缺血性脑血管病患者脑微出血相关因素及其对抗血小板单药治疗的影响分析

目的 研究缺血性脑血管病患者脑微出血（CMB）危险因素及其对抗血小板单药治疗的影响。方法 选取2018年1月至2018年6月该院神经内科接受抗血小板单药治疗的急性缺血性脑血管病患者300例为样本，入院后采集基本资料并完善相关检查，根据梯度回波T2^*加权成像（GRE-T2^*WI）检查结果将患者分为CMB组（176例）和非CMB组（124例），均给予抗血小板聚集治疗，比较两组临床资料及治疗1年内再发梗死、脑出血和病死率，分析影响CMB发病的危险因素以及CMB对抗血小板单药治疗的影响。结果 高龄、高血压、肥胖、脑卒中病史、ACI和脑白质疏松为CMB发生的危险因素（P<0.05）。CMB组和非CMB组抗血小板单药治疗期间脑出血率分别为14.20%和6.45%，差异有统计学意义（P<0.05）。轻度组、中度组和重度组脑出血率分别为9.18%、10.64%和35.48%，差异有统计学意义（P<0.05）。不同部位CMB患者抗血小板单药治疗期间再发脑梗死、脑出血及病死率比较，差异无统计学意义（P>0.05）。结论 高龄、高血压、肥胖、脑卒中病史、ACI及脑白质疏松为缺血性脑血管疾病合并CMB的危险因素。CMB可导致抗血小板单药治疗期间脑出血风险增加，重度CMB者更甚。     

对氧磷脂酶1基因多态性与脑梗死的相关性研究

目的：探讨对氧磷脂酶1（PON1）基因的标签位点（tagSNP）rs854552多态性与脑梗死的相关性。方法：缺血性脑卒中患者按TOAST分型标准分为动脉粥样硬化性脑梗死组393例、腔隙性脑梗死组292例和健康对照组431名。以位于PON1基因的rs854552位点为遗传标记,应用聚合酶链法（PCR）和限制性片段长度多态性法（RFLP）检测PON1基因的多态性。结果：动脉粥样硬化性脑梗死组和腔隙性脑梗死组的PON1基因型及等位基因频率与对照组比差异无统计学意义（P〉0．05）。经性别分层后也未见显著差异。结论：PON1基因（tag SNP）rs854552可能与动脉硬化性脑梗死的发病无关。     

对氧磷酶1基因多态性与缺血性脑卒中的关联研究

目的探讨对氧磷酶1(PON1)基因的rs2299262标签位点(tag SNP)多态性与缺血性脑卒中的相关性。方法本研究共纳入705例缺血性脑卒中患者和406例对照组人群,按TOAST分型标准,分为动脉粥样硬化性脑梗死406例、腔隙性脑梗死299例。以位于PON1基因的rs2299262位点为遗传标记,采用聚合酶链反应(PCR)和限制性片段长度多态性(RFLP)技术检测PON1基因的多态性。结果缺血性脑卒中组、动脉粥样硬化性脑梗死组、腔隙性脑梗死组和对照组的PON1基因型及等位基因频率与对照组的差异无统计学意义(P>0.05)。经性别分层后也未见显著差异。结论PON1基因与缺血性脑卒中的发病可能无关。     

血小板糖蛋白Ⅱb/Ⅲa受体拮抗剂治疗急性缺血性卒中的研究进展

血小板活化在血栓形成中起着重要作用,虽然阿替普酶（alteplase,rtPA）静脉溶栓是治疗 急性缺血性卒中（acute ischemic stroke,AIS）的标准治疗,但国内外一直在探索联合或单独使用各类 抗血小板药物在治疗AIS中的作用。抑制血小板聚集过程最后共同通路的新型抗血小板药物血小板 糖蛋白（GP）Ⅱb/Ⅲa受体拮抗剂,在急性冠脉综合征（acute coronary syndrome,ACS）等心血管疾病 中的安全性和有效性已得到验证,但在AIS中的作用尚存争议,本文拟就相关临床研究作一综述。     

