# Using genomics and functional biology to understand fibrinogen and its effect on thrombotic and atherosclerotic outcomes

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $810,978

## Abstract

PROJECT SUMMARY
 Fibrinogen is essential for normal blood coagulation and is an integral component of inflammatory
pathways. These two processes are deeply intertwined in the development of thrombotic and atherosclerotic
diseases. We can better understand the biological and pathophysiological actions of fibrinogen by functionally
characterizing the genomic contribution to circulating fibrinogen levels. In the Cohorts for Heart and Aging
Research in Genomic Epidemiology (CHARGE) consortium, we carried out genome-wide association studies
(GWAS) in search of genetic determinants of fibrinogen levels. These studies involved tens of thousands of
individuals and identified variants within fibrinogen structural genes, as well as 42 other significantly associated
loci. However, association studies do not explain which genes at these loci functionally influence fibrinogen
levels. It is also important to determine whether genes at these loci act through inflammatory pathways. The
goal of this project is to leverage our expertise in genomic studies and functional biology to generate new
biological knowledge about the genomic regulation of fibrinogen and to characterize the relationship between
fibrinogen and thrombotic and atherosclerotic disease.
 Our study design enables information exchange between functional biologists with expertise in coagulation
biochemistry and thrombosis pathophysiology, and genetic epidemiologists from the CHARGE consortium. The
interdisciplinary team will carry out three specific aims. First, we will use siRNA gene silencing to interrogate
genes at 42 loci identified by GWAS to be associated with fibrinogen levels, determine their effect on fibrinogen
transcription, translation, and secretion, and establish whether these genes modulate fibrinogen levels via an
inflammatory (IL6-STAT3) pathway. Second, we will perform an epigenome-wide association study to examine
the association between fibrinogen levels and blood methylation levels at CpG sites across the genome. These
results are integrated with genetic data to identify genetic variants associated with CpG sites (meQTLs) that
are also associated with fibrinogen levels. Candidate genes at fibrinogen-associated meQTLs will also be
evaluated using the proposed functional biological methods. Third, we will assess the causal relationship
between fibrinogen and thrombotic and atherosclerotic disease using a Mendelian Randomization approach.
Knowledge gained from the functional biology experiments will be used to refine the genetic instrument for
fibrinogen and additionally create an instrument that is composed only of variants related to the IL6-STAT3
pathway.
 This team science approach is innovative in its experimental design and in its potential to reveal important,
new information impacting human health by translating results of genomic association studies into a clear
understanding of fibrinogen's role in thrombotic and atherosclerotic disease.

## Key facts

- **NIH application ID:** 9856473
- **Project number:** 5R01HL141291-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Alanna C Morrison
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $810,978
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856473

## Citation

> US National Institutes of Health, RePORTER application 9856473, Using genomics and functional biology to understand fibrinogen and its effect on thrombotic and atherosclerotic outcomes (5R01HL141291-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856473. Licensed CC0.

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