基因多态性对华法林抗凝疗效的影响

华法林是临床上广泛使用的抗凝药物,其治疗范围窄,个体差异很大。本文就华法林的基因多态性国内外最新研究进展做简要介绍。相关基因的多态性造成了个体差异,影响了华法林的使用剂量。华法林的基因多态性研究为临床指导华法林个体化用药带来了希望。     

基因多态性对华法林低强度抗凝治疗稳定剂量影响的前瞻陛研究

目的 对影响华法林代谢及作用的多个相关基因进行测定,探讨其对中国人群低强度华法林抗凝稳定剂量的影响程度.方法 共纳入170名拟采取低强度华法林抗凝治疗患者,对其与华法林代谢及作用相关的3个基因CYP2C9（rs1057910）、VKORC1（rs9923231）、CYP4F2 （rs2108622）位点的基因多态性（SNP）进行检测,随后给予华法林治疗,目标国际标准化比值（INR）1.8-2.5,观察90天,同时记录患者的临床因素、INR值及华法林稳定剂量,分别判断临床及基因因素对华法林稳定剂量水平的影响作用.结果 CYP2C9、VKORC1、CYP4F2的5个SNP位点的SNP对华法林稳定剂量存在显著影响（P＜0.05）.经多元回归分析,年龄、体表面积、抗凝第4天INR值以及CYP2C9、VKORC1、CYP4F2 的SNP是华法林抗凝稳定剂量的独立影响因素;其中SNP可以独立解释18.6%的华法林稳定剂量的差异.结论 在目标强度为INR1.8-2.5的低强度华法林抗凝治疗中,CYP2C9（rs1057910）、VKORC1（rs9923231）、CYP4F2 （rs2108622）多态性对稳定剂量存在显著影响,可在临床工作中对上述3个SNP位点进行检测,对抗凝初期华法林的剂量进行预先调整.     

载脂蛋白E基因多态性对华法林抗凝疗效的影响

遗传因素是华法林存在个体差异的最重要因素,与药代动力学、药效学及药物转运相关的基因都能够影响华法林的抗凝治疗.近年研究发现,载脂蛋白E(ApoE)基因多态性与华法林个体剂量差异相关.本文就ApoE基因多态性对华法林稳定剂量的影响以及华法林个体化给药方案的研究进展作一综述.     

维生素K环氧化物还原酶复合体1基因多态性对华法林维持剂量的影响

目的 检测维生素K环氧化物还原酶复合体1（VKORC1）基因多态性对华法林维持剂量的影响。方法 研究入选102例使用华法林的汉族人,用限制性酶切的方法检测其C1173T位点多态性,其他临床资料通过随访获得。用独立样本t检验比较不同基因型患者华法林维持剂量的差别,用多重线性回归进行回顾性研究,分析华法林抗凝疗效的影响因素。结果 102例患者的C1173T位点基因型分别为TT基因型83个（81．4％）、CT基因型16个（15．7％）、CC基因型3个（2．9％）。在相同的抗凝目标下国际标准化比值1．5—2．5,TT基因型患者所需华法林剂量明显低于CT／CC基因型,分别为（2．54±0．83）mg／d、（4．19±1．16）mg／d（P〈0．01）。结论 C1173T位点多态性对华法林维持剂量有明显的影响,它能解释大约40％的个体间剂量差异（r^2=0．401）。     

CYP2C9和VKORC1基因多态性对华法林抗凝治疗的影响

华法林是最常用的口服抗凝药物,但它的治疗窗相当窄,达到抗凝治疗的剂量在不同种族和个体间差异较大,甚至可相差20倍。许多临床和环境因素包括年龄、性别、种族、体重、合并疾病和合并用药以及基因突变等影响华法林需要剂量。细胞色素氧化酶P450 2C9(CYP2C9)和维生素K环氧化酶复合物亚单位1(VKORC1)基因多态性很大程度上与华法林剂量个体间差异相关,是对华法林起作用的抗凝药物重要决定因子。本文阐述CYP2C9和VKORC1基因多态性及其对华法林剂量个体差异的影响。     

中国人VKORC1基因多态性对华法林维持剂量影响的Meta分析

目的:分析中国人VKROC1基因多态性对华法林维持剂量的影响。方法:检索2000年至2011年6月相关中、英文数据库,用Stata10.0软件进行Meta分析。结果:共纳入22项研究(共3 449人),中国人VKROC1各基因型频率为AA型比例为80.4%,AG型17.8%,GG型1.8%。与AA型相比,AG型华法林维持剂量较AA增加40.8%(95%CI 36.5～55),纯合GG型较AA型增加84.2%(95%CI:47.7～120.8),2种合并AG+GG型较AA型增加51.7%(95%CI:39.6～63.8)。按剂量要求GG型>AG型>AA型。结论:中国人VKROC1基因多态性频率与其他种族不同,对华法林维持剂量具有重要影响。     

