VKORC1、CYP2C9、CYP4F2、EPHX1基因多态性对华法林剂量的影响

目的:探讨中国汉族人群VKORC1、CYP2C9、CYP4F2和EPHX1基因多态性对华法林剂量的影响。方法:采用限制性片段多态性技术和碱基淬灭探针技术检测197名心脏机械瓣膜置换术后患者的VKO RC1-1639G>A、CYP2C9 1075A>C、CYP4F2 rs2108622和EPHX1 rs2292566的基因多态性,结合患者的临床特征,分析各因素对华法林剂量的影响。结果:VKO RC1-1639G>A、CYP2C9 1075A>C、CYP4F2 rs2108622、EPHX1 rs2292566基因多态性以及体重和年龄分别解释了30.2%、7.0%、2.8%、3.6%、1.9%和1.7%的华法林个体剂量差异,多因素联合可解释46.7%的华法林个体剂量差异。结论:VKORC1-1639G>A和CYP2C9 1075A>C基因多态性是影响华法林稳定剂量重要的遗传因素;CYP4F2 rs2108622和EPHX1 rs2292566基因多态性以及年龄、体重对华法林的稳定剂量有影响,但较小。     

细胞色素P450酶4F2基因多态性对华法林剂量影响的研究

目的：探讨中国苏南地区心脏机械瓣膜置换术后汉族人群细胞色素P450酶4F2（CYP4F2）基因rs2108622多态性对华法林剂量的影响,为以后利用基因多态性指导临床合理用药提供进一步理论依据。方法：采用碱基淬灭探针技术,检测197名心脏机械瓣膜置换术后患者的CYP4F2 rs2108622的基因型,分析与华法林剂量的相关性及影响。结果：CYP4F2 rs2108622基因多态性检测有115例CC型纯合子,73例CT型杂合子,9例TT型突变纯合子;等位基因频率为C 76.9%,T 23.1%;CC型患者华法林的平均稳定剂量为（2.51±0.82）mg·d^-1,CT型为（2.74±0.96）mg·d^-1,TT型为（3.20±1.22）mg·d^-1,采用方差分析方法得到各组间华法林剂量差异P值小于0.05,有显著性差异。结论：在苏南地区心脏机械瓣膜置换术后汉族人群中,CYP4F2 rs2108622基因多态性与华法林剂量相关性有显著性差异,对华法林剂量有影响。     

CYP4F2、CYP2C9和VKORC1基因多态性对中国汉族非瓣膜性房颤患者使用华法林剂量的影响

目的：探讨CYP4F2等基因多态性及临床特征对中国汉族非瓣膜性房颤患者华法林剂量的影响。方法：采用连接酶检测反应（LDR）检测CYP2C9＊3、VKORC11173和CYP4F2的基因型。多元线性回归分析CYP4F2等基因多态性及临床特征对中国汉族非瓣膜性房颤患者华法林剂量个体差异的影响。结果：CYP4F2TT患者的华法林剂量显著高于野生型患者（[3.04±0.98）mgvs.（2.60±0.84）mg,P=0.034）];CYP2C9＊3、VKORC11173和CYP4F2的基因多态性、年龄、体重、血栓史、联合应用胺碘酮以及β受体阻滞药解释了51.7%的华法林剂量个体差异,其中CYP4F2的基因多态性的贡献率为4.8%。结论：CYP4F2的基因多态性对中国汉族非瓣膜性房颤患者的华法林剂量有显著影响;基于临床特征与基因多态性的个体化给药方案可能有助于进一步提高非瓣膜性房颤患者的抗凝安全性。     

