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 #
2R01HL059367-12
Application #
8501824
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
2013-04-15
Budget End
2014-03-31
Support Year
12
Fiscal Year
2013
Total Cost
$759,272
Indirect Cost
$132,021
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
Mahmoodi, Bakhtawar K; Cushman, Mary; Anne Næss, Inger et al. (2017) Association of Traditional Cardiovascular Risk Factors With Venous Thromboembolism: An Individual Participant Data Meta-Analysis of Prospective Studies. Circulation 135:7-16
Chatterjee, Neal A; Giulianini, Franco; Geelhoed, Bastiaan et al. (2017) Genetic Obesity and the Risk of Atrial Fibrillation: Causal Estimates from Mendelian Randomization. Circulation 135:741-754
Arenas de Larriva, Antonio P; Norby, Faye L; Chen, Lin Y et al. (2017) Circulating ceruloplasmin, ceruloplasmin-associated genes, and the incidence of atrial fibrillation in the atherosclerosis risk in communities study. Int J Cardiol 241:223-228
Weng, Lu-Chen; Lunetta, Kathryn L; Müller-Nurasyid, Martina et al. (2017) Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium. Sci Rep 7:11303
Noordam, Raymond; Sitlani, Colleen M; Avery, Christy L et al. (2017) A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. J Med Genet 54:313-323
Fashanu, Oluwaseun E; Heckbert, Susan R; Aguilar, David et al. (2017) Galectin-3 and Venous Thromboembolism Incidence: the Atherosclerosis Risk in Communities (ARIC) Study. Res Pract Thromb Haemost 1:223-230
Justice, Anne E (see original citation for additional authors) (2017) Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits. Nat Commun 8:14977
Kulkarni, Manjusha; Foraker, Randi E; McNeill, Ann M et al. (2017) Evaluation of the modified FINDRISC to identify individuals at high risk for diabetes among middle-aged white and black ARIC study participants. Diabetes Obes Metab 19:1260-1266
Sarnowski, Chloé; Kavousi, Maryam; Isaacs, Steve et al. (2017) Genetic variants associated with earlier age at menopause increase the risk of cardiovascular events in women. Menopause :
Scott, Robert A; Scott, Laura J; Mägi, Reedik et al. (2017) An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. Diabetes 66:2888-2902

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