华法林基因多态性临床应用的研究进展

正华法林是双香豆素类抗凝药,为口服的维生素K拮抗剂,临床上主要用于心房颤动、心脏瓣膜置换术、深静脉血栓和肺栓塞等的抗凝治疗,是抗凝治疗的基石。但是由于其治疗窗较窄,且容易受性别、年龄、遗传、相关药物等因素的影响,导致明显的个体差异。近年来,国内外有研究表明,华法林基因多态性创建的剂量预测模型有助于华法林剂量调整并降低出血风险。本文将结合华法林相关基因多态性、剂量预测模型阐释华法林基因多态性与临床应用的最新研究     

CYP2C9与VKORC1基因变异对华法林初始抗凝治疗反应性的影响

目的 探讨细胞色素P450酶2C9基因(CYP2C9)与维生素K环氧化物还原酶复合物1基因( VKORC1)多态性对中国汉族人华法林初始抗凝治疗反应性的影响.方法 入选2000-2008年广东省人民医院瓣膜置换术后长期口服华法林抗凝治疗的中国汉族患者798例,通过文献检索,选取与华法林药动学和药效学可能相关的CYP2C...     

细胞色素氧化酶P4502 C9以及维生素K环氧化物还原酶复合体1基因多态性对华法林抗凝疗效的影响

目的 研究年龄、体重、身高、体表面积、细胞色素氧化酶P450(CYP2C9)和维生素K环氧化物还原酶复合体1(VKORC1)基因型与华法林剂量的关系.方法 收集临床使用华法林的患者共191例,记录患者的年龄、性别、身高、体重等.利用聚合酶链反应(PCR)和限制性内切酶片段长度多态性(RFLP)技术检测CYP2C9以及VKORC1基因型.结果 VKORC1(-1639G＞A)基因型检测有159例患者为突变纯合子AA型,31例患者为杂合子GA型,1例患者为纯合子GG型.CYP2C9基因型检测有176例患者为*1/*1型,15例患者为杂合子*1/*3型.VKORC1(-1639G＞A)GA+GG组,华法林平均剂量明显高于AA组[(3.36±0.97)mg/d比(1.75±0.56)mg/d,P＜0.01].CYP2C9*1/*1型患者华法林平均剂量高于杂合子*1/*3型患者[(2.06±0.83)mg/d比(1.55±1.32)mg/d,P＜0.05].多元线形回归分析提示年龄、体重以及VKORC1基因型分别解释了约9.3％、7.4％、51.9％的个体间剂量差异,包括年龄、体重、VKORC1和CYP2C9基因型的多变量模型能解释个体间剂量差异约为64.1％.结论 年龄、体重、VKORC1和CYP2C9基因多态性明显影响了华法林剂量.用年龄、体重、VKORC1和CYP2C9基因型的多变量模型给药方法希望提高华法林使用的安全性.     

新癀片对华法林抗凝治疗的影响

心包切开综合征为心内直视术后2～3w或数月患者出现发热、前胸痛,呼吸困难、咳嗽、肌肉痛、关节痛等症状[1].新癀片是一种应用广泛的中成药,其主要成分包括三七、肿节风和牛黄等,药理作用为清热解毒、活血化瘀,消肿止痛.临床观察发现新癀片在治疗心包切开综合征效果显著,但随诊曾发现两位患者术后住院期间服用新癀片,其INR均大大延长,超过4.0,经及时调整华法林和新癀片用量,INR恢复正常.心脏瓣膜置换术是治疗严重瓣膜疾病的最有效手段.随着临床进一步观察,许多瓣膜置换术后患者使用华法林后INR值出现波动,目前国内外尚无针对新癀片引起换瓣术后患者INR值变化的报道,本文旨在探讨新癀片对人工机械瓣膜置换术后华法林抗凝治疗的影响.     

