Epigenetic modifications, especially alterations in DNA methylation in promoter regions of genes, are increasingly being recognized as key factors in the pathogenesis of a wide variety of complex disorders. We propose to investigate the association of global DNA methylation patterns in circulating monocytes in relation to atherosclerosis and monocyte gene expression profiles in the Multi-Ethnic Study of Atherosclerosis (MESA). DNA and RNA will be purified from monocytes isolated from blood samples of a large sample (n=1600) of MESA subjects (44-85 year old, 40% Whites, 27% Blacks, and 21% Hispanics) who are free of clinical atherosclerotic cardiovascular disease (ASCVD) and scheduled to undergo quantitative ultrasound assessment of carotid artery intimal-medial thickness (IMT) and computed tomography-determined calcified coronary plaque at MESA exam 5 (in 2010-2011). The DNA samples will be used to determine genome-wide DNA methylation profiles in a random 1/2 (800) of the participants. Commercial platforms will be used to assay methylation of approximately 27,000 CpG sites covering more than 14,000 well-annotated genes and most CGIs in the genome. RNA from the same monocytes will be used to perform expression profiling of ~25,000 genes, of which more than 12,700 are also present on the methylation assay. Associations between DNA methylation patterns and the extent of atherosclerosis measured by carotid IMT will be determined. Integrative analyses will be performed to elucidate the connections between DNA methylation markers and cellular mRNA expression of cognate genes. Follow-up studies will be performed on subsets of these genes in the remaining cohort to verify DNA methylation/mRNA transcript relationships and their associations with subclinical atherosclerosis. Genomic regions representing confirmed associations will be subsequently investigated using 540 MESA subjects (selected from the 1600 MESA participants) with extremes of IMT phenotypes to reveal functional implications. The proposed studies utilizing this unique and well characterized population will transform the understanding of the role of epigenomics and DNA methylation in relation to atherosclerosis and ASCVD. The knowledge obtained should yield new biomarkers for ASCVD diagnosis and uncover unique therapeutic targets for future targeted interventions. Public Health Relevance: Atherosclerotic cardiovascular disease (ASCVD) remains one of the leading causes of morbidity and mortality world-wide. We propose to investigate the epigenomics of ASCVD through mapping of monocytic DNA methylation profiles. This interdisciplinary, cooperative work will transform our understanding of the etiology and severity of ASCVD.

Public Health Relevance

Atherosclerotic cardiovascular disease (ASCVD) remains one of the leading causes of morbidity and mortality world-wide. We propose to investigate the epigenomics of ASCVD through mapping of monocytic DNA methylation profiles. This interdisciplinary, cooperative work will transform our understanding of the etiology and severity of ASCVD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL101250-02
Application #
7932747
Study Section
Special Emphasis Panel (ZRG1-GGG-M (53))
Program Officer
Paltoo, Dina
Project Start
2009-09-01
Project End
2014-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$754,658
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Levine, Morgan E; Lu, Ake T; Quach, Austin et al. (2018) An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 10:573-591
Liu, C; Marioni, R E; Hedman, Å K et al. (2018) A DNA methylation biomarker of alcohol consumption. Mol Psychiatry 23:422-433
Wan, Ma; Bennett, Brian D; Pittman, Gary S et al. (2018) Identification of Smoking-Associated Differentially Methylated Regions Using Reduced Representation Bisulfite Sequencing and Cell type-Specific Enhancer Activation and Gene Expression. Environ Health Perspect 126:047015
Taylor, Jackson; Reynolds, Lindsay; Hou, Li et al. (2017) Transcriptomic profiles of aging in naïve and memory CD4+ cells from mice. Immun Ageing 14:15
Reynolds, Lindsay M; Magid, Hoda S; Chi, Gloria C et al. (2017) Secondhand Tobacco Smoke Exposure Associations With DNA Methylation of the Aryl Hydrocarbon Receptor Repressor. Nicotine Tob Res 19:442-451
Smith, Jennifer A; Zhao, Wei; Wang, Xu et al. (2017) Neighborhood characteristics influence DNA methylation of genes involved in stress response and inflammation: The Multi-Ethnic Study of Atherosclerosis. Epigenetics 12:662-673
Reynolds, Lindsay M; Lohman, Kurt; Pittman, Gary S et al. (2017) Tobacco exposure-related alterations in DNA methylation and gene expression in human monocytes: the Multi-Ethnic Study of Atherosclerosis (MESA). Epigenetics 12:1092-1100
Zeller, Tanja; Schurmann, Claudia; Schramm, Katharina et al. (2017) Transcriptome-Wide Analysis Identifies Novel Associations With Blood Pressure. Hypertension 70:743-750
Riestra, Pia; Gebreab, Samson Y; Liu, Yongmei et al. (2017) Differentially conserved transcriptomic response to adversity related to self-rated health in the multi-ethnic study of atherosclerosis. Exp Biol Med (Maywood) 242:1812-1819
Joehanes, Roby; Just, Allan C; Marioni, Riccardo E et al. (2016) Epigenetic Signatures of Cigarette Smoking. Circ Cardiovasc Genet 9:436-447

Showing the most recent 10 out of 19 publications