The genetic interaction between VKORC1 c1173t and calumenin a29809g modulates the anticoagulant response of acenocoumarol.
BACKGROUND
The efficacy of oral anticoagulant therapy is largely conditioned by both environmental and genetic factors.


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


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.
González-Conejero
R
R
Centro Regional de Hemodonación, University of Murcia, Murcia, Spain. rocio.gonzalez@carm.es
Corral
J
J
Roldán
V
V
Ferrer
F
F
Sánchez-Serrano
I
I
Sánchez-Blanco
J J
JJ
Marín
F
F
Vicente
V
V
D000074:Acenocoumarol / Q000494:pharmacology*; D000368:Aged; D000925:Anticoagulants / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008954:Models, Biological; D008957:Models, Genetic; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D014812:Vitamin K / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases
D000925:Anticoagulants; D001798:Blood Proteins; C510527:CALU protein, human; D002135:Calcium-Binding Proteins; D014812:Vitamin K; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol