Vorob'eva N M, Panchenko E P, Dobrovol'skiĭ A B, Titaeva E V, Khasanova Z B, Konovalova N V, Postnov A Iu, Kirienko A I
Ter Arkh. 2011;83(6):59-65.
To investigate frequency of carriage of genetic polymorphisms CYP2C9 and VKORC1 in patients with venous thromboembolic complications (VTEC) in Moscow population given warfarin treatment and effects of this carriage on stability of anticoagulation and frequency of hemorrhagic complications (HC) in warfarin treatment.
The study included 111 patients with the history of deep vein thrombosis and/ or pulmonary artery thromboembolism. All the patients received non-fractionated or low-molecular heparin for at least 5 days, then warfarin (target INR 2.0-3.0). Warfarin dose was selected empirically. Gene CYP2C9 and VKORC1 polymorphisms were studied. HC were endpoints.
Genotype CYP2C9*1/1 (a "wild" type) was detected in 94 (84.7%) patients. Of other genotypes - heterozygotes CYP2C91/2 (4.5%) and CYP2C91/3 (10.8%). Genotyping by VKORC1 detected genotype GG (a wild type) in 42.3%, genotype GA--in 48.6%, genotype AA--in 9.1% patients. A mean warfarin dose, supporting an adequaite INR, was asspciated with both genotype CYP2C9 and VKORC1. Warfarin doses were highest in carriers of wile genotypes CYP2C9 and VKORC1 (6,9 and 8,8 mg/day), the lowest--in patients with genotypes CYP2C91/3 and VKORC1 (4,5 and 4,0 mg/day). The carriers of polymorphisms CYP2C91/3 and VKORC1 showed less stable anticoagulation vs carriers of allele variants CYP2C91/1, CYP2C91/2 and genotypes GG, GA VKORC1. An HC rate depended, as a rule, on carriage of genotypes CYP2C91/3 and AA VKORC1. The highest risk of HC was associated with genotype CYP2C91/3. The results of multifactorial regression analysis also indicated that carriage of genotype CYP2C91/*3, a female gender and the range of INR in warfarin treatment > or = 2,66 are independent predictors of HC in VTEC patients on warfarin treatment.
Carriage of gene CYP2C9 and VKORC1 polymorphisms affects suppoting dose of warfarin and rate of hemorrhage in patients with VTEC in Moscow population. Frequency of HC is the highest in carriers of genotypes CYP2C9*1/3 and AA VKORC1, they need minimal supporting dose of warfarin. Carriage of genotype CYP2C91/*3 in line with a female gender and instability of INR is an independent predictor of HC in VTEC patients in Moscow population on warfarin treatment.
研究在接受华法林治疗的莫斯科人群中，静脉血栓栓塞并发症（VTEC）患者携带细胞色素P450 2C9（CYP2C9）和维生素K环氧化物还原酶复合体1（VKORC1）基因多态性的频率，以及这种携带情况对华法林抗凝稳定性和出血并发症（HC）发生率的影响。
该研究纳入了111例有深静脉血栓形成和/或肺动脉血栓栓塞病史的患者。所有患者接受普通肝素或低分子肝素治疗至少5天，然后使用华法林（目标国际标准化比值[INR]为2.0 - 3.0）。华法林剂量根据经验选择。研究了CYP2C9和VKORC1基因多态性。以HC作为研究终点。
在94例（84.7%）患者中检测到CYP2C9*1/1基因型（“野生”型）。其他基因型中，杂合子CYP2C91/2占4.5%，CYP2C91/3占10.8%。通过VKORC1基因分型，42.3%的患者检测到GG基因型（野生型），48.6%为GA基因型，9.1%为AA基因型。维持适宜INR的平均华法林剂量与CYP2C9和VKORC1基因型均有关。野生型CYP2C9和VKORC1携带者的华法林剂量最高（分别为6.9和8.8毫克/天），而CYP2C91/3和VKORC1基因型患者的剂量最低（分别为4.5和4.0毫克/天）。与CYP2C91/1、CYP2C91/2等位基因变体携带者以及GG、GA基因型VKORC1携带者相比，CYP2C91/3和VKORC1基因多态性携带者的抗凝稳定性较差。HC发生率通常取决于CYP2C91/3和VKORC1的AA基因型携带情况。HC风险最高的是CYP2C91/3基因型。多因素回归分析结果还表明，CYP2C91/*3基因型的携带、女性性别以及华法林治疗期间INR≥2.66是接受华法林治疗的VTEC患者发生HC的独立预测因素。
CYP2C9和VKORC1基因多态性的携带情况影响莫斯科人群中VTEC患者的华法林维持剂量和出血发生率。CYP2C9*1/3和VKORC1的AA基因型携带者的HC发生率最高，他们所需的华法林维持剂量最小。CYP2C91/*3基因型与女性性别以及INR不稳定共同构成接受华法林治疗的莫斯科人群中VTEC患者发生HC的独立预测因素。
