Schalekamp Tom, Brassé Bjorn P, Roijers Janine F M, Chahid Youssef, van Geest-Daalderop Johanna H H, de Vries-Goldschmeding Hanneke, van Wijk Eduard M, Egberts Antoine C G, de Boer Anthonius
Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Clin Pharmacol Ther. 2006 Jul;80(1):13-22. doi: 10.1016/j.clpt.2006.04.006.
Our objective was to assess the effects of VKORC1 and CYP2C9 genotypes on severe overanticoagulation and time to achieve stability and their contributions to dose requirement during the initial phase of acenocoumarol treatment.
A prospective follow-up study was conducted at 2 anticoagulation clinics in The Netherlands. We assessed the CYP2C9 genotype (CYP2C92 and CYP2C93 polymorphisms) and the VKORC1 C1173T genotype of the subjects and collected data on international normalized ratio, dose, comedication, and comorbidity.
Of the 231 patients in the cohort, 150 (64.9%) had a VKORC1 C1173T polymorphism and 84 (36.4%) had a CYP2C92 or CYP2C93 allele. Only carriers of a combination of a CYP2C9 polymorphism and a VKORC1 polymorphism had an increased risk of severe overanticoagulation compared with subjects with no polymorphism or only 1 polymorphism (hazard ratio, 3.83 [95% confidence interval, 1.62-9.05]). The time to achieve stability was associated with the possession of the CYP2C9 genotype, not with the VKORC1 genotype (hazard ratio for CYP2C9*3 allele compared with CYP2C9 wild type, 0.59 [95% confidence interval, 0.40-0.87]). Patients with a VKORC1 polymorphism required significantly lower doses than VKORC1 CC wild-type patients. A larger part of the variability in dose requirement was explained by the VKORC1 genotype than by the CYP2C9 genotype (21.4% and 4.9%, respectively).
Being a carrier of a combination of polymorphisms of VKORC1 and CYP2C9, rather than of one of these polymorphisms, is associated with severe overanticoagulation. The time to achieve stability is mainly associated with the CYP2C9 genotype.
我们的目的是评估维生素K环氧化物还原酶复合体1（VKORC1）和细胞色素P450 2C9（CYP2C9）基因多态性对严重抗凝过度及达到稳定状态所需时间的影响，以及它们在醋硝香豆素治疗初始阶段对剂量需求的作用。
在荷兰的2家抗凝门诊进行了一项前瞻性随访研究。我们评估了受试者的CYP2C9基因多态性（CYP2C92和CYP2C93多态性）以及VKORC1 C1173T基因多态性，并收集了国际标准化比值、剂量、合并用药和合并症的数据。
在该队列的231例患者中，150例（64.9%）存在VKORC1 C1173T多态性，84例（36.4%）存在CYP2C92或CYP2C93等位基因。与无多态性或仅有一种多态性的受试者相比，只有CYP2C9多态性和VKORC1多态性同时存在的携带者发生严重抗凝过度的风险增加（风险比，3.83[95%置信区间，1.62 - 9.05]）。达到稳定状态的时间与CYP2C9基因型有关，而与VKORC1基因型无关（与CYP2C9野生型相比，CYP2C9*3等位基因的风险比为0.59[95%置信区间，0.40 - 0.87]）。存在VKORC1多态性的患者所需剂量显著低于VKORC1 CC野生型患者。剂量需求变异的较大部分由VKORC1基因型解释，而非CYP2C9基因型（分别为21.4%和4.9%）。
VKORC1和CYP2C9基因多态性同时存在的携带者，而非仅其中一种多态性的携带者，与严重抗凝过度有关。达到稳定状态的时间主要与CYP2C9基因型有关。