基因多态性与抗血小板药物个体化治疗研究

血小板的活化与聚集在血栓形成的病理生理中起着重要的作用,而抗血小板治疗是动 脉硬化性脑梗死急性期治疗、一级及二级预防的重要组成部分。目前阿司匹林、氯吡格雷为最常用 的抗血小板药物。但抗血小板药物对不同人群血小板抑制作用存在较大差异,人群对抗血小板药 物的低反应性与缺血性脑血管病复发具有相关性,本篇将重点从基因多态性的角度阐述抗血小板 药物抵抗的可能机制,指导临床个体化治疗。     

血小板活化相关基因多态性与脑梗死患者颈动脉狭窄的相关性研究

目的 探讨缺血性脑卒中患者血小板活化相关基因变异与颈动脉狭窄的关系。方法 对236例伴颈动脉狭窄和378例不伴颈动脉狭窄的缺血性脑卒中患者的11个血小板活化相关基因位点多态性、血小板白细胞聚集和血小板聚集进行检测; 采用高分辨率B超评估颈动脉狭窄; 应用广义多因子降维(Generalized multifactor dimensionality reduction,GMDR)法分析这些基因-基因交互是否影响颈动脉狭窄的风险。结果 与不伴颈动脉狭窄患者比较,伴颈动脉狭窄患者的血小板聚集和血小板白细胞聚集增高。单因素分析显示,伴和不伴颈动脉狭窄患者这11个基因位点基因型频率分布无明显差异; 然而,GMDR分析表明,血栓素A2受体(Thromboxanes A2 receptor,TXA2R)rs1131882、血小板膜受体(Platelet membranesreceptors,P2Y1)rs1371097和糖蛋白IIIa(Glycoprotein IIIa,GPIIIa)rs2317676存在有交互作用,这3个基因位点的高交互作用与血小板活化增高有关,为颈动脉狭窄的独立危险因素(OR=2.72,95%CI=1.28～7.82,P=0.001)。结论 Rs1131882、rs1371097和rs2317676的交互作用增加了症状性颈动脉狭窄的风险,可能是颈动脉狭窄的基因标志物; GMDR法对阐明颈动脉狭窄复杂的基因危险因素具有较大的作用。     

阿司匹林对缺血性脑血管病患者抗血小板聚集作用的临床观察

阿司匹林是抗血小板聚集药物，广泛应用在心脑血管疾病的治疗和预防。本研究对日服阿刮匹林75mg的68例缺血性脑血管病（ICVD）患者通过测定其血小板聚集率观察阿司匹林的抗血小板聚集作用。     

氯吡格雷、华法林及他汀类药物治疗缺血性卒中的遗传药理学研究

抗血小板聚集、抗凝及血脂调控药物是临床治疗与预防缺血性卒中（ischaemic stroke,IS）的重要措施,而氯吡格雷、华法林及他汀类药物是其中常用的治疗药物;然而,遗传因素可导致药物代谢酶、转运体及作用靶点等药物反应相关蛋白活性出现个体差异,从而影响药物的疗效和毒副作用。本文将探讨氯吡格雷、华法林及他汀类药物治疗IS的遗传药理学,并分析影响药物疗效及毒副作用的基因多态性,以利个体化的IS治疗与预防     

血小板聚集率检测在颅内动脉瘤介入治疗中的价值

目的 探讨血小板聚集率检测在颅内未破裂动脉瘤介入治疗中的价值。方法 回顾性分析2020年1月至2022年4月使用支架辅助栓塞治疗的215例颅内未破裂动脉瘤的临床资料。术前1 d检测血小板聚集率,术后复查CT、MRI评估出血性和缺血性并发症。结果 术后发生缺血性并发症16例（7.4%）,出血性并发症14例（6.5%）。术前血小板聚集率≤15%的病人出血性并发症发生率（11.8%）较血小板聚集率>15%的病人（3.1%）明显增高（P<0.05）。而血小板聚集率与缺血性并发症无明显关系（P>0.05）。结论 抗血小板药物的使用降低了支架辅助栓塞颅内动脉瘤病人的缺血风险,并且使术前血小板聚集率维持在较低水平,而术前血小板聚集率过低可能是发生出血性并发症的危险因素。当血小板聚集率≤15%时,需警惕出血风险。     

