细胞色素P450酶2C9和维生素K环氧化物还原酶复合体1基因多态性对瓣膜置换术后华法林剂量影响分析

Effects of CYP2C9 and VKORC1 Genetic Polymorphisms on Maintenance Dosage of Warfarin in Patients after Undergoing Mechanical Heart Valve Prostheses Replacement

目的分析细胞色素P450酶2C9(CYP2C9)和维生素K环氧化物还原酶复合体1(VKORC1)基因多态性对瓣膜置换术后华法林剂量的影响。方法选取自2015年3月—2017年12月期间于漯河市中心医院行瓣膜置换术后口服华法林的127例患者为研究对象。采用PCR-RFLP法分别检测其CYP2C9和VKORC1基因型,同时记录患者的华法林日均服用剂量、血浆总浓度及游离浓度。对不同基因型及临床特征与华法林日常服用剂量进行直线相关及多元回归分析。结果华法林日均服用剂量对比,CYP2C9(1061A/C)基因型AA患者显著高于基因型AC患者(P<0.05),VKORC1(1639 G/A)基因型AA患者显著低于基因型AG患者(P<0.05),VKORC1(1173 C/T)基因型TT患者显著低于基因型CT患者(P<0.05)。华法林血浆总浓度及游离浓度对比,VKORC1 (1639 G/A)基因型AA患者显著低于基因型AG患者(P<0.05),VKORC1(1173 C/T)基因型TT患者显著低于基因型CT患者(P<0.05)。女性患者的华法林日均服用剂量显著低于男性患者(P<0.05),≥70岁和60~69岁患者显著低于60岁以下各年龄段(P<0.05)。直线相关分析及多元回归分析结果提示,华法日均服用剂量与CYP2C9、VKORC1基因型和年龄、性别相关(P<0.05)。结论 CYP2C9和VKORC1基因多态性与瓣膜置换术后华法林日常服用剂量个体化相关,同时年龄和性别也是影响因素之一。

Objective To evaluate the effects of CYP2 C9 and VKORC1 Genetic Polymorphisms on Maintenance Dosage of Warfarin in Patients after Undergoing Mechanical Heart Valve Prostheses Replacement.Methods A total of 127 patients taking Warfarin after cardiac valve replacement in our hospital from March of 2015 to December of 2017 were recruited in this study, and clinical indexes such as age, gender, the average daily dose of warfarin and plasma concentration of warfarin dosage were recorded. Genotypes of CYP2 C9 and VKORC1 were detected with polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)technique, and straight line correlation analysis between genotypes and clinical characteristics and multivariate logistic analysis with stable Warfarin dosage were performed. Results Maintenance dose of warfarin in patients with CYP2 C9 1061 A/C AA type was significantly higher than those with CYP2 C9 1061 A/C AC type(P < 0.05). Maintenance dose of warfarin in patients with VKORC1-1639 G/A AG type was significantly higher than those with VKORC1-1639 G/A AA type(P < 0.05). Maintenance dose of warfarin in patients with VKORC1-1173 C/T CT type was significantly higher than those with VKORC1-1173 C/T TT type(P < 0.05).Significant differences of plasma warfarin concentration were also observed between VKORC1-1639 G/A AA and AG as well as VKORC1-1173 C/T TT and CT genotypes(P < 0.05), but not in those with CYP2 C9 1061 A/C genotypes. The average daily dose of warfarin was significantly higher in male patients than in females(P < 0.05). The maintenance dose of warfarin was also significantly higher in patients under 60 years old than those aged above 60 years(P < 0.05). Correlation and multivariate logistic analyses showed that there were statistically significant differences between stable Warfarin dosage with age,gender and different genotypes. Conclusion CYP2 C9 and VKORC1 genotypes also have a close relationship with warfarin plasma concentration,gender and age are the important influencing factors on warfarin daily dose.