Gene Expression and Thrombosis in a Community Based Cohort Study

最近的数据表明，患有急性和慢性心血管疾病(CVD)的患者并没有 不仅增强了血小板的功能，而且还增加了血小板和炎症之间的相互作用 进程。血小板导致急性血栓性闭塞，也是慢性心绞痛发生的原因之一。 动脉硬化。鉴于已确定的危险因素、炎症和血栓生物标志物以及基因分型 利用基因表达的方法对变异进行了广泛的研究，以预测CVD事件 大规模的基于人群的研究还没有报告个人资料。在基于医院的初步数据中，我们 在心血管疾病患者中发现不同的血小板基因表达模式，包括增强的 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NFkappa-B信号通路导致特异性促炎因子和 血栓基因。NFkappa-B依赖基因环氧合酶2和白介素6的表达 也被发现增加了。在此之前，我们已经测量了血管炎症的系统性生物标志物 以社区为基础的3500名中老年男性和女性的Framingham心脏样本 研究(FHS)后代研究。在这些受试者中，炎性生物标志物与传统的心血管疾病有关。 危险因素，以及普遍的临床和亚临床心血管疾病。然而，很大比例的可变性在 血管疾病和血栓形成仍未解释，基因表达对 循环中的外周细胞尚不清楚。这一提议的中心假设是血栓形成增加 由NFkappa-B特异性介导的炎症通路是一种促动脉粥样硬化血栓形成的表型，并且 可被测量为由于NFkappa-B依赖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是一种动脉粥样硬化前表型，受 既有环境因素，也有遗传变异。我们提出以下问题： 1.刺激NFkappa-B通路是否与相关标记物的表达增加有关 血栓形成和炎症加剧？ 2.NFkappa-B依赖表达(RNA)与相关的基因类型(DNA)有什么关系？ 3.已建立的心血管危险因素是否与NFkappa-B依赖的血小板和白细胞变化相关 以社区为基础的个体的基因表达？ 4.血小板和白细胞基因表达的变化是否预示着亚临床和临床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?