Montes Ramón, Ruiz de Gaona Estefanía, Martínez-González Miguel Angel, Alberca Ignacio, Hermida José
Laboratory of Thrombosis and Haemostasis, Haematology Department and Division of Cardiovascular Sciences, Centre for Applied Medical Research, Clínica Universitaria/School of Medicine, University of Navarre, C/Pio XII 55, 3rd floor, 31008 Pamplona, Spain.
Br J Haematol. 2006 Apr;133(2):183-7. doi: 10.1111/j.1365-2141.2006.06007.x.
Much of the variability in the sensitivity to warfarin in anticoagulated patients is associated with the c.-1639G > A polymorphism of the vitamin K-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.
接受抗凝治疗的患者对华法林敏感性的差异，很大程度上与维生素K环氧化物还原酶（VKORC1）基因的c.-1639G>A多态性有关。然而，尚未研究其与接受抗凝治疗患者醋硝香豆素剂量的相关性。对113例接受稳定抗凝治疗、需要低（n=42）、中（n=42）或高（n=21）剂量醋硝香豆素的患者，测定了VKORC1基因的c.-1639G>A基因型。为评估醋硝香豆素需求量与c.-1639G>A变异之间的相关性，拟合了多因素逻辑回归模型，并对年龄、性别以及细胞色素P450 2C9（CYP2C9）的c.430C>T和c.1075A>C变异进行了校正。低剂量醋硝香豆素组中，共有90.5%的患者携带VKORC1:c.-1639G>A的A等位基因。A等位基因独立增加了需要低剂量醋硝香豆素的几率[比值比（OR）9.4；95%置信区间（CI）1.9-46.4；P=0.006]，尤其是存在纯合形式时（OR 44.2；95%CI 5.5-354.6；P<0.001）。高剂量组中A等位基因的频率较低，显示出与高剂量需求呈负相关（OR 0.04；95%CI 0.01-0.22；P<0.001）。因此，VKORC1基因c.-1639G>A多态性的A等位基因与接受抗凝治疗患者对醋硝香豆素的低剂量需求有关。
