CYP2C9与CYP2C19基因多态性对老年非瓣膜性心房颤动患者华法林维持剂量影响

The effects of CYP2C9 and CYP2C19 gene polymorphisms on maintenance dosage of Warfarin in elderly patients with nonvalvular atrial fibrillation

目的探讨CYP2C9与CYP2C19基因多态性对老年非瓣膜性心房颤动(NVAF)患者华法林疗效的影响。方法选取自2013年6月至2015年6月解放军305医院收治的156例老年NVAF患者为研究对象。利用限制性酶切片长度多态性法检测PCR产物。根据CYP2C9和CYP2C19的基因多态性将患者分为4种:CYP2C9野生型(CYP2C9*1*1)、CYP2C9突变型(CYP2C9*3)、CYP2C19野生型(CYP2C19*1*1)、CYP2C19突变型(CYP2C19*2或CYP2C19*3)。根据基因变异情况分为2个基因均无变异、2个基因均有变异、只有CYP2C9基因变异及只有CYP2C19基因变异。记录患者国际标准化比值(INR)首次达标的时间、华法林总用量及平均每日用量。结果 CYP2C9野生基因型患者的INR首次达标时间较突变型患者明显延长,且INR首次达标时所需的华法林总量高于突变型患者,差异有统计学意义(P<0.05);CYP2C19突变基因型患者的INR初次达标天数、华法林达标时总用量及达标平均日用量与野生型患者比较均有所降低,差异无统计学意义(P>0.05);CYP2C9和CYP2C19基因均变异的患者INR首次达标天数、华法林总剂量及平均日用量均低于其他患者,差异有统计学意义(P<0.05);只有CYP2C9基因变异的患者首次INR达标时所需的华法林总剂量和平均日用量减少,与2个基因均无变异的患者比较,差异有统计学意义(P<0.05);而CYP2C9和CYP2C19基因同时变异的患者与只有CYP2C9基因变异患者比较,INR首次达标的平均时间缩短,差异有统计学意义(P<0.05),需要的华法林总剂量及平均日用量有减少的趋势,差异无统计学意义(P>0.05)。结论 CYP2C9基因多态性是影响华法林维持剂量重要的遗传因素,而CYP2C19的基因多态性对华法林的维持剂量影响较小,可根据患者基因型的不同合理分配华法林剂量。

Objective To investigate the effect of cytochrome P450 2 C（ CYP2 C9 and CYP2 C19） polymorphisms on anticoagulant intensity of Warfarin in elderly patients with nonvalvular atrial fibrillation（ NVAF）. Methods A retrospective study was performed on156 cases of elderly NVAF patients who were admitted from June 2013 to June 2015. PCR products were detected via using restriction enzyme section length polymorphism. According to CYP2 C9 and CYP2 C19 polymorphisms,patients were divided into 4 groups：CYP2 C9 wild type group（ CYP2 C9＊ 1＊ 1）,CYP2 C9 mutated type group（ CYP2 C9＊ 3）,CYP2 C19 wild type group（ CYP2 C19＊ 1＊ 1） and CYP2 C19 mutated type group（ CYP2 C19＊ 2 or CYP2 C19＊ 3）. According to the genetic variation,there were two genes that are not mutated,2 genes are mutated,only CYP2 C9 gene variants and only CYP2 C19 gene variants. The time of INR for the first time,the total amount of warfarin and the average daily dose were recorded. Results Patients carrying CYP2 C9 wild type had increased time to the first INR reach target value（ P〈0. 05）,the total Warfarin doses and average daily dose when INR first reached target value were higher than the patients carrying CYP2 C9 mutated type（ P〈0. 05）. In the patients with CYP2 C19 mutation,the time of first INR reach target value,the total Warfarin doses and the average daily dosage were lower than those in the patients with wild type,while there was no statistically significant difference（ P〉0. 05）. Patients carrying CYP2 C9 and CYP2 C19 mutated type had the shortest time to the first INR reach target value,and the total Warfarin doses and average daily dose was the lowest（ P〈0. 05）. Patients carrying CYP2 C9 mutated type had reduced total Warfarin doses and average daily dose when INR first reached target value,compared with the other patients without mutated type,the difference was statistically significant（ P〈0. 05）. CYP2 C9 and CYP2 C19 gene mutation of patients compared to patients with only with the CYP2 C9 gene mutation,the average time of the first INR reach target value,total dose of Warfarin and average daily dosage had a reduced tendency,while had no statistically significant difference（ P〉0. 05）,considering the related to the small sample size. Conclusion The gene polymorphisms of CYP2 C9 are significant hereditary factors influencing Warfarin dose. However,the gene polymorphisms of CYP2 C19 has little influence on Warfarin dose,the Warfarin dose can be allocated according to the different genotypes of patients.