对氧磷酶1Q192R和L55M基因多态性与缺血性卒中再发的相关性研究

目的 分析对氧磷酶1 (paraoxonase 1,PON1)基因多态性与服用氯吡格雷后卒中再发之间的相关性.方法 从南京卒中注册系统中提取2008年5月至2010年4月首发缺血性卒中并长期服用氯吡格雷的患者.采用改良的多重高温连接酶检测反应技术对入选病例的PON1Q192R、PON1 L55M的单核苷酸基因多态性位点进行基因分型并随访,随访的主要终点事件包括缺血性脑血管事件、心肌梗死、血管性死亡;次要终点事件包括出血性血管事件.采用卡普兰-迈耶生存分析法探讨不同基因型患者终点事件的差异性.用单因素、多因素COX回归模型分析临床终点事件发生的相关危险因素.结果 共入组患者625例,平均随访期时间为(12.7±5.1)个月,其主要终点事件的发生率为13.6％ (85/625),其中再发卒中65例(10.4％),血管性死亡13例(2.1％),心肌梗死7例(1.1％).出血性事件发生13例(2.1％).PON1Q192R和PON 1L55M的最小等位基因频率分别为38.1％(238/625)和2.8％(17.5/625).携带QQ/QR的患者主要临床终点事件发生62例(15.7％),非携带者(RR)的主要终点事件发生23例(10.0％),组间差异有统计学意义(HR=1.68,95％ CI1.04～2.71,P=0.030).多因素COX回归模型纳入年龄、性别、体重指数、高血压、糖尿病、高脂血症、冠状动脉粥样硬化心脏病史、吸烟以及合并药物为相关危险因素,分析结果显示:PON1Q192基因型与缺血性卒中患者再发具有一定的相关性(HR =2.39,95％ CI 1.33 ～4.29,P=0.004).结论 在长期服用氯吡格雷抗血小板治疗的缺血性卒中患者中,PON1 Q192基因型携带者再发缺血性脑血管事件的风险明显增高,多因素分析提示PON1 Q192基因型与缺血性脑血管病患者再发具有一定相关性.     

Pharmacogenomics of clopidogrel: evidence and perspectives

Clopidogrel has become the mainstay oral antiplatelet regimen to prevent recurrent ischemic events after acute coronary syndromes or stent placement. However, there is marked interindividual variability in the antiplatelet effects of clopidogrel, and a reduced response to this drug may be a risk factor for ischemic complications. Pharmacogenomic analyses, including candidate-gene and genome-wide association studies, have confirmed that genetic polymorphisms in the hepatic cytochrome P450 (CYP) 2C19 dominantly affect the antiplatelet effects of clopidogrel. CYP2C19 reduced-function alleles have been associated with a significant decrease in clopidogrel responsiveness and a higher risk of adverse cardiac events including stent thrombosis, myocardial infarction, and death in several prospective studies, although these effects were not reproduced in a recent large randomized study that included a randomized control group. The US Food and Drug Administration addressed this issue by adding a boxed warning to the clopidogrel label and suggesting that adjusting the clopidogrel dose or using alternative antiplatelet agents should be potentially implemented for high-risk individuals who are identified based on the CYP2C19 genotype. Although it is promising that CYP2C19 genotyping could be used to guide personalized antiplatelet clopidogrel therapy, currently there is insufficient evidence to recommend routine genetic testing. Prospective randomized clinical trials are necessary to validate this pharmacogenomic approach to clopidogrel therapy. In the most recent trial, paraoxonase-1 (PON1) was identified as a crucial new enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite and the clinical activity of clopidogrel. Further studies are needed to investigate the comprehensive influence of a number of different polymorphisms of CYP2C19 and PON1 variant alleles or other genetic variants on clopidogrel in various ethnic populations.     

