CYP2C9和VKORC1基因多态性与华法林剂量的关系
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摘要
目的探索CYP2C9和VKORC1基因多态性与川东北汉族患者华法林维持剂量的关系。方法采用荧光染色原位杂交测序法,对100例服用华法林的川东北地区汉族患者CYP2C9、VKORC1基因型进行检测并随访,评估CYP2C9、VKORC1对华法林剂量的影响。结果 100例服用华法林达维持剂量的患者中,CYP2C9 1075基因中AA型为89.0%,AC型为11.0%,CC型为0;VKORC1 1639基因中GG型为2.0%,AA型为86.0%,GA型为12.0%。各基因型所需的华法林剂量:CYP2C9 1075 AA基因型为(3.05±0.87) mg/d,AC基因型为(2.13±0.54)mg/d,VKORC1 1639 GG+GA基因型为(4.90±1.22)mg/d,AA基因型为(2.58±0.65)mg/d。不同基因型的华法林维持剂量两两相比,均具有统计学意义(P<0.05)。结论 CYP2C9和VKORC1基因多态性会影响川东北地区汉族患者华法林的剂量,检测结果可为临床治疗中调整华法林剂量提供依据。
Objective To explore the relationship between CYP2 C9 and VKORC1 gene polymorphisms and warfarin maintenance dose in northeastern Sichuan Han patients. Methods CYP2 C9 and VKORC1 genotypes were detected by using fluorescent in situ hybridizationstaining sequencing detection system from 100 unrelated Han patients in northeastern Sichuan Province, and 100 patients taking warfarin were followed up to assess the effect of CYP2 C9 and VKORC1 on warfarin dosage. Results Among 100 patients who received maintenance dose at warfarin, there is 89.0% of AA type, 11.0% of AC type and 0% of CC type in CYP2 C9 1075 gene; 2.0% of GG type, 86.0% of AA type and 12.0% of GA type in VKORC1 1639 gene. The amount of warfarin in different genotypes is as follows: 3.05 ± 0.87 mg/d of AA type, 2.13 ± 0.54 mg/d of AC type in CYP2 C9 1075 gene; 4.90 ± 1.22 mg/d of GG + GA type, 2.58 ± 0.65 mg/d of AA type in VKORC1 1639 gene. The maintenance dose of warfarin with different genotypes was respectively compared to P< 0.05, both of them were statistically significant. Conclusion CYP2 C9 and VKORC1 gene polymorphisms may affect the dose of warfarin in patients of Han nationality in northeastern Sichuan. The results of CYP2 C9 and VKORC1 gene polymorphisms may provide evidence for adjusting the dose of warfarin in clinical treatment.
Objective To explore the relationship between CYP2 C9 and VKORC1 gene polymorphisms and warfarin maintenance dose in northeastern Sichuan Han patients. Methods CYP2 C9 and VKORC1 genotypes were detected by using fluorescent in situ hybridizationstaining sequencing detection system from 100 unrelated Han patients in northeastern Sichuan Province, and 100 patients taking warfarin were followed up to assess the effect of CYP2 C9 and VKORC1 on warfarin dosage. Results Among 100 patients who received maintenance dose at warfarin, there is 89.0% of AA type, 11.0% of AC type and 0% of CC type in CYP2 C9 1075 gene; 2.0% of GG type, 86.0% of AA type and 12.0% of GA type in VKORC1 1639 gene. The amount of warfarin in different genotypes is as follows: 3.05 ± 0.87 mg/d of AA type, 2.13 ± 0.54 mg/d of AC type in CYP2 C9 1075 gene; 4.90 ± 1.22 mg/d of GG + GA type, 2.58 ± 0.65 mg/d of AA type in VKORC1 1639 gene. The maintenance dose of warfarin with different genotypes was respectively compared to P< 0.05, both of them were statistically significant. Conclusion CYP2 C9 and VKORC1 gene polymorphisms may affect the dose of warfarin in patients of Han nationality in northeastern Sichuan. The results of CYP2 C9 and VKORC1 gene polymorphisms may provide evidence for adjusting the dose of warfarin in clinical treatment.
引文
[1] 中华医学会心血管病学分会.华法林抗凝治疗的中国专家共识[J].中华内科杂志,2013,52(1):76-82.
