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: 7190771
• 负责人: JANE E Freedman
• 金额: $ 75.85万
• 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/7190771
• 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; Polymerase Chain Reaction; Population; Process; Proteins; Regulation; Relative (related person); Reporting; Research; Research Personnel; Risk Factors; Role; Sampling; Selection Bias; Signal Pathway; Single Nucleotide Polymorphism; Site; Smoke; 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 1; cyclooxygenase 2; cyclophosphamide/doxorubicin/lomustine protocol; design; disease phenotype; follow-up; genetic analysis; genetic variant; insight; middle age; novel; peripheral blood; programs; protein expression; receptor; tool; vascular inflammation

DESCRIPTION (provided by applicant): 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 cyclooxygenase 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?

描述(申请人提供)：最近的数据表明，急性和慢性心血管疾病(CVD)患者不仅血小板功能增强，而且血小板和炎症过程之间的相互作用也增加。血小板会导致急性血栓闭塞，也会导致动脉粥样硬化的慢性过程。虽然已确定的危险因素、炎症和血栓生物标志物以及基因变异已被广泛研究以预测CVD事件，但利用基因表达谱的方法在大规模人群研究中尚未见报道。在基于医院的初步数据中，我们发现了心血管疾病患者血小板基因表达的不同模式，包括炎性Toll受体和5-脂氧合酶的表达增强。重要的是，这些蛋白都刺激促炎因子NFkappa-B信号通路，从而导致特定的促炎基因和血栓形成基因的表达。NFkappa-B依赖基因环氧合酶2和白介素6的表达也增加。此前，我们在弗雷明翰心脏研究(FHS)后代研究的3500名中老年男性和女性的社区样本中测量了血管炎症的系统性生物标记物。在这些受试者中，炎性生物标志物与传统的CVD危险因素以及常见的临床和亚临床CVD相关。然而，血管疾病和血栓形成中的很大一部分变异性仍然不清楚，循环外周细胞基因表达的贡献也是未知的。这一建议的中心假设是，NFkappa-B特异性介导的血栓和炎症途径的增加是一种促动脉粥样硬化血栓形成的表型，可以被测量为由于NFkappa-B依赖的活性而增强的基因和生物标记物的表达。我们假设这些基因的表达本身就是一种动脉粥样硬化前表型，受环境因素和遗传变异的影响。我们提出以下问题：1.NFkappa-B途径的刺激是否与血栓和炎症增强的相关标志物的表达增加有关？2.NFkappa-B依赖的表达(RNA)与相关的基因型别(DNA)之间有什么关系？3.已有的CVD危险因素是否与NFkappa-B依赖的血小板和白细胞基因表达的变化相关？4.血小板和白细胞中基因表达的变化是否预示着亚临床和临床CVD？