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The genetic interaction between VKORC1 c1173t and calumenin a29809g modulates the anticoagulant response of acenocoumarol
Author(s) -
GONZÁLEZCONEJERO R.,
CORRAL J.,
ROLDÁN V.,
FERRER F.,
SÁNCHEZSERRANO I.,
SÁNCHEZBLANCO J.J.,
MARÍN F.,
VICENTE V.
Publication year - 2007
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2007.02630.x
Subject(s) - acenocoumarol , vkorc1 , medicine , confidence interval , odds ratio , pharmacogenetics , genotype , gastroenterology , anticoagulant , pharmacology , atrial fibrillation , cyp2c9 , warfarin , biology , genetics , cytochrome p450 , metabolism , gene
Summary. 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 ≥ 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.