Multiethnic and multiomics analysis of longitudinal changes in DNA methylation and Cardiovascular health

Project Summary Cardiovascular disease (CVD) remains the leading causes of death in older Americans; innovative and effective approaches to control CVD are urgently needed. Existing evidence suggests that DNA methylation (DNAm) could be a key mechanism in the development of CVD. However, a major knowledge gap remains in distinguishing between methylation loci that causally contribute to disease and those that are the consequence of the early disease phenotype. Thus, the extent to which DNAm can be harnessed to optimize current strategies for CVD prevention and treatment is unknown. We propose to investigate longitudinal change in DNAm (LC-DNAm) across four population-based cohort studies: the Atherosclerosis Risk in Communities (ARIC) Study, the Coronary Artery Risk Development in Young Adults Study (CARDIA), the Framingham Heart Study (FHS), and the Multi-Ethnic Study of Atherosclerosis (MESA). Our analyses will integrate longitudinal epigenome-wide DNAm information with behavioral and clinical cardiovascular health risk factors, genetic and multi-omics markers, and adjudicated incident CVD and death events to identify causal DNAm loci, determinants of causal DNAm loci, and pathogenic pathways uniting causal DNAm and CVD. We will pursue the following four Aims: 1) To determine the prospective relationships between cardiovascular health factors and LC-DNAm; 2) To examine genetic variants associated with LC-DNAm and their relationship with CVD; 3) To identify transcriptomic, proteomic, and metabolomic signatures of LC-DNAm and their relationship with CVD; and 4) To determine relationships of LC-DNAm with CVD and mortality. We have established a multi- disciplinary team with long-standing experience for DNAm analysis. We expect to generate multiple novel bioinformatic datasets, which will provide lines of evidence, complementary to shorter-term experimental research conducted in more controlled conditions. By demonstrating the importance of leveraging longitudinal data to tease out causal influences of DNAm on CVD and mortality, this project will impact design and interpretation of future research for other age-related diseases underpinned by aberrant DNAm.