Cardiovascular Department, Intermountain Medical Center, 5121 South Cottonwood Street, Murray, UT 84157, USA.
J Thromb Thrombolysis. 2010 Oct;30(3):358-64. doi: 10.1007/s11239-010-0467-3.
Warfarin anticoagulation is complicated by the highly variable inter-individual response. Approximately 50% of the dose variability arises from clinical factors and variants in two genes, CYP2C9 (*2 and 3 variants) and VKORC1 -1173 C > T. We tested variants in five additional genes (EPHX1, PROC, APOE, CYP4F2, CALU and a new variant in VKORC1 in an attempt to further reduce the variability in predicted stable warfarin dose. Consecutive consenting outpatients requiring anticoagulation on stable warfarin dose (target INR 2-3) were genotyped; the association of SNP genotypes with stable warfarin dose was evaluated using the test of linear contrasts in analysis of variance (ANOVA). Study participants were 71 ± 13 years, 53% female, 85 ± 23 kg, body mass index 29 ± 7 kg/m(2). Genotypes were in Hardy-Weinberg equilibrium with the exception of VKORC1 -1639. Weekly stable dosages were 31.7 ± 13.9 mg/week; median: 30 mg/week, range: 11-70 mg/week. Significant associations with dose were seen for VKORC1 -1639 (P < 0.001), CYP2C92 (P = 0.005) and *3 (P = 0.003), the CYP4F2 SNP (P-trend = 0.00037), and VKORC1 3730 (p-trend = 0.042). In linear regression, age, sex, weight, and CYP2C9 *2 and *3 and VKORC1-1639 genotype explained 42% of variance. The addition of CYP4F2 genotype to the regression model increased the degree of variance explained to 47%. Addition of VKORC1 SNP -1639 to a model eliminated the association of VKORC1 3730 with warfarin dose (P-trend = 0.74), but -1639 remained highly significant. No impact on dose was observed for the other tested genetic variants.
华法林抗凝治疗的个体反应差异很大。大约 50%的剂量差异是由临床因素和两个基因（CYP2C92 和3 变异体）和 VKORC1-1173C>T 变异引起的。我们检测了另外五个基因（EPHX1、PROC、APOE、CYP4F2、CALU 和 VKORC1 中的一个新变异体）的变异体，试图进一步降低预测稳定华法林剂量的变异性。连续同意接受稳定华法林剂量（目标 INR 2-3）抗凝治疗的门诊患者进行基因分型；使用方差分析（ANOVA）中的线性对比检验评估 SNP 基因型与稳定华法林剂量的关联。研究参与者为 71±13 岁，53%为女性，85±23kg，体重指数 29±7kg/m2。除 VKORC1-1639 外，基因型均符合 Hardy-Weinberg 平衡。每周稳定剂量为 31.7±13.9mg/周；中位数：30mg/周，范围：11-70mg/周。与剂量显著相关的有 VKORC1-1639（P<0.001）、CYP2C92（P=0.005）和3（P=0.003）、CYP4F2 SNP（P-趋势=0.00037）和 VKORC13730（p-趋势=0.042）。在线性回归中，年龄、性别、体重以及 CYP2C92 和3 和 VKORC1-1639 基因型解释了 42%的变异。将 CYP4F2 基因型加入回归模型增加了解释变异的程度至 47%。将 VKORC1 SNP-1639 加入模型消除了 VKORC13730 与华法林剂量的关联（P-趋势=0.74），但-1639 仍然具有高度显著性。其他测试的遗传变异体对剂量没有影响。