[2] 史佩,王楠,杨立霞.华法林药物相关基因组学研究进展[J].中西医结合心血管病电子杂志,2016,4(30):20-22.
[3] Yuan HY,Chen JJ,Lee MT,et al.A novel fimetional VKORCl Promoter Polymorphism is associated with inter-individual and inter-ethnie differences in warfarin sensitivity[J].Hum MolGenet,2005,14:1745-1751.
[4] 张敏,王果,周宏激.华法林个体差异的遗传药理学因素[J].中国药理学通报,2008,24 (7):857-860.
[5] Gan GG,Phipps ME,Lee MMT,et al.Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations[J].Annals of Hematology,2011,90(6):635-641.
[6] Zhang J,Chen Z,Chen C.Impact of CYP2C9,VKORC1 and CYP4F2 genetic polymorphisms on maintenance warfarin dosage in Han-Chinese patients:A systematic review and meta-analysis[J].Meta Gene,2016,9(C):197-209.
[7] Sun X,Wanying Y U,Wanle M A,et al.Impact of the CYP4F2 gene polymorphisms on the warfarin maintenance dose:A systematic review and meta-analysis[J].Biomedical Reports,2016,4(4):498-506.
[8] Dang MT,Hambleton J,Kayser SR.The influence of ethnicity on warfarin dosage requirement[J].Ann Pharmacother,2005,39:1008-1012.
[9] Sconce EA,Khan TI,Wynne HA,et al.The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements:proposal for a new dosing regimen[J].Blood,2005,106:2329-2333.
[10] Wakamiya T,Hokosaki T,Tsujimoto SI,et al.Effect of VKORC1,CYP2C9,CFP4F2,and GGCX,Gene Polymorphisms on Warfarin Dose in Japanese Pediatric Patients[J].Molecular Diagnosis & Therapy,2016,20(4):393-400.
[11] Kou H,Rui M,Gao D,et al.GW28-e1078 Study of CYP2C9 and VKORC1 gene polymorphism on warfarin steady-state therapeutic dose and individual anticoagulation effect[J].Journal of Shanxi Medical University,2017,35(1):26-32.
[12] Ta?k?n BD,Kula S,Ergün MA,et al.The effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirements in a pediatric population[J].Anatolian Journal of Cardiology,2016,16(10):791-796.
[13] Huang TS,Zhang L,He Q,et al.DNA sensors to assess the effect of VKORC1,and CYP2C9,gene polymorphisms on warfarin dose requirement in Chinese patients with atrial fibrillation[J].Australasian Physical & Engineering Sciences in Medicine,2017,40(1):1-10.
[14] Shiitake F,McGinnis R,Bourgeois S,et al.A genome-wide association study confirms VKORC1,CYP2C9,and CYP4F2 as principal genetic determinants of warfarin dose[J].PLoS Genet,2009,5:e1000433.
[15] Caldwell MD,Berg RL,Zhang KQ,et al.Evaluation of Genetic Factors for Warfarin Dose Prediction[J].Clin Med Res,2007,5(1):8-16.
[16] Garcia D,Crowther M A,Ageno W.Practical management of coagulopathy associated with warfarin[J].Bmj,2010,340(7752):918-920.
[17] Silan C,Dogan O T,Silan F,et al.The prevalence of VKORC1,1639 G>A and CYP2C9*2*3,genotypes in patients that requiring anticoagulant therapy in Turkish population[J].Molecular Biology Reports,2012,39(12):11017-11022.
[18] Rathore SS,Agarwal SK,Pande S,et al.Frequencies of VKORC1 -1639 G>A,CYP2C9*2 and CYP2C9*3 genetic variants in the Northern Indian population[J].Bioscience Trends,2010,4(6):333.
[19] 阳丽梅,黄旭慧,王少明,等.基于CYP2C9、VKORC1及CYP4F2基因多态性的华法林给药模型的验证[J].中国医院药学杂志,2013,33(23):1957-1961.
[20] 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[J].中国心血管病研究,2016,14(7):639-642.
[21] Limdi NA,Wiener H,Goldstein JA,et al.Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy[J].Blood Cells Molecules & Diseases,2009,43(1):119-128.
[22] 刘佳,朱华,陆强,等.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[J].中国医院药学杂志,2017,37(11):1078-1081.
