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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GGG-M (53))
Program Officer
Srinivas, Pothur R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
Public Health & Prev Medicine
Schools of Medicine
United States
Zip Code
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
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
Joehanes, Roby; Just, Allan C; Marioni, Riccardo E et al. (2016) Epigenetic Signatures of Cigarette Smoking. Circ Cardiovasc Genet 9:436-447
Chi, Gloria C; Liu, Yongmei; MacDonald, James W et al. (2016) Long-term outdoor air pollution and DNA methylation in circulating monocytes: results from the Multi-Ethnic Study of Atherosclerosis (MESA). Environ Health 15:119
Ma, Yiyi; Follis, Jack L; Smith, Caren E et al. (2016) Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Am J Clin Nutr 103:567-78
Yi, Hui; Breheny, Patrick; Imam, Netsanet et al. (2015) Penalized multimarker vs. single-marker regression methods for genome-wide association studies of quantitative traits. Genetics 199:205-22
Reynolds, Lindsay M; Ding, Jingzhong; Taylor, Jackson R et al. (2015) Transcriptomic profiles of aging in purified human immune cells. BMC Genomics 16:333
Ding, Jingzhong; Reynolds, Lindsay M; Zeller, Tanja et al. (2015) Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease. Diabetes 64:3464-74
Needham, Belinda L; Smith, Jennifer A; Zhao, Wei et al. (2015) Life course socioeconomic status and DNA methylation in genes related to stress reactivity and inflammation: The multi-ethnic study of atherosclerosis. Epigenetics 10:958-69
Reynolds, Lindsay M; Wan, Ma; Ding, Jingzhong et al. (2015) DNA Methylation of the Aryl Hydrocarbon Receptor Repressor Associations With Cigarette Smoking and Subclinical Atherosclerosis. Circ Cardiovasc Genet 8:707-16

Showing the most recent 10 out of 12 publications