# The Molecular Genetics of Von Willebrand Factor Secretion

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $603,504

## Abstract

Project Abstract
Plasma concentrations of von Willebrand Factor (VWF), a central component of primary hemostasis, vary five-
fold in human populations and are controlled by the balance of cellular secretion rates and half-life in the
circulation. The critical role of plasma VWF concentration in hemostasis is demonstrated by the increased risk
for the bleeding disorder von Willebrand disease (VWD) in individuals with low plasma VWF and the heightened
risk for venous thromboembolic disease, myocardial infarction, and ischemic stroke in individuals with high
plasma VWF. Patients with bleeding phenotypes and low concentrations of plasma VWF are diagnosed Type I
VWD, the most common inherited bleeding disorder. This proposal refers to VWF coding changes as cis variants.
To date, the accepted understanding of the functional consequences of VWF cis variation originates from low-
throughput, laboratory-based investigations of patient-derived mutations. But the vast majority of potential VWF
missense variants have never been characterized, which leads to uncertainty when clinicians identify new
variants of unknown significance in their patients with bleeding phenotypes. In healthy individuals, plasma VWF
levels are highly heritable (64.5%) and mostly determined by variation outside the VWF locus. For example,
common blood type–linked variants in the ABO gene determine ~20% of the variation in plasma VWF. Genome-
wide association studies (GWAS) have identified multiple genetic loci outside of the VWF locus where common
variants are associated with altered plasma VWF levels, implicating a strong role in VWD. The impact of these
trans variants on plasma VWF levels is further implicated by the fact that 30% of the population of individuals
with moderately low VWF (30-50 I.U./dL) and bleeding have no identifiable mutation in the VWF gene. Therefore,
a large gap in the understanding of VWF biology that drives bleeding or thrombosis risk is the role of cis and
trans genetic variants. The objective of this proposal is to comprehensively characterize VWF cis variation and
to identify a network of genes harboring trans genetic variants that are critical for VWF secretion. To achieve this
objective, Aim I will use high-throughput techniques to validate and expand a deep mutational scan of VWF and
generate a comprehensive map of cis missense variants that alter VWF secretion. Aim II will identify trans genes
critical for VWF secretion in a reporter cell line and in a cultured endothelial cell system using lentiviral delivered
CRISPR/Cas9. Both aims will take advantage of access to whole genome sequencing data from several hundred
patients with VWD Type I in the NHLBI-funded Zimmerman Program on VWF Biology. The combined experience
of the assembled group of investigators will leverage the group’s previous history of collaborative science and
capitalize on complementary expertise with deep mutational scanning, CRISPR screening, and VWF biology.
Results from the propose...

## Key facts

- **NIH application ID:** 10851476
- **Project number:** 1R01HL172780-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Karl C Desch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $603,504
- **Award type:** 1
- **Project period:** 2024-05-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851476

## Citation

> US National Institutes of Health, RePORTER application 10851476, The Molecular Genetics of Von Willebrand Factor Secretion (1R01HL172780-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10851476. Licensed CC0.

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