北方地区老年患者VKORC1、CYP2C9、CYP4F2基因多态性对华法林抗凝效果的影响

目的:观察VKORC1、CYP2C9、CYP4F2基因多态性对北方地区机械瓣膜置换术后老年患者(60~75岁)华法林抗凝作用的影响。方法:研究纳入68例在北京安贞医院接受机械瓣膜置换术后华法林抗凝治疗的北方地区老年患者,同期入组68例接受瓣膜置换术后中青年患者(18~59岁),用Illumina SNP Golden Gate芯片技术检测患者VKORC1、CYP2C9、CYP4F2单核苷酸多态位点,随机抽取20%样本用Sanger法直接测序验证,统计分析各组患者华法林抗凝指标差异和老年组患者3种基因位点多态性与华法林稳定剂量的相关性。结果:136例患者VKORC1 rs9923231、CYP2C9 rs1057910、CYP4F2 rs2108622基因分布符合遗传平衡,老年组患者华法林日均稳定剂量(2.89±1.00)mg·d~(-1)显著低于中青年组(3.29±0.90)mg·d~(-1)(P<0.05)。老年患者携带VKORC1 rs9923231 CT突变型患者华法林稳定剂量(3.56±0.89)mg·d~(-1)显著高于TT纯合型患者(2.72±0.96)mg·d~(-1)(P<0.01)。老年组CYP2C9、CYP4F2各基因型组间华法林剂量无统计学差异(P>0.05)结论:老年患者服用华法林剂量明显减低,建议老年患者服用华法林时考虑检测VKORC1基因。     

心房颤动患者CYP2C9、VKORC1基因多态性与华法林药物敏感度的关系

目的分析心房颤动(AF)患者CYP2C9、VKORC1基因多态性与华法林药物敏感度的关系。方法根据华法林给药累计剂量,将27例AF患者分为低起效剂量组和高起效剂量组;根据达标时间,分为短起效时间组和长起效时间组。比较高、低起效剂量组和长、短起效时间组CYP2C9、VKORC1不同基因型华法林的起效剂量和起效时间。结果高、低起效剂量组rs1057910(CYP2C9*3)及长、短起效时间组VKORC1 rs9923231基因构成差异有统计学意义(P<0.05)。与AA基因型比较,CYP2C9 rs1057910 AC基因型华法林起效剂量降低,VKORC1 rs9923231 GA基因型华法林起效时间缩短(P<0.05)。华法林药物敏感度可分为低度敏感、中度敏感和高度敏感3种。结论应结合临床实际对口服华法林行抗凝治疗的AF患者进行CYP2C9、VKORC1基因多态性检测,以便从基因类型角度合理分配华法林剂量。     

CYP2C9及VKORC1基因多态性对心脏瓣膜置换术后华法林个体剂量差异的研究

目的 研究湖北地区汉族人细胞色素P450酶2C9(CYP2C9)基因和维生素K环氧化物还原酶复合体1(VKORC1)基因多态性分布特点及其对华法林稳态剂量的影响.方法 收集2012年3-8月湖北地区汉族临床使用华法林的患者108例作为华法林组,选择同期健康受试者85名为对照组.采用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)技术检测CYP2C9和VKORC1基因型,并比较不同基因型华法林稳态剂量.结果 两组基因型频率和等位基因频率分布比较差异无统计学意义(P＞0.05).华法林组中CYP2C9基因*1/* 3型较*1/*1型华法林稳态剂量小,VKORC1基因AA型较GA型华法林稳态剂量小(P＜0.05,P＜0.01).除了检测的3个多态位点,还发现了50多个变异位点.结论 在湖北地区汉族人群中,存在CYP2C9和VKORC1基因多态性,且不同基因型患者间华法林稳态剂量存在差异,华法林基因相关变异位点需要进一步证实.     

基因多态性对华法林谷浓度及维持剂量的影响

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法测定其谷浓度,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~<1.0μg?mL-1 、1.0~2.0μg?mL-1 及超过2.0μg?mL-1范围时,其临床有效率（69.23%,82.6%,63.41%）显著高于0. 5μg?mL-1以下浓度范围(48.39%)（P<0.05）,且0.5~<1.0μg?mL-1 及超过2.0μg?mL-1浓度范围华法林的临床有效率相近（P>0.05）。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（P>0.05）。携带AG/GG、CT/ TT型和野生型（*1/*1）基因型的患者,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（P >0.05）。结论 VKORC1(-1639G/A)、CYP2C9*3、CYP4F2(rs2108622) 和CYP2C19*2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。     

三种华法林基因预测模型与心脏瓣膜置换术后华法林剂量的相关性研究

目的 研究湖北地区汉族人细胞色素P450 (CYP) 2C9基因和维生素K环氧化物还原酶复合体1(VKORC1)基因型;评估3种不同华法林剂量预测模型与其剂量的相关性.方法 收集我院收治的心脏瓣膜置膜术后应用华法林的108例患者并获取华法林稳态剂量,采用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)技术检测CYP2C9和VKORC1基因型.比较3种基因预测模型结果与实际华法林稳态剂量的相关性.结果 根据基因型判断的华法林用药剂量与稳态剂量相关性更大,同时预测模型3相关性略高于预测模型2.结论 在湖北地区汉族人群中,存在CYP2C9和VKORC1基因多态性,且不同基因型患者华法林用量存在差异,预测模型有助于预测华法林稳态剂量.     

