Epidemiology of Venous Thrombosis and Pulmonary Embolism

描述(申请人提供)：静脉血栓栓塞症(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。我们建议将血栓栓塞症病因纵向调查(LITE)续期4年，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)队列中对VTE进行的前瞻性研究，包括21,680名参与者，跟踪时间超过20年。在之前的三个项目期间，共发生了726起VTE，我们通过55篇出版物成功地确定或澄清了VTE的多种遗传和非遗传风险因素。尤其是与因子XI(F11)和纤维蛋白原伽马(FGG)区域相关的耐人寻味的GWAS发现。我们计划通过增加静脉血栓栓塞症病例，解决与静脉血栓栓塞症风险因素相关的新假说，并使用来自所有项目期的信息来提高对静脉血栓栓塞症发生的理解，从而在此基础上继续研究这些发现。我们的目标是：(1)将ARIC的VTE活动后续活动再延长六年，将小型VTE活动的数量增加226个，总数达到952个。(2)测试VTE事件与已经被测量的新的生物标记物的前瞻性关联：维生素D标记物；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记物。(3)测定血浆凝血因子XI和Y纤维蛋白原水平，并确定其与VTE的关系。(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关联的可能功能变异。(5)在ARIC和CHS白种人中进行遗传关联分析，以确定与重要的血浆中间表型(aPTT、von Willebrand因子、FVIII、FXI和Y纤维蛋白原)相关的低频变异，并评估与VTE关联的任何显著变异。这项研究旨在为VTE的风险提供新的信息，对VTE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.