基因多态性对华法林低强度抗凝治疗稳定剂量影响的前瞻性研究

摘要

目的 对影响华法林代谢及作用的多个相关基因进行测定,探讨其对中国人群低强度华法林抗凝稳定剂量的影响程度.方法 共纳入170名拟采取低强度华法林抗凝治疗患者,对其与华法林代谢及作用相关的3个基因CYP2C9(rs1057910)、VKORC1(rs9923231)、CYP4F2 (rs2108622)位点的基因多态性(SNP)进行检测,随后给予华法林治疗,目标国际标准化比值(INR)1.8~2.5,观察90天,同时记录患者的临床因素、INR值及华法林稳定剂量,分别判断临床及基因因素对华法林稳定剂量水平的影响作用.结果 CYP2C9、VKORC1、CYP4F2的5个SNP位点的SNP对华法林稳定剂量存在显著影响(P＜0.05).经多元回归分析,年龄、体表面积、抗凝第4天INR值以及CYP2C9、VKORC1、CYP4F2 的SNP是华法林抗凝稳定剂量的独立影响因素;其中SNP可以独立解释18.6%的华法林稳定剂量的差异.结论 在目标强度为INR1.8~2.5的低强度华法林抗凝治疗中,CYP2C9(rs1057910)、VKORC1(rs9923231)、CYP4F2 (rs2108622)多态性对稳定剂量存在显著影响,可在临床工作中对上述3个SNP位点进行检测,对抗凝初期华法林的剂量进行预先调整.%Objective To detect the influences of multiple relative genes on warfarin metabolism and actions, and explore their influencing degree on the stable doses of warfarin low intensity anticoagulation in Chinese population. Methods The patients ( n=170 ) planed to be treated with warfarin low intensity anticoagulation were chosen, and gene polymorphisms ( SNP ) in 3 sites of genes related to warfarin metabolism and actions including CYP2C9 ( rs1057910 ) , VKORC1 ( rs9923231 ) and CYP4F2 ( rs2108622 ) were detected in the patients. Then the patients were treated with warfarin with target value of International Normalized Ratio (INR ) from 1.8 to 2.5 and observed for 90 days. The clinical factors, INR values and stable doses of warfarin were recorded, and influencing effects of clinical and genetic factors on stable doses of warfarin were evaluated. Results The SNP of CYP2C9, VKORC1 and CYP4F2 in 3 sites had significant influences on the stable doses of warfarin ( P<0.05 ) . The multiple regression analysis showed that age, body surface area, INR value on the 4th day of anticoagulation and SNP of CYP2C9, VKORC1 and CYP4F2 were independent influencing factors on the stable doses of warfarin, among which SNP explained independently the difference in 18.6% stable doses of warfarin. Conclusion In the warfarin low intensity anticoagulation treatment with target value of INR from 1.8 to 2.5, SNP of CYP2C9, VKORC1 and CYP4F2 have significant influences on the stable doses of warfarin. The above-mentioned 3 sites of SNP can be detected for regulating in advance the doses of warfarin in early anticoagulative stage.