CYP2C9和VKORC1基因多态性对华法林剂量的影响研究
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摘要
目的探究细胞色素氧化酶2C9(CYP2C9)基因和维生素K环氧化物还原酶复合物1基因(VKORC1)-1639 G/A多态性对华法林初始抗凝剂量的影响。方法 200例使用华法林患者,观察患者使用华法林5～7 d后凝血酶原时间(PT)和国际标准化比值(INR),记录患者服用华法林初次达标天数、总用量和平均每日用量,同时测定患者CYP2C9位点基因型(*1、*2、*3)和VKORC1-1639位点基因型(AA、AG、GG)。结果 CYP2C9*1、CYP2C9*2/*3 VKORC1-1639 AG/GG基因型患者初次达标天数分别为(14.47±1.52)、(9.77±0.91)d,总用量分别为(115.13±11.47)、(56.31±5.49)mg,平均每日用量分别为(5.22±0.53)、(4.36±0.44)mg, CYP2C9*1、CYP2C9*2/*3 VKORC1-1639 AA基因型患者初次达标天数分别为(9.24±0.94)、(5.37±0.52)d,总用量分别为(52.37±5.14)、(15.56±1.42)mg,平均每日用量分别为(3.02±0.35)、(3.21±0.36)mg;CYP2C9*1、CYP2C9*2/*3 VKORC1-1639 AG/GG基因型患者初次达标天数均长于CYP2C9*1、CYP2C9*2/*3 VKORC1-1639 AA基因型患者,总用量及平均每日用量均大于CYP2C9*1、CYP2C9*2/*3 VKORC1-1639 AA基因型患者,差异有统计学意义(P<0.05)。结论对于服用华法林的患者,对CYP2C9、VKORC1-1639基因多态性的测定具有重要指导价值,能帮助临床实施个体化用药,值得临床应用与推广。
Objective To investigate the effect of cytochrome oxidase 2 C9(CYP2 C9) gene and vitamin K epoxide reductase complex 1(VKORC1)-1639 G/A polymorphism on the initial anticoagulant dose of warfarin. Methods There were 200 patients treated with warfarin. Their prothrombin time(PT) and international normalized ratio(INR) were observed after 5～7 d of warfarin, and first standard-reaching day of warfarin administration, total dosage and daily dosage of warfarin were recorded. The genotypes of CYP2 C9(* 1, * 2, * 3) and VKORC1-1639(AA, AG, GG) were also determined at the same time. Results Patients with CYP2 C9*1 and CYP2 C9*2/*3 VKORC1-1639 AG/GG genotypes had first standard-reaching day respectively as(14.47±1.52),(9.77±0.91)d, total dosage respectively as(115.13±11.47),(56.31±5.49)mg, and mean daily dosage respectively as(5.22±0.53),(4.36±0.44)mg. Patients with CYP2 C9*1 and CYP2 C9*2/*3 VKORC1-1639 AA genotypes had first standard-reaching day respectively as(9.24±0.94)、(5.37±0.52)d, total dosage respectively as(52.37±5.14),(15.56±1.42)mg, and mean daily dosage respectively as(3.02±0.35),(3.21±0.36)mg. Patients with CYP2 C9*2/*3 VKORC1-1639 AG/GG genotypes had longer first standard-reaching day than patients with CYP2 C9*1 and CYP2 C9*2/*3 VKORC1-1639 AA genotypes, and more total dosage and mean daily dosage than patients with CYP2 C9*1 and CYP2 C9*2/*3 VKORC1-1639 AA genotypes. Their difference was statistically significant(P<0.05).. Conclusion For the patients taking warfarin, it has important guiding value for the determination of CYP2 C9 and VKORC1-1639 gene polymorphism, and can help to implement individualized drug use in clinic. It is worthy of clinical application and promotion.
Objective To investigate the effect of cytochrome oxidase 2 C9(CYP2 C9) gene and vitamin K epoxide reductase complex 1(VKORC1)-1639 G/A polymorphism on the initial anticoagulant dose of warfarin. Methods There were 200 patients treated with warfarin. Their prothrombin time(PT) and international normalized ratio(INR) were observed after 5～7 d of warfarin, and first standard-reaching day of warfarin administration, total dosage and daily dosage of warfarin were recorded. The genotypes of CYP2 C9(* 1, * 2, * 3) and VKORC1-1639(AA, AG, GG) were also determined at the same time. Results Patients with CYP2 C9*1 and CYP2 C9*2/*3 VKORC1-1639 AG/GG genotypes had first standard-reaching day respectively as(14.47±1.52),(9.77±0.91)d, total dosage respectively as(115.13±11.47),(56.31±5.49)mg, and mean daily dosage respectively as(5.22±0.53),(4.36±0.44)mg. Patients with CYP2 C9*1 and CYP2 C9*2/*3 VKORC1-1639 AA genotypes had first standard-reaching day respectively as(9.24±0.94)、(5.37±0.52)d, total dosage respectively as(52.37±5.14),(15.56±1.42)mg, and mean daily dosage respectively as(3.02±0.35),(3.21±0.36)mg. Patients with CYP2 C9*2/*3 VKORC1-1639 AG/GG genotypes had longer first standard-reaching day than patients with CYP2 C9*1 and CYP2 C9*2/*3 VKORC1-1639 AA genotypes, and more total dosage and mean daily dosage than patients with CYP2 C9*1 and CYP2 C9*2/*3 VKORC1-1639 AA genotypes. Their difference was statistically significant(P<0.05).. Conclusion For the patients taking warfarin, it has important guiding value for the determination of CYP2 C9 and VKORC1-1639 gene polymorphism, and can help to implement individualized drug use in clinic. It is worthy of clinical application and promotion.
