ViennaLab Diagnostics GmbH, Gaudenzdorfer Guertel 43-45, 1120, Vienna, Austria.
Eur J Clin Pharmacol. 2010 Jun;66(6):591-8. doi: 10.1007/s00228-010-0809-2. Epub 2010 Apr 8.
Phenprocoumon, similar to other coumarin-derived anticoagulants, is associated with a large variation in the individual dose requirement to achieve stable anticoagulation. Polymorphisms in the vitamin K epoxide reductase complex subunit 1 (VKORC1) and the liver enzyme cytochrome P450 2C9 (CYP2C9) effectively account for the variability in warfarin and acenocoumarol response but are less well-defined pharmacogenetic predictors in phenprocoumon therapy.
A retrospective study was performed on 185 outpatients attending anticoagulation clinics in Austria and Germany. These patients were genotyped for the VKORC1 -1639G>A and 3730G>A polymorphisms as well as for the CYP2C9 *2 and *3 polymorphisms using a reverse hybridisation-based teststrip assay.
The VKORC1 -1639A allele, which was present at a frequency of 41.4% in the study cohort, significantly reduced the mean weekly phenprocoumon dose by 3 mg (19%) in the heterozygous and by 6.7 mg (43%) in the homozygous state compared to wild-type carriers (15.5 +/- 6.8 mg, p < 0.0001). A stepwise multiple regression analysis revealed that VKORC1 -1639G>A, age and CYP2C9*3 were the major independent determinants of phenprocoumon dose, accounting for 14.2, 9.1 and 4.7% of its variability, respectively (p </= 0.0007). The CYP2C9*2 polymorphism had a marginal influence (1.4%) and failed to reach statistical significance (p = 0.062). The VKORC1 3730G>A genotype had no additional predictive power for individual dose variability.
Similar to warfarin and acenocoumarol, the VKORC1 -1639G>A polymorphism had the highest impact on the maintenance dose of phenprocoumon. The factor age was the second most important predictor and explained a greater percentage of the variability than CYP2C9 genotype.
与其他香豆素类抗凝剂类似，苯丙香豆素的个体剂量需求存在较大差异，以达到稳定抗凝效果。维生素 K 环氧化物还原酶复合物亚基 1（VKORC1）和肝酶细胞色素 P450 2C9（CYP2C9）的多态性有效解释了华法林和醋硝香豆素反应的变异性，但在苯丙香豆素治疗中，其作为药理学遗传预测因素的作用尚不清楚。
对在奥地利和德国接受抗凝门诊治疗的 185 名门诊患者进行了回顾性研究。使用反向杂交测试条测定 VKORC1-1639G>A 和 3730G>A 多态性以及 CYP2C92 和3 多态性，对这些患者进行了基因分型。
VKORC1-1639A 等位基因在研究队列中的频率为 41.4%，与野生型携带者相比，杂合子中平均每周苯丙香豆素剂量降低 3 毫克（19%），纯合子中降低 6.7 毫克（43%）（15.5+/-6.8mg，p<0.0001）。逐步多元回归分析显示，VKORC1-1639G>A、年龄和 CYP2C9*3 是苯丙香豆素剂量的主要独立决定因素，分别占其变异性的 14.2%、9.1%和 4.7%（p</=0.0007）。CYP2C9*2 多态性的影响较小（1.4%），且无统计学意义（p=0.062）。VKORC1 3730G>A 基因型对个体剂量变异性无额外预测能力。
与华法林和醋硝香豆素类似，VKORC1-1639G>A 多态性对苯丙香豆素的维持剂量影响最大。年龄是第二个最重要的预测因素，比 CYP2C9 基因型解释了更大比例的变异性。
