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.

Public Health Relevance

This prospective epidemiologic study is identifying novel personal characteristics and genetic variants that contribute to increased risk of venous thromboembolism, i.e., blood clots in veins that may travel and block blood supply to organs. This will have important implications for the prevention and treatment of this common and significant cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059367-13
Application #
8652322
Study Section
Special Emphasis Panel (ZRG1-PSE-H (02))
Program Officer
Olson, Jean
Project Start
1998-02-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
13
Fiscal Year
2014
Total Cost
$625,771
Indirect Cost
$99,288
Name
University of Minnesota Twin Cities
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Cushman, Mary; O'Meara, Ellen S; Heckbert, Susan R et al. (2016) Body size measures, hemostatic and inflammatory markers and risk of venous thrombosis: The Longitudinal Investigation of Thromboembolism Etiology. Thromb Res 144:127-32
Vu, Khanh N; Ballantyne, Christie M; Hoogeveen, Ron C et al. (2016) Causal Role of Alcohol Consumption in an Improved Lipid Profile: The Atherosclerosis Risk in Communities (ARIC) Study. PLoS One 11:e0148765
Yu, Bing; Li, Alexander H; Metcalf, Ginger A et al. (2016) Loss-of-function variants influence the human serum metabolome. Sci Adv 2:e1600800
van Leeuwen, Elisabeth M; Sabo, Aniko; Bis, Joshua C et al. (2016) Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels. J Med Genet 53:441-9
Rodriguez, Santiago; Gaunt, Tom R; Guo, Yiran et al. (2016) Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array. Eur J Hum Genet 24:106-12
Roberts, Jason D; Dewland, Thomas A; Glidden, David V et al. (2016) Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation. Am Heart J 175:9-17
Tin, A; Balakrishnan, P; Beaty, T H et al. (2016) GCKR and PPP1R3B identified as genome-wide significant loci for plasma lactate: the Atherosclerosis Risk in Communities (ARIC) study. Diabet Med 33:968-75
Keaton, Jacob M; Hellwege, Jacklyn N; Ng, Maggie C Y et al. (2016) GENOME-WIDE INTERACTION WITH SELECTED TYPE 2 DIABETES LOCI REVEALS NOVEL LOCI FOR TYPE 2 DIABETES IN AFRICAN AMERICANS. Pac Symp Biocomput 22:242-253
Liu, Ching-Ti; Raghavan, Sridharan; Maruthur, Nisa et al. (2016) Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin. Am J Hum Genet 99:56-75
Begum, Ferdouse; Ruczinski, Ingo; Li, Shengchao et al. (2016) Identifying a Deletion Affecting Total Lung Capacity Among Subjects in the COPDGene Study Cohort. Genet Epidemiol 40:81-8

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