Deep vein thrombosis (DVT) and pulmonary embolism (PE), collectively referred to as venous thromboembolism (VTE), is the third most common cause of vascular death in the US, after only heart attacks and strokes. Current data suggest that genetic factors contribute to > 60% of VTE risk. However, known common variants, confirmed in recent genome-wide association studies (GWAS), such as Factor V Leiden and the ABO blood group, account for only half of this risk. The remaining genetic determinants for VTE are yet to be determined but may involve a combination of common polymorphisms, rare mutations and structural genomic variants. In preliminary studies, we have completed the exome sequencing of 8 individuals with unprovoked VTE. By focusing on 27 genes corresponding to known coagulation, fibrinolytic, and VTE gene networks, we identified 13 heterozygous mutations at 8 loci. Additionally, we investigated the genetic determinants of plasma von Willebrand Factor (VWF), a plasma protein with an established effect on thrombosis risk, by genotyping and measuring VWF levels in 3384 individuals, in 579 sibships from the Genes and Blood Clotting Study (Ginsburg, Desch, University of Michigan) and the Trinity Student Study (Brody, Malloy, NHGRI and Trinity College, Ireland). Our GWAS of VWF antigen levels confirm ABO and VWF as the major common loci regulating plasma VWF with 4 additional novel loci identified by linkage analysis that were undetected by GWAS.
Aim 1 of this proposal will extend the study of this cohort to other potential modifiers of thrombosis risk such as FV, FVIII, plasminogen, PAI-1, D-dimer, antithrombin III, Protein S, and Protein C.
Aim II and III focus on analysis of a cohort of VTE patients in order to adequately address the potential contribution of rare variants influencing VTE risk. We propose to perform whole exome sequencing in a discovery group of 250 patients with unprovoked VTE and compare the identified mutation patterns with those in controls. Loci with significant clustering of rare variats will be analyzed by targeted resequencing and/or genotyping in a larger replication cohort. DNA samples for analysis will be drawn from established cohorts in collaboration with the GIFT Study (Visser and Reitsma, Leiden University, NL) and the ELATE and DODS cohorts (Kearon, McMaster, Canada). We have assembled an experienced, integrated team of investigators from several disciplines such as experimental genomics, statistical genetics, coagulation and thrombosis biology, medical genetics and clinical care. The results should significantly advance our understanding of the genetic basis of VTE pathogenesis and enhance our capacity to identify patients at high risk for VTE.

Public Health Relevance

Venous Thromboembolic Disease (VTE) is a clinically important problem. Genetic risk for VTE is a complex genetic trait involving multiple genes and environmental interactions. This proposal uses state of the art genetic techniques to uncover novel genetic risk factors affecting VTE risk.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL112642-04
Application #
8895383
Study Section
Special Emphasis Panel (ZRG1-VH-J (02))
Program Officer
Kindzelski, Andrei L
Project Start
2012-08-15
Project End
2016-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
4
Fiscal Year
2015
Total Cost
$382,918
Indirect Cost
$136,668
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
van Rooij, Frank J A; Qayyum, Rehan; Smith, Albert V et al. (2017) Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis. Am J Hum Genet 100:51-63
Ma, Qianyi; Jacobi, Paula M; Emmer, Brian T et al. (2017) Genetic variants in ADAMTS13 as well as smoking are major determinants of plasma ADAMTS13 levels. Blood Adv 1:1037-1046
Emmer, Brian T; Ginsburg, David; Desch, Karl C (2016) Von Willebrand Factor and ADAMTS13: Too Much or Too Little of a Good Thing? Arterioscler Thromb Vasc Biol 36:2281-2282
Ozel, A B; McGee, B; Siemieniak, D et al. (2016) Genome-wide studies of von Willebrand factor propeptide identify loci contributing to variation in propeptide levels and von Willebrand factor clearance. J Thromb Haemost 14:1888-98
Machiela, Mitchell J; Zhou, Weiyin; Sampson, Joshua N et al. (2015) Characterization of large structural genetic mosaicism in human autosomes. Am J Hum Genet 96:487-97
Desch, Karl C (2015) Dissecting the genetic determinants of hemostasis and thrombosis. Curr Opin Hematol 22:428-36
Ozel, A Bilge; Moroi, Sayoko E; Reed, David M et al. (2014) Genome-wide association study and meta-analysis of intraocular pressure. Hum Genet 133:41-57
Ma, Qianyi; Ozel, Ayse B; Ramdas, Shweta et al. (2014) Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels. Blood 124:3155-64
Wu, Cynthia; Dwivedi, Dhruva J; Pepler, Laura et al. (2013) Targeted gene sequencing identifies variants in the protein C and endothelial protein C receptor genes in patients with unprovoked venous thromboembolism. Arterioscler Thromb Vasc Biol 33:2674-81