Gene Expression and Thrombosis in a Community Based Cohort Study

基于社区的队列研究中的基因表达和血栓形成

• 批准号: 7536423
• 负责人: JANE E Freedman
• 金额: $ 71.77万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7536423
• 关键词: Acute; Arachidonate 5-Lipoxygenase; Atherosclerosis; Biological Assay; Biological Markers; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cells; Chronic; Clinical; Cohort Studies; Communities; Complement Factor B; Confocal Microscopy; Data; Databases; Development; Diabetes Mellitus; Dinoprostone; Disease; Elderly man; Environmental Risk Factor; Enzymes; Epidemiologic Studies; Evaluation; Event; Framingham Heart Study; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genotype; Grant; Haplotypes; Heart failure; Hospitals; Housekeeping Gene; Individual; Inflammation; Inflammatory; Interleukin-1 Receptors; Interleukin-6; Investigation; Knowledge; Lead; Length; Leukocytes; Measures; Medial; Mediating; Methods; Microarray Analysis; Molecular; Molecular Profiling; Mononuclear Leukocytes; Myocardial Infarction; NF-kappa B; Nuclear; PTGS1 gene; Participant; Pathway interactions; Patients; Pattern; Peripheral; Phenotype; Process; Proteins; Regulation; Relative (related person); Reporting; Research; Research Personnel; Risk Factors; Role; Sampling; Selection Bias; Signal Pathway; Single Nucleotide Polymorphism; Site; Smoking; Stroke; Sudden Death; TLR1 gene; TLR2 gene; Thick; Thrombosis; Toll-Like Receptor 1; Unstable angina; Variant; Vascular Diseases; Woman; Work; atherothrombosis; base; cardiovascular disorder risk; cofactor; coronary artery calcification; cyclooxygenase 2; design; disease phenotype; follow-up; genetic analysis; genetic variant; insight; middle age; novel; offspring; peripheral blood; population based; programs; protein expression; receptor; tool; vascular inflammation

Recent data suggest that patients with both acute and chronic cardiovascular disease (CVD) have not only enhanced platelet function, but also increased interactions between platelets and the inflammatory process. Platelets lead to acute thrombotic occlusion and also contribute to the chronic process of atherosclerosis. Whereas established risk factors, inflammatory and thrombotic biomarkers, and genotypic variations have been examined extensively to predict CVD events, methods utilizing gene expression profiles have not been reported from large population-based studies. In preliminary hospital-based data, we found distinct patterns of platelet gene expression in patients with CVD including enhanced expression of the inflammatory Toll receptors and 5-lipoxygenase. Importantly, these proteins all stimulate the pro- inflammatory NFkappa-B signaling pathway that leads to expression of specific pro-inflammatory and thrombotic genes. Expression of the NFkappa-B dependent genes cyclooxygehase 2 and interleukin 6 were also found to be increased. Previously, we have measured systemic biomarkers of vascular inflammation in the community-based sample of 3500 middle-aged and elderly men and women of the Framingham Heart Study (FHS) Offspring Study. In these subjects, inflammatory biomarkers were related to traditional CVD risk factors, and prevalent clinical and subclinical CVD. However, a large proportion of the variability in vascular disease and thrombosis remains unexplained and the contribution of gene expression from circulating peripheral cells is unknown. The central hypothesis of this proposal is that increased thrombotic and inflammatory pathways specifically mediated by NFkappa-B are a pro-atherothrombotic phenotype and can be measured as enhanced gene and biomarker expression due to NFkappa-B dependent activity. We hypothesize that the expression of these genes is itself a proatherosclerotic phenotype that is influenced by both environmental factors and genetic variability. We propose the following questions: 1. Is stimulation of the NFkappa-B pathway associated with increased expression of relevant markers of enhanced thrombosis and inflammation? 2. What is the relation between NFkappa-B dependent expression (RNA) and the relevant genotypes(DNA)? 3. Do established CVD risk factors correlate with NFkappa-B dependent changes in platelet and leukocyte gene expression in community-based individuals? 4. Do changes in gene expression in platelets and leukocytes predict subclinical and clinical CVD?

最近的数据表明，患有急性和慢性心血管疾病（CVD）的患者没有 不仅增强了血小板功能，而且还增加了血小板与炎症之间的相互作用 过程。血小板导致急性血栓闭塞，也导致血栓形成的慢性过程。 动脉粥样硬化。鉴于已确定的危险因素、炎症和血栓生物标志物以及基因型 变异已被广泛检查以预测CVD事件，利用基因表达的方法 大规模基于人群的研究尚未报告概况。在基于医院的初步数据中，我们 发现 CVD 患者血小板基因表达的独特模式，包括 炎症 Toll 受体和 5-脂氧合酶。重要的是，这些蛋白质都刺激亲 炎症 NFkappa-B 信号通路导致特定促炎症和 血栓基因。 NFκ-B依赖性基因环氧化酶2和白细胞介素6的表达 还发现有所增加。此前，我们测量了血管炎症的全身生物标志物 Framingham Heart 的 3500 名中老年男性和女性的社区样本 研究（FHS）后代研究。在这些受试者中，炎症生物标志物与传统 CVD 相关 危险因素以及流行的临床和亚临床 CVD。然而，很大一部分的变异性 血管疾病和血栓形成仍然无法解释，并且基因表达的贡献 循环外周细胞未知。该提案的中心假设是血栓形成增加 NFκ-B 特异性介导的炎症途径是促动脉粥样硬化血栓形成的表型 可以通过由于 NFκ-B 依赖性活性而增强的基因和生物标志物表达来测量。我们 假设这些基因的表达本身就是一种促动脉粥样硬化表型，受以下因素影响 环境因素和遗传变异。我们提出以下问题： 1. NFkappa-B 通路的刺激与相关标记物的表达增加相关吗？ 增强血栓形成和炎症？ 2. NFkappa-B依赖性表达（RNA）与相关基因型（DNA）之间有什么关系？ 3. 已确定的 CVD 危险因素是否与血小板和白细胞中 NFkappa-B 依赖性变化相关 基于社区的个体的基因表达？ 4. 血小板和白细胞基因表达的变化是否可以预测亚临床和临床CVD？