Institute of Cardiology, Me-dical Academy, Lithuanian University of Health Sciences, Suki-lėlių 17, 50161 Kaunas, Lithuania.
Medicina (Kaunas). 2011;47(1):25-30.
A clinical effect of warfarin depends on highly polymorphic drug-metabolizing (CYP2C9) and drug-target (VKORC1) enzymes. The objective of this study was to investigate the impact of CYP2C92, CYP2C93, and VKORC1 (G-1639A) polymorphisms on the variability of warfarin dosage requirements in Lithuanian patients after heart valve replacement.
The study included 83 patients with a mean age of 65.2 years (SD, 13.31) after heart valve replacement with an achieved stable international normalized ratio of 2-3.5. The restriction fragment length polymorphism method was used to identify polymorphisms of VKORC1 and CYP2C9.
Daily warfarin dosage significantly correlated with weight (r=0.4087) and height (r=0.3883) of the patients. Patients younger than 60 years required significantly higher daily warfarin dosages than older patients. Two-thirds (66.3%) of the patients had the wild-type (WT) CYP2C9*1/1 genotype; 38.6% and 54.2% of the patients had WT VKORC1 (G/G) and VKORC1 (G/A) genotypes, respectively. WT CYP2C91/1 genotype was associated with a higher daily warfarin dosage (5.84 mg [SD, 2.84]) as compared to other CYP2C9 genotypes. Carriers of WT VKORC1 (G/G) required a higher warfarin dose as compared to (A/A) carriers (6.20±2.78 mg and 3.75±1.40 mg, respectively; P=0.04). Patients having CYP2C91/*1 or 1/*2 in combination with VKORC1 (G/G) or (G/A) genotypes required the highest daily warfarin dosage in comparison to other combinations of genotypes.
The Lithuanian study sample is characterized by high a frequency (92.8%) of VKORC1 G/G and G/A genotypes that determines a higher warfarin-loading dose. Analysis of combined CYP2C9 and VKORC1 gene variants allows the prediction of warfarin dosage. These results can be used to individualize treatment with warfarin in the field of heart surgery in Lithuania.
本研究旨在探讨细胞色素 P450 2C9（CYP2C9）2、CYP2C93 和维生素 K 环氧化物还原酶复合物亚基 1（VKORC1）（G-1639A）多态性对立陶宛心脏瓣膜置换术后患者华法林剂量需求变异性的影响。
本研究纳入 83 例心脏瓣膜置换术后患者，平均年龄 65.2 岁（标准差 13.31），国际标准化比值（INR）达到 2-3.5。采用限制性片段长度多态性方法检测 VKORC1 和 CYP2C9 多态性。
华法林的日剂量与患者的体重（r=0.4087）和身高（r=0.3883）显著相关。年龄小于 60 岁的患者需要的华法林日剂量显著高于年龄较大的患者。三分之二（66.3%）的患者为野生型（WT）CYP2C9*1/1 基因型；38.6%和 54.2%的患者分别为 WT VKORC1（G/G）和 VKORC1（G/A）基因型。WT CYP2C91/1 基因型与较高的华法林日剂量（5.84mg[标准差，2.84]）相关，而其他 CYP2C9 基因型则较低。与（A/A）携带者相比，WT VKORC1（G/G）携带者需要更高的华法林剂量（6.20±2.78mg 和 3.75±1.40mg，P=0.04）。与其他基因型组合相比，同时携带 CYP2C91/*1 或 1/*2 与 VKORC1（G/G）或（G/A）基因型的患者需要更高的华法林日剂量。
立陶宛研究样本中 VKORC1 G/G 和 G/A 基因型的频率较高（92.8%），这决定了较高的华法林负荷剂量。分析 CYP2C9 和 VKORC1 基因变异的联合作用可以预测华法林的剂量。这些结果可用于立陶宛心脏外科领域华法林个体化治疗。
