Gene Expression and Thrombosis in a Community Based Cohort Study

描述（由申请人提供）：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，而且血小板与炎症过程之间的相互作用增加。血小板导致急性血栓闭塞，也有助于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型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尚未在大型人群研究中报道。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，包括炎症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的NFkappa-B信号通路，导致特异性促炎和血栓形成基因的表达。NFkappa-B依赖性基因环氧化酶2和白细胞介素6的表达也增加。此前，我们在弗雷明汉心脏研究（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生物标志物。在这些受试者中，炎症生物标志物与传统的CVD危险因素以及流行的临床和亚临床CVD相关。然而，血管疾病和血栓形成的很大一部分变异性仍未得到解释，循环外周细胞基因表达的贡献尚不清楚。该提议的中心假设是，NFkappa-B特异性介导的血栓形成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，可以通过NFkappa-B依赖性活性导致的基因和生物标志物表达的增强来测量。我们假设这些基因的表达本身就是一种受环境因素和遗传变异影响的前动脉粥样硬化表型。我们提出以下问题：NFkappa-B通路的刺激是否与血栓和炎症相关标志物的表达增加有关？2. NFkappa-B依赖性表达（RNA）与相关基因型（DNA）之间的关系是什么？3. 社区个体血小板和白细胞基因表达的NFkappa-B依赖性变化是否与已确定的心血管疾病危险因素相关？4. 血小板和白细胞基因表达的变化能预测亚临床和临床CVD吗？

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?