基因多态性对华法林谷浓度及维持剂量的影响

Effects of Gene Polymorphisms on Warfarin Trough Concentration and Maintenance Dose

关键词:  华法林  维持剂量  谷浓度  基因多态性  房颤

Key words:  warfarin  maintenance dose  trough concentrations  gene polymorphisms  atrial fibrillation

摘要:

目的 探讨VKORC1（-1639G/A）、CYP2C9*3、CYP4F2（rs2108622）和CYP2C19*2基因多态性在中国心房颤动群体中的表达，分析其对房颤患者华法林谷浓度及维持剂量的影响。方法 收集75例房颤患者的华法林血样，采用HPLC-UV测定其谷浓度，PCR-RFLP法检测VKORC1（-1639G/A）、CYP2C9*3、CYP4F2（rs2108622）和CYP2C19*2基因分型。明确基因多态性对华法林谷浓度及维持剂量的影响。结果 华法林稳态谷浓度在0.5~<1.0，1.0~2.0，>2.0 μg·mL^-1时，其临床有效率分别为69.23%，82.6%，63.41%，显著高于谷浓度<0.5 μg·mL^-1时的48.39%（P<0.05），且华法林浓度0.5~<1.0 μg·mL^-1与>2.0 μg·mL^-1的临床有效率相近。VKORC1（-1639G/A）、CYP2C9*3、CYP4F2（rs2108622）和CYP2C19*2等位基因频率分别为8.65%，7.35%，20%，30%。VKORC1位点AA型、CYP4F2位点CC型患者华法林稳态谷浓度分别低于AG/GG及CT/TT型患者（P<0.01），而CYP2C9*3、CYP2C19*2各基因型间对华法林稳态谷浓度无显著差异。携带AG/GG、CT/TT型和野生型（*1/*1）的患者，华法林维持剂量分别高于携带AA型、CC型和杂合型（*1/*3）的患者（P<0.01），而CYP2C19*2各基因型间与华法林维持剂量无显著差异。结论 VKORC1（-1639G/A）、CYP2C9*3、CYP4F2（rs2108622）基因多态性显著影响房颤患者华法林的维持剂量，且VKORC1（-1639G/A）、CYP4F2（rs2108622）基因多态性与房颤患者华法林谷浓度密切相关。

Abstract:

OBJECTIVE To investigate the distribution of VKORC1(-1639G/A), CYP2C9*3, CYP4F2(rs2108622) and CYP2C19*2 gene polymorphism in China population with atrial fibrillation, and then clarify its effect on Trough concentration and maintenance dose of warfarin. METHODS Warfarin blood samples were collected from 75 patients with atrial fibrillation, the trough concentrations were detected by HPLC-UV and genotypes were measured by PCR-RFLP method. The association between different genotypes on concentration and maintenance dose of warfarin were analyzed. RESULTS Warfarin with trough concentrations of 0.5-<1.0 μg·mL^-1, 1.0-2.0 μg·mL^-1 and >2.0 μg·mL^-1 showed higher curative effect(69.23%, 82.6%, 63.41%) than that with 0.5 μg·mL^-1(48.39%) (P<0.05), while between 0.5-<1.0 μg·mL^-1 and >2.0 μg·mL^-1 showed similar curative effect. The allele frequency of VKORC1(-1639G/A), CYP2C9*3, CYP4F2(rs2108622) and CYP2C19*2 were 8.65%, 7.35%, 20%, 30%, respectively. Significant difference of warfain trough concentrations were observed between VKORC1 (-1639G/A) AA and AG/GG as well as CYP4F2(rs2108622) CC and CT/TT genotype(P<0.01), while not among those with CYP2C9*3 and CYP2C19*2 genotypes. Maintenance dose of warfarin in patients with VKORC1(-1639G/A) AG/GG, CYP2C9*3 *1/*1 and CYP4F2(rs2108622) CT/TT were significantly higher than those with VKORC1(-1639G/A) AA, CYP2C9*3 *1/*3 and CYP4F2(rs2108622) CC genotype(P<0.01), respectively. However, there was no statistical significance in those with CYP2C19*2 genotypes. CONCLUSION VKORC1(-1639G/A), CYP2C9*3 and CYP4F2(rs2108622) gene polymorphism significantly affect the maintenance warfarin dose of patients with atrial fibrillation. Furthermore, VKORC1 (-1639G/A) and CYP4F2(rs2108622) gene polymorphism have a close effect on warfarin trough concentration.