# A Longitudinal Epigenetic Study of Atherosclerosis

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $1,309,468

## Abstract

Little is known about the epigenetic bases of atherosclerotic cardiovascular disease (CVD) risk. Our recent
large cross-sectional study revealed many monocyte transcriptome and epigenome signatures associated with
subclinical atherosclerosis. Some of these genomic features appeared to partially mediate the relationship
between traditional CVD risk factors (e.g. age, obesity, and smoking) and measures of atherosclerosis. The
transcriptome signatures included an H3K9me2 demethylase transcription coactivator, ARID5B, which is
known to promote adipogenesis and smooth muscle development. Methylation of ARID5B enhancer was
inversely associated with both ARID5B expression and atherosclerosis. Our experimental in vitro study further
showed that ARID5B promotes expression of genes involved in atherosclerosis-related pro-inflammatory and
lipid metabolism pathways after lipopolysaccharide (LPS) stimulation. These results support a pivotal epigenetic
checkpoint for controlling immunometabolic homeostasis and promoting chronic inflammatory reactions, which
may contribute to atherosclerosis. These data set a compelling stage for prospective studies of the candidate
genomic features and mechanistic dissection of the role of ARID5B in atherogenesis. The goals of our
proposed study are to identify atherosclerosis associated “promising” genomic features that are predictive of
atherogenesis and its progression, to characterize their associations with plaque vulnerability, to determine
their genetic and non-genetic predictors, and to elucidate their mechanistic linkage to atherogenesis. We will
study 1,892 randomly selected subjects from four Multi-Ethnic Study of Atherosclerosis (MESA) field centers
that have planned genomic, DNA methylomic, and transcriptomic data from purified CD14+ monocytes, as well
as concurrent assessment of CVD risk factors and ultrasonographic carotid plaque burden from MESA Exam
5. We will repeat ultrasound imaging to quantify and characterize carotid plaques, and re-evaluate DNA
methylomic and transcriptomic profiles of monocytes at MESA Exam 6, and we will perform in vivo and in vitro
functional studies to achieve the following specific aims: Aim 1. To validate predictive effects of
atherosclerosis-associated genomic features identified at Exam 5 on initiation and progression of
atherosclerosis in a prospective study with 6-years of follow-up. Aim 2. To characterize the associations of the
“promising” genomic features with carotid plaque vulnerability. Aim 3. To identify potential temporal and causal
relationships between known genetic and non-genetic CVD risk factors, the “promising” genomic features, and
plaque burden. Aim 4. To determine the functional consequences of alterations of most the “promising”
genomic features. If successful, the identified “promising” genomic features will provide mechanistic insights
into the etiology of atherosclerosis and potential targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 9999844
- **Project number:** 7R01HL135009-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** YONGMEI LIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,309,468
- **Award type:** 7
- **Project period:** 2016-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999844

## Citation

> US National Institutes of Health, RePORTER application 9999844, A Longitudinal Epigenetic Study of Atherosclerosis (7R01HL135009-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999844. Licensed CC0.

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