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 美国发病率和死亡率的贡献者。我们建议纵向续订4年 血栓栓塞症病因学(LITE)的研究，这是一项超过30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)。在上一次 在五个项目期内，我们在127份出版物中成功地确定或澄清了多重遗传和非遗传 静脉血栓栓塞症的危险因素。我们计划在这些发现的基础上，通过增加静脉血栓形成病例，解决新的假设 与VTE蛋白质组风险标记相关，并使用来自所有项目阶段的信息来提高理解 静脉血栓栓塞的发生和可能的预防。 Lite的3个续订目标是：目标1：将ARIC中的VTE事件跟进延长4年，增加 小型VTE活动总数增加140个，达到1,224个。目标2：利用一大批基于适体的 ARIC中可用的血浆蛋白质组学数据(n~5,000个人类蛋白质)，以进行前瞻性研究 非癌症静脉血栓栓塞症发病的蛋白质组学风险标记物(11,600人中552例)，以及ADD 来自HUNT3研究的相同蛋白质组学数据(n=200例非癌症VTE和200例随机亚 队列)。我们预计还可以添加5000名CHS参与者的相同蛋白质组学数据 开发了150个VTE。我们将独立复制MESA研究中的重要蛋白质(n=175非 6,500名参与者中的癌症VTE病例)和HUNT3的独立部分(n=500名额外的非 癌症VTE病例和亚队列n=500)。我们将验证排名前5位的、复制的、基于适配子的 通过商业分析，或在不存在的情况下，通过开发有针对性的定量蛋白质 采用液-质联用法进行分析。目标3：在小说的ARIC中进行GWA 在AIM 2中鉴定和复制的蛋白质，并在MESA和MESA中复制任何重要的遗传关联 HUNT3。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 调查结果。 LITE是美国为数不多且最有成效的VTE前瞻性研究之一。为期4年的续订将提供 前所未有的机会，通过以下方式解决NHLBI的几个重要战略研究重点 多个队列中约5,000个基于适体的蛋白质标记与VTE风险有关。我们希望发现未被发现的 以及通向VTE的潜在因果路径，目的是提供关于VTE的关键新知识 病因学，识别无缘无故VTE风险的方法，以及获得新的干预措施的潜在途径 预防和治疗静脉血栓形成。

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.