Epidemiology of Venous Thrombosis and Pulmonary Embolism

描述（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4年更新，这是一项在社区动脉粥样硬化风险（ARIC）研究和心血管健康研究（CHS）队列中进行的VTE前瞻性研究，包括21，680名参与者跟踪了20多年。在前三个项目期间，发生了726例VTE，我们通过55篇出版物成功地确定或阐明了VTE的多种遗传和非遗传风险因素。特别有趣的GWAS发现涉及因子Xi（F11）和纤维蛋白原γ（FGG）区域。我们计划在此继续研究期间以这些发现为基础，通过增加VTE病例，解决与VTE风险因素相关的新假设，并使用所有项目期间的信息来提高对VTE发生率的理解。 我们的目标是：（1）将ARIC的VTE事件随访延长6年，使LITE VTE事件数量增加226例，总计952例。(2)检测偶发性VTE与已经测量的新生物标志物的前瞻性关联：维生素D标志物;肝功能障碍的测量;镰状细胞特征;亚临床甲状腺功能障碍的标志物。(3)测量血浆因子Xi和Y纤维蛋白原水平，并确定其与VTE的相关性。(4)对ARIC和CHS白人的F11和FGG外显子区域进行精细定位研究，以确定我们观察到的这些区域与GWAS中VTE相关性的可能功能变体。(5)在ARIC和CHS白人中进行遗传关联分析，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，并评价与VTE相关的任何显著变异。 本研究旨在提供有关VTE风险的新信息，对预防和治疗VTE具有潜在意义。

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.