Epidemiology of Venous Thrombosis and Pulmonary Embolism

描述（由申请人提供）：静脉血栓栓塞（VTE），包括深静脉血栓形成和肺栓塞，是美国发病率和死亡率的主要因素。我们建议对血栓栓塞病因学纵向调查（LITE）进行为期4年的更新，这是一项社区动脉粥样硬化风险研究（ARIC）和心血管健康研究（CHS）队列中VTE的前瞻性研究，包括21,680名参与者，随访超过20年。在前三个项目期间，有726例静脉血栓栓塞发生，我们通过55篇出版物成功地确定或澄清了静脉血栓栓塞的多种遗传和非遗传风险因素。特别有趣的GWAS发现与因子XI （F11）和纤维蛋白原γ (FGG)区域有关。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，提出与静脉血栓栓塞危险因素相关的新假设，并利用所有项目期间的信息来提高对静脉血栓栓塞发生的理解。我们的目标是：(1)将VTE事件在ARIC的随访时间延长6年，将LITE VTE事件的数量增加226次，总数达到952次。(2)测试静脉血栓栓塞与已经测量的新型生物标志物的前瞻性关联：维生素D标志物；肝功能障碍的措施；镰状细胞性状；亚临床甲状腺功能障碍的标志。(3)测定血浆XI因子和Y纤维蛋白原水平，确定其与静脉血栓栓塞的关系。(4)对ARIC和CHS白人的F11和FGG外显子区域进行精细的图谱研究，以确定我们观察到的GWAS中这些区域与VTE相关的可能功能变异。(5)对ARIC和CHS白种人进行遗传关联分析，以确定与重要血浆中间表型（aPTT、血管性血友病因子、FVIII、FXI和Y纤维蛋白原）相关的低频变异，并评估与静脉血栓栓塞相关的任何显著变异。本研究旨在提供静脉血栓栓塞风险的新信息，对静脉血栓栓塞的预防和治疗具有潜在的意义。

DESCRIPTION (provided by applicant): 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 in the Atherosclerosis Risk in Communities (ARIC) Study and Cardiovascular Health Study (CHS) cohorts, comprising 21,680 participants followed for more than two decades. In the previous three project periods, during which 726 VTEs occurred, we successfully identified or clarified, via 55 publications, multiple genetic and non-genetic risk factors for VTE. Especially intriguing GWAS findings relate to the factor XI (F11) and fibrinogen gamma (FGG) regions. We plan to build upon these findings during this continuation, by adding VTE cases, addressing new hypotheses related to risk factors for VTE, and using the information from all project periods to improve understanding of VTE occurrence. Our aims are to: (1) Extend VTE event follow-up in ARIC for six more years, increasing the number of LITE VTE events by 226, to a total of 952. (2) Test the prospective association of incident VTE with novel biomarkers already being measured: Vitamin D markers; measures of liver dysfunction; sickle cell trait; markers of subclinical thyroid dysfunction. (3) Measure plasm levels of factor XI and Y fibrinogen and determine their association with VTE. (4) Conduct a fine mapping study of the F11 and FGG exonic regions in ARIC and CHS whites to identify the likely functional variants underlying our observed associations of these regions with VTE in GWAS. (5) Conduct genetic association analyses in ARIC and CHS whites to identify low frequency variants associated with important plasma intermediate phenotypes (aPTT, von Willebrand factor, FVIII, FXI, and Y fibrinogen), and to evaluate any significant variants for associations wih VTE. This study is designed to provide new information on risk for VTE, with potential implications for prevention and treatment of VTE.