引文
[1]陈晓英,彭齐,胡大清,等. CYP2C9及VKORC1基因多态性对华法林稳态剂量和模型预测剂量的相关性研究.华中科技大学学报(医学版), 2015, 44(1):92-95.
[2]寇惠娟,邓捷,朱参战,等. CYP2C9和VKORC1基因多态性对华法林稳态治疗剂量及个体化抗凝疗效的影响.山西医科大学学报, 2017, 48(11):20-25.
[3]赵晓丽,史琼华,黄宏伟,等.云南地区汉族人群CYP2C9和VKORC1基因多态性研究.重庆医学, 2018, 47(8):1052-1054.
[4]安琳娜,曹红,林筱琦.新疆维吾尔族患者CYP2C9和VKORC1基因多态性分布及不同种族间的比较.中国药房,2015, 36(24):3332-3334.
[5]肖成,胡莹,王玉明,等.昆明汉族人群VKORC1、CYP2C9基因多态性对华法林稳态剂量的影响及预测剂量模型的建立.山东医药, 2018, 58(10):21-24.
[6]Zhuang W, Wen W, Xuan B, et al. Effect of CYP2C9, CYP4F2and VKORC1 genetic polymorphisms on pharmacokinetics and pharmacodynamics of mean daily maintenance dose of warfarin in Chinese patients. Blood Coagulation&Fibrinolysis, 2015,26(2):167-174.
[7]赵红丽,李潞,张晓丹,等.非瓣膜病心房颤动患者VKORC1及CYP2C9基因多态性与华法林临床应用的关系.实用医学杂志, 2016, 32(11):1777-1779.
[8]Villegas-Torres B, Sánchez-Girón F, Jaramillo-Villafuerte K, et al. Genotype frequencies of VKORC1 and CYP2C9 in native and Mestizo populations from Mexico, potential impact for coumarin dosing. Gene, 2015, 558(2):235-240.
[9]柴树红,陈丽,谷苞,等.荧光PCR-熔解曲线法检测新疆回族人群CYP2C9和VKORC1基因多态性研究.国际检验医学杂志, 2016, 37(17):2371-2373.
[10]Lin G, Yi L, Zhang K, et al. Improvements in CYP2C9 Genotyping Accuracy Are Needed:A Report of the First Proficiency Testing for Warfarin-related CYP2C9 and VKORC1 Genotyping in China.Journal of Cardiovascular Pharmacology, 2015, 66(2):129-134.
[11]张晓丹,赵红丽,李潞,等.非瓣膜病房颤患者VKORC1与CYP2C9基因多态性华法林抗凝剂量模型临床疗效评价.中国心血管病研究, 2016, 14(7):639-642.
[2]寇惠娟,邓捷,朱参战,等. CYP2C9和VKORC1基因多态性对华法林稳态治疗剂量及个体化抗凝疗效的影响.山西医科大学学报, 2017, 48(11):20-25.
[3]赵晓丽,史琼华,黄宏伟,等.云南地区汉族人群CYP2C9和VKORC1基因多态性研究.重庆医学, 2018, 47(8):1052-1054.
[4]安琳娜,曹红,林筱琦.新疆维吾尔族患者CYP2C9和VKORC1基因多态性分布及不同种族间的比较.中国药房,2015, 36(24):3332-3334.
[5]肖成,胡莹,王玉明,等.昆明汉族人群VKORC1、CYP2C9基因多态性对华法林稳态剂量的影响及预测剂量模型的建立.山东医药, 2018, 58(10):21-24.
[6]Zhuang W, Wen W, Xuan B, et al. Effect of CYP2C9, CYP4F2and VKORC1 genetic polymorphisms on pharmacokinetics and pharmacodynamics of mean daily maintenance dose of warfarin in Chinese patients. Blood Coagulation&Fibrinolysis, 2015,26(2):167-174.
[7]赵红丽,李潞,张晓丹,等.非瓣膜病心房颤动患者VKORC1及CYP2C9基因多态性与华法林临床应用的关系.实用医学杂志, 2016, 32(11):1777-1779.
[8]Villegas-Torres B, Sánchez-Girón F, Jaramillo-Villafuerte K, et al. Genotype frequencies of VKORC1 and CYP2C9 in native and Mestizo populations from Mexico, potential impact for coumarin dosing. Gene, 2015, 558(2):235-240.
[9]柴树红,陈丽,谷苞,等.荧光PCR-熔解曲线法检测新疆回族人群CYP2C9和VKORC1基因多态性研究.国际检验医学杂志, 2016, 37(17):2371-2373.
[10]Lin G, Yi L, Zhang K, et al. Improvements in CYP2C9 Genotyping Accuracy Are Needed:A Report of the First Proficiency Testing for Warfarin-related CYP2C9 and VKORC1 Genotyping in China.Journal of Cardiovascular Pharmacology, 2015, 66(2):129-134.
[11]张晓丹,赵红丽,李潞,等.非瓣膜病房颤患者VKORC1与CYP2C9基因多态性华法林抗凝剂量模型临床疗效评价.中国心血管病研究, 2016, 14(7):639-642.