# Analysis of Whole Genome Sequence and Hemostasis Phenotypes

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $640,459

## Abstract

PROJECT SUMMARY
Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) play an essential role in blood
coagulation. We have led genome-wide association studies that successfully identified loci contributing to plasma
FVIII and VWF levels. Many of the identified genetic determinants affect both FVIII and VWF, while some loci
affect only FVIII or only VWF. We performed Mendelian randomization (MR) and found associations of
genetically determined FVIII and VWF levels with several arterial and venous thrombotic diseases. Despite these
advances, knowledge gaps remain in understanding the genetics of FVIII and VWF levels, especially in
understudied populations such as Hispanics. More complex regulatory mechanisms such as epistasis and
epigenetics remain uncharacterized. Finally, because many of the identified loci are shared between FVIII and
VWF, it has been difficult to determine the extent to which they play an independent or coordinated role in the
pathology of thrombotic disease.
The overall goals of the renewal of R01 HL139553 are to generate new biological knowledge about the genetic
and epigenetic regulation of FVIII and VWF in multi-ancestry populations and gain a better understanding of how
these hemostatic factors play a role in the development of thrombotic diseases. In Aim 1, we will identify new
genomic loci and improve fine-mapping of existing loci by measuring FVIII and VWF in plasma from 14,000
Hispanics with whole genome sequence data from the Hispanic Community Health Study / Study of Latinos and
combining it with existing multi-ancestry data from CHARGE and TOPMed. We will also evaluate epistatic effects
with the ABO blood group. In Aim 2, we will perform an epigenome-wide association study to examine the
association of FVIII and VWF levels with blood methylation levels at CpG sites across the genome and identify
genetic variants associated with these CpG sites. We will characterize the function of known and newly identified
loci from Aims 1 and 2 using in vitro and in vivo models. In Aim 3, we will use the genetic variants regulating
FVIII and VWF identified in Aims 1 and 2 as genetic instruments in MR analyses to assess whether FVIII and/or
VWF levels are causally related to the risk of several arterial and venous thrombotic diseases. The expected
outcomes are to have identified and validated novel genetic and epigenetic determinants of FVIII and VWF
levels, and to have elucidated the independent or coordinated effects of FVIII and VWF in thrombotic diseases.
These results are anticipated to have an important positive impact because they will provide evidence of the
relative importance of coagulation (i.e., via FVIII) or platelets (i.e., via VWF) in different thrombotic diseases,
thereby informing the targeted use of existing and novel therapies.

## Key facts

- **NIH application ID:** 10849923
- **Project number:** 5R01HL139553-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** PAUL STEFAN DE VRIES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $640,459
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849923

## Citation

> US National Institutes of Health, RePORTER application 10849923, Analysis of Whole Genome Sequence and Hemostasis Phenotypes (5R01HL139553-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10849923. Licensed CC0.

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