[2] 史佩,王楠,杨立霞.华法林药物相关基因组学研究进展[J].中西医结合心血管病电子杂志,2016,4(30):20-22.
[3] Yuan HY,Chen JJ,Lee MT,et al.A novel fimetional VKORCl Promoter Polymorphism is associated with inter-individual and inter-ethnie differences in warfarin sensitivity[J].Hum MolGenet,2005,14:1745-1751.
[4] 张敏,王果,周宏激.华法林个体差异的遗传药理学因素[J].中国药理学通报,2008,24 (7):857-860.
[5] Gan GG,Phipps ME,Lee MMT,et al.Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations[J].Annals of Hematology,2011,90(6):635-641.
[6] Zhang J,Chen Z,Chen C.Impact of CYP2C9,VKORC1 and CYP4F2 genetic polymorphisms on maintenance warfarin dosage in Han-Chinese patients:A systematic review and meta-analysis[J].Meta Gene,2016,9(C):197-209.
[7] Sun X,Wanying Y U,Wanle M A,et al.Impact of the CYP4F2 gene polymorphisms on the warfarin maintenance dose:A systematic review and meta-analysis[J].Biomedical Reports,2016,4(4):498-506.
[8] Dang MT,Hambleton J,Kayser SR.The influence of ethnicity on warfarin dosage requirement[J].Ann Pharmacother,2005,39:1008-1012.
[9] Sconce EA,Khan TI,Wynne HA,et al.The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements:proposal for a new dosing regimen[J].Blood,2005,106:2329-2333.
[10] Wakamiya T,Hokosaki T,Tsujimoto SI,et al.Effect of VKORC1,CYP2C9,CFP4F2,and GGCX,Gene Polymorphisms on Warfarin Dose in Japanese Pediatric Patients[J].Molecular Diagnosis & Therapy,2016,20(4):393-400.
[11] Kou H,Rui M,Gao D,et al.GW28-e1078 Study of CYP2C9 and VKORC1 gene polymorphism on warfarin steady-state therapeutic dose and individual anticoagulation effect[J].Journal of Shanxi Medical University,2017,35(1):26-32.
[12] Ta?k?n BD,Kula S,Ergün MA,et al.The effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirements in a pediatric population[J].Anatolian Journal of Cardiology,2016,16(10):791-796.
[13] Huang TS,Zhang L,He Q,et al.DNA sensors to assess the effect of VKORC1,and CYP2C9,gene polymorphisms on warfarin dose requirement in Chinese patients with atrial fibrillation[J].Australasian Physical & Engineering Sciences in Medicine,2017,40(1):1-10.
[14] Shiitake F,McGinnis R,Bourgeois S,et al.A genome-wide association study confirms VKORC1,CYP2C9,and CYP4F2 as principal genetic determinants of warfarin dose[J].PLoS Genet,2009,5:e1000433.
[15] Caldwell MD,Berg RL,Zhang KQ,et al.Evaluation of Genetic Factors for Warfarin Dose Prediction[J].Clin Med Res,2007,5(1):8-16.
[16] Garcia D,Crowther M A,Ageno W.Practical management of coagulopathy associated with warfarin[J].Bmj,2010,340(7752):918-920.
[17] Silan C,Dogan O T,Silan F,et al.The prevalence of VKORC1,1639 G>A and CYP2C9*2*3,genotypes in patients that requiring anticoagulant therapy in Turkish population[J].Molecular Biology Reports,2012,39(12):11017-11022.
[18] Rathore SS,Agarwal SK,Pande S,et al.Frequencies of VKORC1 -1639 G>A,CYP2C9*2 and CYP2C9*3 genetic variants in the Northern Indian population[J].Bioscience Trends,2010,4(6):333.
[19] 阳丽梅,黄旭慧,王少明,等.基于CYP2C9、VKORC1及CYP4F2基因多态性的华法林给药模型的验证[J].中国医院药学杂志,2013,33(23):1957-1961.
[20] 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[J].中国心血管病研究,2016,14(7):639-642.
[21] Limdi NA,Wiener H,Goldstein JA,et al.Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy[J].Blood Cells Molecules & Diseases,2009,43(1):119-128.
[22] 刘佳,朱华,陆强,等.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[J].中国医院药学杂志,2017,37(11):1078-1081.