中国汉族人群基于临床特征和基因型华法林个体化给药模型的研究

目的：评价中国汉族人群临床特征及基因型对华法林剂量的影响,并构建华法林给药模型,为临床华法林个体化给药提供参考。方法：按照设定标准选取某医院2011年1月至2013年10月行心脏瓣膜手术后接受华法林抗凝治疗并达到华法林稳定剂量的中国汉族人群203例,对纳入人群进行CYP2C9＊3、VKORC1-1639G/A基因多态性检测,结合基因型及患者临床特征,分析对华法林稳定剂量的影响,并采用多元逐步线性回归分析建立数学模型。结果：性别、吸烟、饮酒及高血压病史对华法林剂量无明显影响（P＞0.05）。华法林剂量与年龄呈负相关（r=-0.155,P=0.027）;与身高、体质量呈正相关（r=0.166、0.190,P=0.009、0.003）。CYP2C9＊3、VKORC1-1639G/A基因多态性对华法林剂量的影响在统计学上有统计学差异（P＜0.01）。拟合得到华法林给药模型D=2.855－1.173×CYP2C9（AC）＋0.020×W－0.024×A＋4.064×VKORC1（GG）＋1.486×VKORC1（GA）。结论：华法林的剂量受到年龄、身高、体质量及CYP2C9＊3、VKORC1-1639G/A基因多态性的影响,依据华法林给药模型可优化华法林个体化给药方案,但仍有待于临床进一步验证。     

VKORC1-3673G>A、CYP2C9*3、CYP4F2 rs2108622和CYP2C19*2基因多态性对中国汉族房颤患者华法林维持剂量的影响

目的 探讨VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622和CYP2C19^*2位点基因多态性对中国汉族房颤患者华法林维持剂量的影响。方法 收集107例服用华法林达维持剂量的汉族房颤患者的血样和临床相关资料,应用PCR-RFLP法检测VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622和CYP2C19^*2基因型,采用独立样本t检验分析基因型与华法林维持剂量的相关性。多元线性回归建立给药模型,探讨基因多态性对华法林维持剂量的影响。结果 VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622基因多态性和患者年龄、体质量能解释45.2%的华法林维持剂量差异。CYP2C19^*2基因多态性对本研究人群华法林维持剂量无影响。结论 VKORC1-3673G>A、CYP2C9^*3、CYP4F2 rs2108622基因多态性显著影响中国汉族房颤患者的华法林维持剂量。     

The effect of polymorphisms in STX4 on Warfarin dosage in Chinese cardiovascular disease patients

VKORC1 and CYP2C9 have been shown to be strongly associated with Warfarin dosing. However, it is still unclear whether other common genetic variants also contribute to the variation in Warfarin dosing. In the present study, we aim to investigate possible effects of single nucleotide polymorphisms (SNPs) in other candidate genes (CYP4F2, CACNA1C and STX4), as well as several factors, on stable daily Warfarin dosage (DWMD) in Chinese cardiovascular disease patients. 207 cardiovascular disease patients treated with Warfarin were recruited from Beijing Hospital. DNA was extracted from the blood samples collected one day after Warfarin administration. Nine SNPs (i.e. rs9923231, rs9934438, rs7294, rs1799853, rs1057910, rs4086116, rs2108622, rs216013 and rs10871454 in five genes (i.e. VKORC1, CYP2C9, CYP4F2, CACNA1C and STX4) were analyzed using ligase detection reactions (LDR). Univariate analyses and multiple linear regression analyses were performed to analyze the associations between SNPs and other factors (i.e. body surface area (BSA), Statin medication) and DWMD. Four SNPs (i.e. rs9923231, rs9934438, rs7294 in VKORC1 and rs10871454 in STX4) had significant statistically effects on DWMD. The multiple linear regression model showed that rs10871454 in STX4, BSA, statin medication, and rs1057910 in CYP2C9 were the significant independent covariates of DWMD. SNP (rs10871454) in STX4 had the strongest effect on Warfarin dosing among the examined candidate genes, indicating that it might serve as a key genetic factor for prediciting the Warfarin maintenance dose in Chinese patients.     

