# High-dimensional Mediation Analysis of Cardiovascular Traits with Multi-omics Data

> **NIH NIH R21** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $121,500

## Abstract

Abstract
Cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke, is the leading cause of
mortality and morbidity in both men and women in the US. Well-established risk factors for CVD include
modifiable lifestyle and non-modifiable host/biological variables, such as smoking, diet, BMI, age, sex, and
race/ethnicity, as well as quantitative cardiovascular traits, such as total cholesterol, triglyceride, high-
density/low-density lipoprotein cholesterol, blood pressure, and fasting glucose. However, it is not yet clear
through which molecular mechanisms these lifestyle/host risk factors influence the cardiovascular traits and
CVD risk. Large-scale multiplatform omics data, including whole-genome sequencing, DNA methylation, and
gene expression data, have been recently generated in tens of thousands of well-phenotyped individuals in the
NHLBI Trans-Omics for Precision Medicine (TOPMed) program. These large-scale multi-omics and phenotype
data resources provide an unprecedented opportunity to investigate the relationships among
environmental/lifestyle risk factors and cardiovascular traits, and how molecular phenotypes work as
intermediate factors between them. However, it remains a significant analytical challenge to delineate those
complex relationships in the presence of multiple types of high-dimensional omics data. The objective of this
research is to capitalize on the multi-omics and phenotype data in the TOPMed program and our recently
developed statistical methods for high-dimensional mediation analysis to quantify the extent to which DNA
methylation and gene expression mediate the effects of environmental/lifestyle risk factors on (Aim 1)
quantitative cardiovascular traits and (Aim 2) the risk of incident CVD. We will identify mediating markers
based on high-dimensional variable selection methods and estimate the total mediation effects of DNA
methylation and gene expression, each alone and jointly, using 6,000 individuals in the Framingham Heart
Study (FHS) study as the discovery cohort and over 2,000 and 1,000 individuals, respectively, in the Women’s
Health Initiative (WHI) and Multi-Ethnic Study of Atherosclerosis (MESA) as validation cohorts. This study will
provide deep insights into molecular phenotypes and biological pathways that mediate the effect of
lifestyle/host risk factors on cardiovascular traits and CVD risk. Our findings may contribute to the discovery of
novel biomarkers and therapeutic targets for CVD, and biomarker-based precision prevention for this
devastating disease. The multi-omics-based mediation analysis pipeline established and refined through this
proposed research will also be applicable to other heart, lung and blood diseases in the TOPMed program.

## Key facts

- **NIH application ID:** 10984574
- **Project number:** 1R21HL170213-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Peng Wei
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $121,500
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984574

## Citation

> US National Institutes of Health, RePORTER application 10984574, High-dimensional Mediation Analysis of Cardiovascular Traits with Multi-omics Data (1R21HL170213-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10984574. Licensed CC0.

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