Epidemiology of Venous Thrombosis and Pulmonary Embolism

项目摘要 静脉血栓栓塞症（VTE），包括深静脉血栓形成和肺栓塞，是一种主要的 在美国的发病率和死亡率的贡献者，我们提出了一个4年的纵向更新， 血栓栓塞病因学研究（LITE），一项在美国开展的超过3年的VTE前瞻性研究 社区动脉粥样硬化风险研究（ARIC）和心血管健康研究（CHS）。上一 五个项目期间，我们成功地确定或澄清，在127出版物，多基因和非基因 VTE的危险因素。我们计划在这些发现的基础上，通过增加静脉血栓栓塞病例，解决新的假设 与VTE蛋白质组学风险标志物相关，并使用所有项目期间的信息来提高理解 静脉血栓栓塞症的发生和可能的预防。 LITE的3个更新目标是：目标1：将ARIC中的VTE事件随访延长4年， LITE职业技术教育活动总数减少140个，总数达到1 224个。目标2：利用大量基于适体的， ARIC中的血浆蛋白质组学数据（n~ 5，000种人类蛋白质），用于进行以下前瞻性研究： 非癌症VTE事件的蛋白质组风险标志物（11，600例患者中的552例），并添加 来自HUNT 3研究的相同蛋白质组学数据（n=200例偶发非癌症VTE和200例随机亚组VTE） 群组）。我们预计还能够在5,000名CHS参与者中添加相同的蛋白质组学数据， 建立了150个职业教育机构。我们将在梅萨研究中独立复制重要蛋白质（n=175个非 6，500名参与者中的癌症VTE病例）和HUNT 3的独立部分（n=500名额外的非 癌症VTE病例和子队列n=500）。我们将验证前5名新的，可复制的，基于适体的 通过商业测定或在不存在的情况下通过开发靶向定量蛋白质 使用液相色谱-质谱法测定。目标3：在小说的ARIC中进行GWAS 在Aim 2中鉴定和复制的蛋白质，并在梅萨中复制任何显著的遗传关联， Hunt 3.我们还将进行孟德尔随机化研究，以阐明 重要的蛋白质生物标志物和VTE，然后进行网络分析，以整合基因组和蛋白质组学 调查结果。 LITE是美国为数不多且最具成效的VTE前瞻性研究之一。4年的续约将提供 前所未有的机会，以解决几个重要的NHLBI战略研究优先事项， 在多个队列中，约5，000种基于适体的蛋白质标记物与VTE风险相关。我们希望找出未被发现的 以及导致VTE的潜在因果途径，旨在提供有关VTE的重要新知识 病因学，识别无端静脉血栓栓塞风险人群的方法，以及新干预措施的潜在途径。 预防和治疗VTE。

Project Summary Venous thromboembolism (VTE), comprising deep venous thrombosis and pulmonary embolism, is a major contributor to morbidity and mortality in the U.S. We propose a 4-year renewal of the Longitudinal Investigation of Thromboembolism Etiology (LITE), a prospective study of VTE over 3+ decades in the Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS). In the previous five project periods, we successfully identified or clarified, in 127 publications, multiple genetic and non-genetic risk factors for VTE. We plan to build upon these findings, by adding VTE cases, addressing new hypotheses related to VTE proteomic risk markers, and using information from all project periods to improve understanding of VTE occurrence and possible prevention. LITE's 3 renewal aims are to: Aim 1: Extend VTE event follow-up in ARIC for 4 more years, increasing the total number of LITE VTE events by 140, to a total of 1,224. Aim 2: Leverage a large panel of aptamer-based, plasma proteomics data (n~5,000 human proteins) available in ARIC to conduct a prospective study of proteomic risk markers for incident non-cancer VTE (n=552 cases among 11,600 individuals), and add identical proteomics data from the HUNT3 Study (n=200 incident non-cancer VTEs and 200 random sub- cohort). We anticipate also being able to add identical proteomics data on 5,000 CHS participants who developed 150 VTEs. We will independently replicate significant proteins in the MESA study (n=175 non- cancer VTE cases among 6,500 participants) and an independent portion of HUNT3 (n=500 additional non- cancer VTE cases and subcohort n=500). We will validate the top 5 novel, replicated, aptameric-based proteins by either commercial assays or, where non-existent, by developing targeted quantitative protein assays using liquid chromatography-mass spectrometry. Aim 3: Conduct a GWAS in ARIC of the novel proteins identified and replicated in Aim 2, and to replicate any significant genetic associations in MESA and HUNT3. We will also conduct a Mendelian randomization study to elucidate the causal relation between significant protein biomarkers and VTE, followed by a network analysis to integrate the genomic and proteomic findings. LITE is one of the few and most productive US prospective studies on VTE. A 4-year renewal will offer unprecedented opportunities to address several significant NHLBI strategic research priorities by relating ~5,000 aptamer-based protein markers to VTE risk in multiple cohorts. We expect to identify undiscovered and potentially causal pathways leading to VTE, with the aim of providing critical new knowledge about VTE etiology, methods to identify people at risk of unprovoked VTE, and potential paths to new interventions for the prevention and treatment of VTE.