved in the pharmacogenetics of anticoagulant therapy, and confirm that specific genetic profiles defined by different polymorphisms will determine the initial response and dose required to achieve a stable and safe INR.

MeSH terms

  • Acenocoumarol / pharmacology*
  • Aged
  • Anticoagulants / metabolism*
  • Blood Proteins / metabolism
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / metabolism*
  • Genetic Variation
  • Humans
  • Male
  • Middle Aged
  • Mixed Function Oxygenases / genetics*
  • Models, Biological
  • Models, Genetic
  • Pharmacogenetics
  • Polymorphism, Genetic
  • Vitamin K / metabolism
  • Vitamin K Epoxide Reductases

Substances

  • Anticoagulants
  • Blood Proteins
  • CALU protein, human
  • Calcium-Binding Proteins
  • Vitamin K
  • Mixed Function Oxygenases
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases
  • Acenocoumarol