Gene Expression and Thrombosis in a Community Based Cohort Study

最近的数据表明，急性和慢性心血管疾病（CVD）患者没有 不仅增强了血小板功能，而且增加了血小板与炎症因子之间的相互作用。 过程血小板减少导致急性血栓性闭塞，也有助于慢性过程， 动脉粥样硬化然而，已确定的风险因素，炎症和血栓形成生物标志物， 变异已被广泛研究，以预测CVD事件，方法利用基因表达 大规模人群研究尚未报告其特征。在初步的医院数据中，我们 发现CVD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。重要的是，这些蛋白质都能刺激前- 炎性NF κ B信号通路，导致特异性促炎和 血栓形成基因NF-κ B依赖性基因环氧化酶2和白细胞介素6的表达与NF-κ B依赖性基因的表达呈负相关。 也被发现增加。以前，我们已经测量了血管炎症的全身生物标志物， 以社区为基础的样本3500名中老年男女的博爱之心 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 危险因素和流行的临床和亚临床CVD。然而，大部分的变化， 血管疾病和血栓形成仍然无法解释，基因表达的贡献， 循环外周细胞未知。这一建议的中心假设是， 和NF κ B特异性介导的炎症途径是促动脉粥样硬化血栓形成表型， 可以测量为由于NF κ B依赖性活性而增强的基因和生物标志物表达。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， 环境因素和遗传变异。我们提出以下问题： 1. NF-κ B通路的刺激是否与以下相关标志物的表达增加相关： 血栓形成和炎症加剧 2. NF κ B依赖性表达（RNA）与相关基因型（DNA）之间的关系是什么？ 3.确定的CVD危险因素与血小板和白细胞NF κ B依赖性变化相关吗 基因在社区个体中的表达 4.血小板和白细胞基因表达的变化是否能预测亚临床和临床CVD？

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?