Influence of VEGF gene polymorphisms on the severity of ankylosing spondylitis

OBJECTIVES: To investigate the role of polymorphisms of the vascular endothelial growth factor (VEGF) gene in susceptibility to ankylosing spondylitis (AS), and their relationship to clinical features and radiographic severity. METHODS: This study included 157 patients with AS and 140 healthy unrelated controls. Polymorphisms of the VEGF gene were analysed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism assay and amplification refractory mutation system-PCR. Haplotypes were reconstructed using the Bayesian algorithm. Radiographic severity was assessed by the Bath Ankylosing Spondylitis Radiological Index (BASRI). RESULTS: The genotype frequencies of the polymorphisms were in Hardy-Weinberg equilibrium. The distributions of genotypes and alleles did not differ between AS patients and controls. Among the six haplotypes reconstructed based on the tight linkage disequilibrium at positions -2578, -1154 and -634 (pairwise linkage disequilibrium coefficient, r = 0.361-0.706), no haplotype was associated with susceptibility to AS. Clinical features were analysed for the four haplotypes (CGC, CGG, AAG, AGG) which were prevalent. In carriers of the AGG haplotype, the frequency of cervical spine involvement was significantly higher (P = 0.002, P(corr) = 0.036) and that of patients showing a BASRI score >6 was also higher (P = 0.025, P(corr) = 0.45). CONCLUSIONS: This study demonstrates that polymorphisms of the VEGF gene may contribute to disease severity in AS.     

Influence of cancer-related gene polymorphisms on clinicopathological features in colorectal cancer

Background and Aim:  Single nucleotide polymorphisms (SNP) are shown to be related with cancer incidence. It has been reported that CCND1 , p21 ^cip1 DCC , MTHFR, and EXO1 are related with the risk of malignant neoplasm, but few studies have mentioned the prognosis of the patients. We investigated the SNP of patients and related this to clinicopathological features, including survival rate.
Method:  DNA from the tissues of primary colorectal cancer was obtained from surgical resections of 114 patients (68 males and 46 females, 29–83 years). The CCND1 polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and those of other genes were investigated by the TaqMan method. The polymorphisms obtained were statistically analyzed for the relationship with clinicopathological features.
Results:  The CG  +  GG allele was more invasive than the CC allele in histological tumor depth in the DCC codon 201 ( P  = 0.0086). The 677TT allele in MTHFR had a larger tumor size than the 677CC allele ( P  = 0.028). In EXO1 P757L polymorphism, patients with the TT allele had a statistically reduced survival rate compared with the other alleles. In CCND1 polymorphisms, we found no statistical significance in clinicopathological features.
Conclusions:  From these preliminary data, these polymorphisms would be candidates predicting the clinicopathological features of colorectal cancer, but further more systematic gene analyses are warranted.     

Influence of warfarin dose-associated genotypes on the risk of hemorrhagic complications in Chinese patients on warfarin

This study was designed to evaluate the effect of the warfarin dose-associated genotypes, CYP2C9*3 (rs1057910), VKORC1 ?1639 G/A (rs9923231), and CYP4F2 1347 C/T (rs2108622), on hemorrhagic complications in Han Chinese patients. Consecutively recruited patients requiring more than 1 year of warfarin treatment were followed from the initiation of warfarin anticoagulation for at least 3 months. CYP2C9*3, VKORC1 ?1639 G/A, and CYP4F2 1347 C/T were genotyped by sequencing. The association between genotypes and warfarin hemorrhagic complications was evaluated using Cox proportional hazard regression, adjusted for demographic and clinical factors. Of 312 eligible patients obtaining stable warfarin anticoagulation in 3 months, 11 major and 69 minor hemorrhages occurred over 147 person-years. The CYP2C9*3 genotype conferred an increased risk of all [hazard ratio (HR) 3.07, 95 % confidence interval (CI) 1.57–6.01] and minor hemorrhage (HR 3.28, 95 % CI 1.62–6.65), but not major hemorrhage (HR 0.44, 95 % CI 0.04–4.72). CYP2C9*3 also conferred an increased risk of over-anticoagulation with international normalization ratio (INR) ≥4 (HR 2.92, 95 % CI 1.08–7.85). VKORC1 ?1639 G/A, and CYP4F2 rs2108622 did not confer significant increase in risk for hemorrhage or over-anticoagulation. Kaplan–Meier curves showed that time to all hemorrhagic events was significantly shorter for patients with CYP2C9*3 genotype than non-carriers (P = 0.001), but not for patients with VKORC1 ?1639 G/A or CYP4F2 rs2108622 genotype (P = 0.3 and 0.2). CYP2C9*3 may be the main genetic factor in hemorrhagic complications in Chinese patients under warfarin anticoagulation.     

