非遗传因素与基因多态性对华法林临床用药稳定维持剂量的影响

Influence of genetic polymorphisms and non-genetic factors on the maintenance dose of warfarin

目的评价非遗传因素和基因多态性对中国人群患者华法林用药稳定剂量的影响，为华法林个体化用药提供临床指导。方法选取正在服用华法林进行抗凝、连续2次国际标准化比值（internationalnormalizedratio，INR）达标的门诊及住院患者200人，记录其基本信息和临床用药情况，用Sanger直接测序法进行4种基因共8种多态性的检测，用统计学分析评价遗传与非遗传因素对华法林用药剂量的影响并建立数学模型。结果在非遗传因素中，年龄和身高对华法林用药剂量有显著的影响，用药剂量随年龄增长有降低的趋势，而随身高的增长有升高的趋势。20岁年龄组与60岁年龄组华法林用药剂量差异达到1．81mg／天，身高140cm组与180cm组的用药剂量差异达1．06mg／天。在遗传因素中，VKORCI-1639G／A位点、CyP2C9430c／T位点、CYP2C9107SA／c位点、Cyf）4F2V433M位点对华法林用药剂量有显著影响，野生型和突变型患者华法林用药剂量的差异从0．35mg／天到0．84mg／天不等。结论遗传和非遗传因素均为影响华法林个体化用药的重要因素，临床上应尽可能全面地考虑这些因素。建立合理的华法林稳定剂量的预测算法对华法林用药的安全性和有效性具有重要的意义。

Objective To assess the influence of genetic polymorphisms and non-genetic factors on warfarin maintenance dose variations in order to provide guidance for personalized use of warfarin. Methods Two hundred patients from outpatient and inpatient with stable international normalized ratio（INR） were recruited. Clinical data and blood samples were collected. Genotypes of 4 genes involved in warfarin metabolic pathways were determined with Sanger sequencing. Based on statistical analysis of warfarin maintenance dosage, a mathematical model was established. Results Among non-genetic factors, the age and height have significant influence in warfarin dosage. The dosage is negatively correlated with age but positively correlated with height. The difference in dosage for between the 2~3-year-old group and 60-year-old group has reached 1.81 mg/day, and that for between the 140 cm in height and 180 cm in height groups has reached 1.06 mg/day. VKORC1 -- 1639G/A, CYPgC9 430C/T, CYP2C9 1075A/C and CYP4F2 V433M polymorphisms have significant influence on stable warfarin dosage. The dosage for patients with wild type and mutant genotypes has varied from 0.35 mg/day to 0.84 mg/day. Conclusion Non-genetic factors and genetic polymorphisms play important roles in personalized variations of warfarin maintenance dose. The establishment of mathematical models considering multiple factors is helpful in evaluating the safety and effectiveness of warfarin dosage.