DNA methylation modules associate with incident cardiovascular disease and cumulative risk factor exposure

Authors: WESTERMAN, KENNETH - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY; SEBASTIANI, PAOLA - BOSTON UNIVERSITY; JACQUES, PAUL - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY; LIU, SIMIN - BOSTON UNIVERSITY; DEMEO, DAWN - BRIGHAM & WOMEN'S HOSPITAL; ORDOVAS, JOSE - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY

Submitted to: Journal of Clinical Epigenetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/12/2019
Publication Date: 10/15/2019
Citation: Westerman, K., Sebastiani, P., Jacques, P., Liu, S., Demeo, D., Ordovas, J.M. 2019. DNA methylation modules associate with incident cardiovascular disease and cumulative risk factor exposure. Journal of Clinical Epigenetics. 11:142. https://doi.org/10.1186/s13148-019-0705-2.
DOI: https://doi.org/10.1186/s13148-019-0705-2

Interpretive Summary: Epigenetics, a system of chemical marks that links genetics to environmental factors such as diet, may be important in increasing our prediction and understanding of cardiovascular disease risk. Here, we examined DNA methylation (a type of epigenetic mark) at a set of hundreds of thousands of sites across the genome to see whether it was predictive of future cardiovascular events. We used a series of statistical procedures to analyze groups of these sites together in order to create more interpretable results and found multiple groups (modules) with significant associations. Furthermore, we found statistical associations between these epigenetic modules and both current and past exposure to cardiovascular risk factors such as body weight and cholesterol levels. Overall, these results suggest that DNA methylation can act as a biomarker of cardiovascular disease, generate hypotheses for future research, and more concretely show that epigenetics can provide a "molecular readout" of past risk factor exposures.

Technical Abstract: Background: Epigenome-wide association studies using DNA methylation have the potential to uncover novel biomarkers and mechanisms of cardiovascular disease (CVD) risk. However, the direction of causation for these associations is not always clear, and investigations to-date have generally failed to replicate at the level of individual loci. Here, we undertook module- and region-based DNA methylation analyses of incident CVD in the Women's Health Initiative (WHI) and Framingham Heart Study Offspring Cohort (FHS) in order to find more robust epigenetic biomarkers for cardiovascular risk. Methods and Findings: We applied weighted gene correlation network analysis (WGCNA) and the Comb-p algorithm to find methylation modules and regions associated with incident CVD in the WHI dataset. We discovered two modules whose activation correlated with CVD risk and replicated across cohorts. One of these modules was enriched for development-related processes and overlaps strongly with epigenetic aging sites. For the other, we showed preliminary evidence for monocyte-specific effects and statistical links to cumulative exposure to traditional cardiovascular risk factors. Additionally, we found three regions (associated with the genes SLC9A1, SLC1A5, and TNRC6C) whose methylation associates with CVD risk. Conclusions: In sum, we present several epigenetic associations with incident CVD that reveal potential monocyte biology-related mechanisms for CVD risk as well as a novel link between DNA methylation and cumulative cardiovascular risk factor exposure.