Background: Venous thromboembolism (VTE) strikes 1-2/1000 Americans annually, and is a common cause of cardiovascular death. The etiology of VTE is multi-factorial, with both genetic and environmental factors contributing to incidence. However, known genetic and environmental risk factors explain less than 50% of VTE incidence and genome-wide association studies (GWAS) have been unsuccessful in identifying novel loci. Little is known about possible gene-environment interactions. Setting: This study will be performed by an experienced, multidisciplinary, multi-institutional group of thromboembolism researchers, genetic and cardiovascular epidemiologists, and experts in statistical genetics working at Harvard University and the Mayo Clinic. Investigators on this project have decades of experience conducting genetic and epidemiological studies, and have published hundreds of peer reviewed papers relevant to the current proposal. Research Plan: We will examine data from the Nurses' Health Studies I & II (NHS I&II) and the Health Professionals Follow Up (HPFS) study. NHS I&II and HPFS are ongoing prospective cohort studies of 121,700 and 116,686 female nurses, and 51,529 male health professionals. For each of the three cohorts, data describing VTE and prospective environmental exposures have been collected for more than 25 years. We will perform the first exome wide association study (XWAS) of VTE in 2,500 VTE cases and 2,500 controls, using the newly available Illumina(R) HumanExome BeadChip that includes 220,000 coding genetic variants to a population prevalence of 0.005%. We will replicate our top XWAS findings in an independent clinic-based sample of 2000 VTE cases and 2000 controls from the Mayo Clinic. Additionally, we will include custom content on the exome chip to perform deep replication of the top 5,000 single nucleotide polymorphisms (SNPs) identified in two previously completed VTE GWAS. Lastly, we will study interactions between confirmed genetic polymorphisms and four key environmental risk factors for VTE identified in our prior work: obesity, physical inactivity, smoking, and postmenopausal hormone use. Relevance to Public Health: VTE is a common and deadly disease, a fact highlighted by the Acting Surgeon General of the United States who in 2008 issued a 'Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism' urging more research on the causes, prevention, and treatment of deep vein thrombosis. The current proposal will be the most comprehensive assessment of genetic and environmental risk factors for VTE to date, will provide insight into the basic pathophysiology of VTE and has the potential to impact clinical practice. Our approach is both innovative and is cost-effective as it builds on decades of prospective data collection from three large cohorts and existing data. Our analyses will result in identification of novel common genetic loci for VTE. Given the high population prevalence of risk factors and the high mortality of VTE, the potential public health impact of this work is large.

Public Health Relevance

This study is designed to identify novel genetic risk factors for venous thromboembolism (VTE), a common and potentially fatal disease of blood clotting, and to study the interaction between these genetic factors and several established environmental risk factors for VTE. To do this, we will perform the first exome wide association study (XWAS) of VTE in 2500 cases and 2500 matched controls from three large prospective cohort studies, as well as a validation of prior genome wide association study (GWAS) results and a systematic analysis of the interaction between genes and four environmental risk factors we identified in our prior work. This work will provide insight into the basic pathophysiology of VTE, improve our ability to assess the risk of these blood clots in an individual and help us design strategies to prevent VTE in the general population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL116854-03
Application #
8797103
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Qasba, Pankaj
Project Start
2013-02-01
Project End
2018-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
3
Fiscal Year
2015
Total Cost
$605,099
Indirect Cost
$73,514
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Harrington, L B; Hagan, K A; Mukamal, K J et al. (2018) Alcohol consumption and the risk of incident pulmonary embolism in US women and men. J Thromb Haemost 16:1753-1762
Hagan, K A; Harrington, L B; Kim, J et al. (2018) Reduction in physical function in women after venous thromboembolism. J Thromb Haemost :
Kim, Jihye; Kraft, Peter; Hagan, Kaitlin A et al. (2018) Interaction of a genetic risk score with physical activity, physical inactivity, and body mass index in relation to venous thromboembolism risk. Genet Epidemiol 42:354-365
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Solomon, Terry; Smith, Erin N; Matsui, Hiroko et al. (2016) Associations Between Common and Rare Exonic Genetic Variants and Serum Levels of 20 Cardiovascular-Related Proteins: The Tromsø Study. Circ Cardiovasc Genet 9:375-83
Hinds, David A; Buil, Alfonso; Ziemek, Daniel et al. (2016) Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis. Hum Mol Genet 25:1867-74
Trégouët, D A; Delluc, A; Roche, A et al. (2016) Is there still room for additional common susceptibility alleles for venous thromboembolism? J Thromb Haemost 14:1798-802
Sumner, Jennifer A; Kubzansky, Laura D; Kabrhel, Christopher et al. (2016) Associations of Trauma Exposure and Posttraumatic Stress Symptoms With Venous Thromboembolism Over 22 Years in Women. J Am Heart Assoc 5:

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