Genetic discovery and functional validation to identify precursors of clot embolization in those with a deep vein thrombosis

Active Project Grant Awarded Last action

Award ID
R01HL147894
Recipient
Awarding agency
Obligated
$6,569,358

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 94% complete
Originally
Funding
  • $5,848,563.00 Federal
  • $720,795.00 Non-federal
Place of performance
Seattle, WA 98195, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Venous thromboembolism (VTE) is a clinical condition that includes deep vein thrombosis (DVT), a clot in the deep veins of the legs and pelvis, and pulmonary embolism (PE), a clot in the pulmonary arteries. Pulmonary emboli are primarily a consequence of a dislodged DVT clot that travels from the deep veins to the lungs, obstructing blood flow; they are too often fatal. The aim of this proposal is to identify genetic variation associated with venous clot embolization to the lungs in those with a DVT and to characterize the biology and pathology underlying this process. Little is known about factors associated with embolization, including genetic factors, and the knowledge GAP is wide. The only established genetic predictor of embolization is RS6025 variant in the coagulation factor v (FV) structural gene (F5); RS6025 has been shown repeatedly to be a stronger predictor of dvts without a PE (odds ratios [or] ~4.8) than of dvts with a PE (or ~2.1). We know a lot about the functional consequence of the F5 variant RS6025 on FV protein function, but our understanding does not explain the differential DVT-PE effect. We have preliminary data indicating that another non- synonymous F5 variant, RS4524-not in linkage disequilibrium with RS6025-is also differentially associated with DVT-PE risk. Further, this differential in DVT-PE risk for the F5 variants is not observed for other well- established VTE variants, including F2 (prothrombin) and ABO. No large-scale genetic discovery effort has been undertaken to identify new loci differentially associated with DVT-PE risk, nor has a systematic investigation of known loci been pursued to characterize the underlying biology. The aims of this proposal will address these scientific gaps. The research settings are the international network against venous thrombosis (invent) consortium, which has amassed over 35,000 VTE cases from 15 studies with genome-wide markers, and the wolberg laboratory at the university of north carolina at chapel hill, which specializes in mechanisms of clot formation, structure, and stability. There are 3 aims. Aim 1: VTE sub-phenotyping: using existing study information on the classification of VTE, we will sub-phenotype 35,049 VTE cases to identify those with DVT alone and those with PE, with or without a diagnosed DVT. Aim 2: genetic discovery: we will then conduct a genome-wide association study meta-analysis that estimates the risk of PE among those with a DVT. Agnostic and candidate-variant testing will be conducted. Replication will be conducted in over 12,000 VTE cases. Aim 3: functional biology: we will conduct functional interrogations of genes and their variants that are known to be differentially associated with DVT-PE risk. Our approach will be to provide biologic evidence from systematic and reductive, function-focused experiments. Initial work will focus on F5 RS6025 and RS4524; subsequent work will interrogate other novel associations in functional assays of clot formation, structure, and stability. This work will advance our biologic understanding of venous clot embolization to the lungs and may present opportunities to reduce fatalities attributable to PE.

Transactions

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Subawards

Subrecipient Amount Awarded
Universitetet I Tromsø - Norges Arktiske Universitet Genetic Discovery and Functional Validation to Identify Precursors of Clot Embolization in those with a Deep Vein Thrombosis. $10,527
Academisch Ziekenhuis Leiden $9,123
University Of North Carolina At Chapel Hill $267,361
Adera $3,845
Mayo Clinic $21,188
Brigham & Womens Hospital Inc. $41,473
Regents Of The University Of Minnesota $11,504
Universitetet I Tromsø - Norges Arktiske Universitet Genetic Discovery and Functional Validation to Identify Precursors of Clot Embolization in those with a Deep Vein Thrombosis $10,667

Quick answers

Who received award R01HL147894?

R01HL147894 was awarded to University Of Washington by National Heart Lung and Blood Institute (National Institutes of Health) on June 1, 2021.

How much is award R01HL147894 worth?

$6,569,358 has been obligated on R01HL147894: $5,848,563 in federal funding and $720,795 in non-federal funding.

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