Effect of CYP2C9, VKORC1, CYP4F2 and GGCX genetic variants on warfarin maintenance dose and explicating a new pharmacogenetic algorithm in South Indian population

Objective

To determine the influence of genetic polymorphisms on warfarin maintenance dose and to explicate an algorithm using the pharmacogenetic and clinical factors to determine the maintenance and/or starting dose of warfarin in South Indian patients receiving warfarin therapy.

Methods

Patients receiving stabilized warfarin therapy (n?=?257) were included in the study. Single nucleotide polymorphisms (SNPs) of CYP2C9 (rs1799853 and rs1057910), VKORC1 (rs9923231, rs7196161, rs2884737, rs9934438, rs8050894, rs2359612 and rs7294), CYP4F2 (rs2108622) and GGCX (rs11676382) were genotyped by the quantitative real time-PCR method.

Results

The mean daily maintenance dose of warfarin was found to be 4.7?±?2.1 mg/day. Patients with the CYP2C9*1/*2, *1/*3 and *2/*3 variant genotypes required a 51.0 (2.8 mg), 60.9 (2.3 mg) and 62.2 % (2.2 mg) lower daily maintenance dose of warfarin, respectively, than those patients with the CYP2C9*1/*1 wild-type genotype (5.2 mg) (p?<?0.0001). The genetic variants of CYP2C9, VKORC1 and GGCX were associated with decreased warfarin dose, except for rs7196161, rs7294 and rs2108622 which were associated with an increased warfarin dose. Genetic variations of CYP2C9 (*2 and *3), VKORC1 (rs9923231, rs7294, rs9934438 and rs2359612), CYP4F2, GGCX and non-genetic factors such as age, body weight, clinical status (post mechanical valve replacement) could explain up to 62.1 % of the overall variation (adjusted r ² 60.2 %, p?<?0.0001) in warfarin maintenance dose.

Conclusion

Genetic polymorphisms of CYP2C9, VKORC1, CYP4F2 and GGCX are important predictive factors of warfarin maintenance dose, and the developed algorithm will be useful to predict the required maintenance and/or starting warfarin dose in South Indian populations.     

Pharmacogenomics of warfarin in populations of African descent

Warfarin is the most commonly prescribed oral anticoagulant worldwide despite its narrow therapeutic index and the notorious inter- and intra-individual variability in dose required for the target clinical effect. Pharmacogenetic polymorphisms are major determinants of warfarin pharmacokinetic and dynamics and included in several warfarin dosing algorithms. This review focuses on warfarin pharmacogenomics in sub-Saharan peoples, African Americans and admixed Brazilians. These ‘Black’ populations differ in several aspects, notably their extent of recent admixture with Europeans, a factor which impacts on the frequency distribution of pharmacogenomic polymorphisms relevant to warfarin dose requirement for the target clinical effect. Whereas a small number of polymorphisms in VKORC1 (3673G > A, rs9923231), CYP2C9 (alleles *2 and *3, rs1799853 and rs1057910, respectively) and arguably CYP4F2 (rs2108622), may capture most of the pharmacogenomic influence on warfarin dose variance in White populations, additional polymorphisms in these, and in other, genes (e.g. CALU rs339097) increase the predictive power of pharmacogenetic warfarin dosing algorithms in the Black populations examined. A personalized strategy for initiation of warfarin therapy, allowing for improved safety and cost-effectiveness for populations of African descent must take into account their pharmacogenomic diversity, as well as socio-economical, cultural and medical factors. Accounting for this heterogeneity in algorithms that are ‘friendly’ enough to be adopted by warfarin prescribers worldwide requires gathering information from trials at different population levels, but demands also a critical appraisal of racial/ethnic labels that are commonly used in the clinical pharmacology literature but do not accurately reflect genetic ancestry and population diversity.     

