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.