PON1 activity and genotype in patients with arterial ischemic stroke and in healthy individuals

OBJECTIVE: Paraoxonase-1 (PON1) is an esterase with antioxidant properties. Low PON1 enzyme activity or specific allelic polymorphisms seem to be associated with the risk of developing coronary artery disease or acute ischemic stroke (AIS). Our objective was to determine the distribution of both PON1 enzyme activity and its genotype in a group of patients with AIS. MATERIALS AND METHODS: PON1 activity and the relative Q192R and L55M polymorphisms in the PON1 gene were assessed on 126 survivors of a first AIS and in 92 healthy subjects. RESULTS: The genotype distribution for PON1 Q192R and L55M polymorphisms was similar in AIS patients and healthy subjects, but patients carrying the QRLL or RRLL genotype combination had lower PON1 enzyme activity compared with healthy subjects with the same genotype. CONCLUSION: We postulate that lower than expected PON1 enzyme activity within specific genotypes might explain the reported association between R and L alleles and the risk of developing AIS.     

The paraoxonase gene polymorphism in stroke patients and lipid profile

Objectives –  The paraoxonase (PON) gene can reduce the risk of developing atherosclerosis. We investigated the associations between PON polymorphisms and ischemic stroke. We also investigated the associations between PON polymorphisms and lipid profile in stroke patients.
Methods –  A total of 350 patients with ischemic stroke and 242 control subjects in Korean population were genotyped for the PON1M55 L, PON1Q192R, PON2A148 G and PON2S311C polymorphisms using melting point analysis with LightCycler real-time polymerase chain reaction (PCR) technology.
Results –  There were no significant differences in genotype and allele distribution of the PON polymorphisms between the ischemic stroke patients and control subjects. The concentration of total homocysteine was significantly different in the PON1M55 L polymorphism ( P  = 0.047), and the apolipoprotein (Apo)B concentration was significantly different in the PON1Q192R polymorphism ( P  = 0.02) in stroke patients. The concentrations of low-density lipoprotein (LDL) cholesterol and ApoB were significantly different between the PON2A148 G ( P  = 0.011, P  = 0.000, respectively) and PON2S311C polymorphisms ( P  = 0.046, P  = 0.003, respectively) in stroke patients.
Conclusions –  This study did not provide association between PON gene polymorphisms and ischemic stroke. However, it confirmed that the PON1L55 L allele is associated with plasma concentration of total homocysteine and that the PON2G148 G and PON2S311S allele is associated with plasma concentrations of LDL cholesterol and ApoB.     

miRNA靶基因3''-UTR单核苷酸多态性在缺血性脑卒中的研究进展

缺血性脑卒中(IS)是脑组织缺血坏死引起的神经功能障碍性疾病,其发生发展是遗传因素和环境危险因素共同作用的结果。微小RNA(miRNA)通过与靶基因mRNA 3'端非编码区(3'-UTR)碱基配对,引起靶基因mRNA的降解或翻译抑制,在转录后水平调控基因表达。IS相关基因miRNA靶区存在的单核苷酸多态性(SNPs)与IS的遗传易感性和预后有关。该文拟对miRNAs靶基因(VEGF、IL-1、NLRP3、MTHFR、PON1、BDNF、CRP、HDAC9) 3'-UTR SNPs与IS遗传易感性和预后的关联做一综述。     

Paraoxonase 2 gene C311S polymorphism is associated with a risk of large vessel disease stroke in a Polish population

BACKGROUND: Oxidative stress plays a role in atherosclerosis. Human paraoxonase (PON) gene products exhibit antioxidant properties. We studied the significance of the Q192R and M55L polymorphisms of the PON1 gene and the C311S polymorphism of the PON2 gene in different etiologies of ischemic stroke. METHODS: One hundred and thirty-six patients with large vessel disease (LVD) stroke, 140 with small vessel disease stroke, 272 with cardioembolic stroke, and their age- and sex-matched controls were included. PON genotypes were evaluated by PCR-RFLP analyses. RESULTS: The distribution of PON1 polymorphisms was similar in each stroke group and in the respective controls. Genotypes with the C allele of the PON2 gene C311S polymorphism were overrepresented in LVD stroke patients as compared with their controls, both in univariate and multivariate (dominant model: OR = 1.58, 95% CI: 1.006-2.48) analyses. CONCLUSION: The genotype with the C allele of the PON2 gene is a risk factor for LVD stroke in a Polish population.     