Influence of the concomitant use of heparin on the effects of warfarin during catheter ablation for atrial fibrillation

Warfarin is widely used to perform catheter ablation for atrial fibrillation (AF). Heparin is usually administered during this procedure to prevent thromboembolic events, while protamine is used to reduce the incidence of bleeding complications. The purpose of this study was to investigate the influence of heparin and protamine administration on the effects of warfarin and its safety. The subjects included 226 AF patients (206 males, 54.9 ± 9.1 years, paroxysmal/persistent AF: 118/108) undergoing AF ablation with the discontinuation of warfarin administration over 2 days. Heparin was administered to achieve an activated clotting time (ACT) above 300 s during the procedure. Several parameters of the coagulation status, including the prothrombin time international normalized ratio (PT-INR) and ACT values, measured immediately before and after protamine infusion were compared. The mean value of PT-INR prior to ablation was 1.9 ± 0.6. At the end of the procedure, the mean ACT and PT-INR values were 348.0 ± 52.9 and 2.9 ± 0.7, respectively. Following the infusion of 30 mg of protamine, both the ACT and PT-INR values significantly decreased, to 159.6 ± 31.0 (p < 0.0001) and 1.6 ± 0.3 (p < 0.0001), respectively. No cases of symptomatic cerebral infarction were observed, although femoral hematomas developed in 17 (7.5 %) of the patients without further consequence. The concomitant use of heparin augments the effect of warfarin. Meanwhile, protamine administration immediately reverses both the ACT and PT-INR, indicating the applicability of protamine for AF ablation in patients under the mixed administration of heparin and warfarin.     

Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment

Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin. Genetic polymorphisms in CYP2C9 producing variants with altered catalytic properties have been identified. Patients (n = 561) with a target international normalized ratio (INR) of 2.5 who had been treated with warfarin for more than 2 months were anonymously genotyped for the wild-type CYP2C9*1 allele and the 2C9*2 and 2C9*3 variants. The mean maintenance dose of warfarin in patients who were wild-type for both alleles was 5.01 mg. The maintenance dose of warfarin was significantly related to genotype (Kruskall-Wallis, chi(2) = 17.985, P =.001) with mean maintenance doses in patients with variant alleles between 61% and 86% of that in wild-type patients. The odds ratio for the 2C9*2 allele in patients with a maintenance dose of 1. 5 mg or less was 5.42 (95% CI 1.68-17.4). The odds ratio for one or more variant alleles in patients developing an INR of 8.0 or greater was 1.52 (95% CI 0.64-3.58). The SD of the mean INR, percentage of high INRs, and person-time spent in range were determined as parameters of stability. There was no difference between patients grouped according to genotype for any parameter of stability. This study confirmed an association between CYP2C9 genotype and warfarin sensitivity. However, the possession of a variant allele does not increase the likelihood of severe over-anticoagulation or stability of anticoagulation during long-term therapy. (Blood. 2000;96:1816-1819)     

The differential effects of age on the association of KLOTHO gene polymorphisms with coronary artery disease

The Klotho knockout mouse is thought to be a good animal model for human aging. Recent studies have reported on the association of KLOTHO gene mutation with cardiovascular disease in humans. We observed the frequencies of single nucleotide polymorphisms, that is, G-395A in the promoter region, C1818T in exon 4, and a functional variant, KL-VS, of KLOTHO gene in Koreans, and we investigated their relationships with the presence of coronary artery disease (CAD) in patients who had undergone coronary angiograms. A total of 274 subjects who underwent coronary angiograms because of chest pain were enrolled, and their blood pressure, body mass index, fasting blood glucose level, and lipid profiles were measured. Genotypings were performed on samples of their blood with real-time polymerase chain reaction. Two single nucleotide polymorphisms, G-395A and C1818T, complied with Hardy-Weinberg equilibrium. For the KL-VS genotype, 1 homozygote subject for the adverse allele was detected among the entire population (GG for F352V and CC for C370S). When the subjects were classified into 4 groups according to the number of stenotic vessels, there were no differences among the mean values of the cardiovascular risk factors, except for age and the fasting blood glucose levels, which showed a significant difference between that of the normal and the diseased vessel groups. There were no differences in the prevalence of CAD according to the genotypes of the G-395A polymorphism; however, for the C1818T polymorphism, those subjects with the T allele showed a lower prevalence of CAD than those with the CC genotype. When the subjects were divided into 2 groups according to age, in the group younger than 60 years, T allele carriers of the C1818T polymorphism showed a lower prevalence of CAD than did the noncarriers. In the group older than 60 years, A allele carriers of the G-395A polymorphism showed a lower prevalence of CAD than did the noncarriers. On the haplotype analysis, the GG-CC haplotype showed an increased risk for CAD with an odds ratio of 2.594 (95% confidence interval, 1.385-4.858; P = 0.003). Differential effects of age were observed in the association of KLOTHO G-395A and C1818T polymorphisms with CAD in Koreans. The KL-VS variant seems to be rarely found in the Korean population. These results infer the possibility of the KLOTHO gene being a candidate gene of atherosclerosis in humans, and further research on this topic needs to be done.