Influence of CYP4F2 rs2108622 (V433M) on warfarin dose requirement in Asian patients

Warfarin exhibits wide interpatient variability in dosing requirements. Recent studies have shown a novel polymorphism (rs2108622, V433M) in the CYP4F2 gene to be associated with variability in warfarin requirements in Caucasians. The purpose of this study was to evaluate the impact of rs2108622 on warfarin dose requirements in the Asian population. The mean warfarin dose was found to be significantly lower in patients carrying homozygous wild-type allele CC when compared with patients carrying variant alleles CT and TT (CC vs CT+TT: 3.0 mg/day vs 3.75 mg/day, p = 0.033). In patients harboring VKORC1 diplotypes associated with low warfarin requirements, a linear regression model which included age, weight, CYP2C9 and CYP4F2 variants accounted for 38% of the variability in warfarin dose. Approximately 11% of the dose variation was explained by CYP4F2 rs2108622 (p = 0.004). The influence of rs2108622 in patients harboring VKORC1 diplotypes associated with high warfarin requirements was not significant. This study suggests that CYP4F2 rs2108622 may significantly affect warfarin dose requirements in carriers of VKORC1 low-dose-associated diplotypes.     

CYP2C9、VKORC1基因多态性对华法令抗凝治疗维持剂量的影响

目的：研究细胞色素P4502C9基因（CYP2C9）和维生素K环氧化物还原酶复合物1基因（VKORC1）在华法令抗凝治疗患者的多态性分布,并探讨其对抗凝剂量的影响。方法：收集74例服用华法令抗凝治疗病人的外周血,测定其凝血酶原时间国际标准化比值（INR）和CYP2C9、VKORC1基因类型,探讨基因多态性的分布特点,以及华法令维持剂量与基因多态性的关系。结果：CYP2C9基因分布主要为野生型,突变型较少,抗凝治疗的维持剂量野生型组与突变组无明显差别。 VKORC1基因型的分布AA型为主,AG型较少,GG型未见,抗凝治疗的维持剂量AG组明显高于AA组。结论：CYP2C9、VKORC1基因在中国汉族人群中具有遗传多态性, VKORC1基因的多态性在华法令抗凝治疗中具有显著意义。     

基于连接酶反应快速检测华法林相关基因VKORC1、CYP2C9多态性

目的：建立基于连接酶反应检测华法林相关基因分型分布的新方法。方法：设计多重PCR体系,构建多重PCR/连接酶检测方法检测华法林相关基因（VKORC1、CYP2C9）多态性,并用本方法检测207份北方汉族人血样DNA。结果：本研究检测结果未发现rs1799853（CYP2C9＊2）突变。CYP2C9＊3,VKORC1：1173C〉T,VKORC1：3730G〉A,VKORC1：-1639G〉A等4个SNP位点的发生率分别为4.35%、5.80%、5.31%、6.76%。位于CYP2C9第三个内含子的rs4086116发生率为10.14%。结论：本方法可靠、迅速,自动化程度高,检测结果与既往报道相符。     

CYP2C9和VKORCl基因多态性对肺栓塞患者华法林维持剂量的影响

目的 研究细胞色素P450酶2C9(CYP2C9)及维生素K环氧化物还原酶复合体亚单位1(VKORCl)基因多态性对中国肺栓塞患者华法林维持剂量的影响.方法 对108例INR已稳定达标的中国肺栓塞患者,采用TaqMan MGB探针法,检测CYP2C9*2、*3位点和VKORCl-1639A＞G位点基因型.记录患者的年龄、性别、体重、身高及华法林日平均剂量.结果 VKORCl -1639AG或GG基因型患者华法林稳定日均剂量明显高于AA基因型患者(5.81±1.93vs 3.33±1.11mg,P ＜0.001);CYP2C9*2或*3变异的患者华法林稳定日均剂量低于无变异的患者(2.57±1.31 vs 3.97±1.67mg,P＜0.001);包括患者性别、年龄、身高、体重、CYP2C9和VKORC1基因型等因素在内的华法林稳定剂量预测模型可解释51.1％左右的华法林稳定剂量个体差异(R2=0.511,P＜0.001).结论 CYP2C9和VKORC1基因型检测对指导中国肺栓塞患者个体化应用华法林有一定的临床意义.