Coagulation Factors and Recurrence of Ischemic and Bleeding Adverse Events in Patients with Acute Coronary Syndromes

In the last years, management and prognosis of patients with acute coronary syndromes (ACS) are significantly improved. Nowadays antithrombotic (antiplatelet plus anticoagulant drugs) therapy represents the main treatment of ACS patients. Anticoagulant drugs are particularly helpful in the acute phase of ACS, whereas in the chronic phase are maintained only in selected cases. Many studies demonstrate that exists a significant variability in the coagulation factor levels between patients affected by ACS. This variation on coagulation factors levels is due to environmental (smoking, inflammation, sex, oral contraceptive, triglycerides, diabetes mellitus) and genetic determinants. Particularly several gene polymorphisms have been selected and clearly associated with significant variations in the coagulation factors values. The heightened levels of tissue factor, factor VII and fibrinogen are related with a “hypercoagulable status” and with a higher occurrence of ischemic complications after ACS and/or PCI. On the contrary, less data are available regarding the relationship between coagulation factors levels (or their gene polymorphisms) and bleeding complications. Recently, new anticoagulant drugs have been developed. They show less side effects and a better tolerability and, probably, their selected use in patients with a “hypercoagulable status” may improve the clinical outcome after ACS. In this review we analyze the current available data and we discuss how this finding may be useful for planning future studies to optimize the treatment of ACS patients.     

Involvement of paraoxonase 1 genetic variants in Alzheimer's disease neuropathology

Evidence suggests that the genes involved in brain lipid homeostasis are of particular relevance for Alzheimer's disease (AD) etiology. Among these genes, that encoding paraoxonase 1 ( PON1 ) has gained newfound interest from a public health perspective, as recent studies have suggested that PON1 L55M and Q192R genetic variants might affect individual susceptibility to environmental events, such as exposure to cholinesterase inhibitors. Cholinesterase inhibitor therapy being the treatment of choice for patients with mild to moderate AD, we sought to answer two main questions: (i) are these genetic variants associated with increased AD risk, earlier age of onset/death, or shorter AD duration; and (ii) do they affect the neuropathological hallmarks of AD? This genetic study used a large cohort of clinical and autopsy-confirmed AD cases and age-matched, cognitively intact controls from the Douglas Hospital Brain Bank, Quebec, Canada ( n  = 1066). The evidence presented here suggests multiple gender-specific effects of PON1 polymorphisms on AD etiopathology. The L55M Met allele exerts an AD risk-enhancing effect only in men ( P  < 0.001), whereas both men and women carrying the M55M/Q192Q genotype exhibit increased survival (2.5 years, P  < 0.05) and later age of onset (1.5 years, P  < 0.05). These genetic variants are also individually and significantly associated, sometimes in opposite directions for both genders, with β-amyloid levels ( P  < 0.001), senile plaque accumulation ( P  < 0.001) and choline acetyltransferase activity ( P  < 0.05) in, respectively, two of two, five of six, and three of six brain areas. These results suggest an involvement of the PON1 gene in AD etiopathology and responses to treatment.     

Genetic variability in response to clopidogrel therapy and its clinical implications

This article concentrates on individual genetic differences responsible for variations of action of clopidogrel, which have been found to be partially responsible for increased cardiovascular events in patients with coronary artery disease under dual antiplatelet therapy. According to these results, genotyping for the relevant gene polymorphisms, especially for the CYP2C19 loss-of-function alleles, has been discussed to be an effective method of individualising and optimising clopidogrel treatment. However, due to the facts that 1) there are no prospective studies demonstrating a clinical benefit of personalising antiplatelet therapy based on genotyping; 2) CYP2C19 polymorphisms account for only approximately 12% of variability in clopidogrel platelet response; 3) the positive predictive value of CYP2C19 loss-of-function polymorphisms for cardiovascular events in patients with acute coronary syndrome undergoing percutaneous coronary intervention is only approximately 12% - 20%; 4) it is likely that other clinical factors and risk constellations might be of greater clinical importance; and 5) it is unknown whether a specific genetic polymorphism is capable of influencing outcome for the individual patient; genetic profiling cannot be recommended for routine use at present but will remain of considerable scientific interest.