The c.−1639G > A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients

Much of the variability in the sensitivity to warfarin in anticoagulated patients is associated with the c.−1639G > A polymorphism of the vitaminK-epoxide reductase (VKORC1) gene. However, its association with the acenocoumarol dose in patients under anticoagulant therapy has not been studied. The c.−1639G > A genotype of VKORC1 was determined in 113 patients on stable anticoagulation requiring low (n = 42), medium (n = 42) or high (n = 21) acenocoumarol doses. To evaluate the association between acenocoumarol requirements and the c.−1639G > A variant, multivariate logistic regression models were fitted, adjusting for age, gender, and the c.430C > T and c.1075A > C variants of cytochrome P450 2C9 (CYP2C9). A total of 90·5% of the patients in the low acenocoumarol dose group carried the A allele of VKORC1:c.−1639G > A. The A allele independently increased the odds of requiring a low acenocoumarol dose [odds ratio (OR) 9·4; 95% confidence interval (CI) 1·9–46·4; P = 0·006], especially when the homozygous form was present (OR 44·2; 95% CI 5·5–354·6; P < 0·001). The A allele was less frequent in the high dose group showing an inverse association with the requirement for high doses (OR 0·04; 95% CI 0·01–0·22; P < 0·001). The A allele of the c.−1639G > A polymorphism of VKORC1 is therefore associated with a low-dose requirement for acenocoumarol in patients receiving anticoagulant therapy.