Submitted to: Circulation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/11/2025
Publication Date: 7/14/2025
Citation: Carbonneau, M., Li, Y., Qu, Y., Zheng, Y., Wood, A.C., Wang, M., Liu, C., Huan, T., Joehanes, R., Guo, X., Yao, J., Taylor, K.D., Tracy, R.P., Durda, P., Liu, Y., Johnson, W.C., Post, W.S., Blackwell, T., Rotter, J.I., Rich, S.S., Redline, S., Fornage, M., Wang, J., Ning, H., Hou, L., Lloyd-Jones, D., Ferrier, K., Min, Y.I., Carson, A.P., Raffield, L.M., Teumer, A., Grabe, H.J., Völzke, H., Nauck, M., Dörr, M., Domingo-Relloso, A., Fretts, A., Tellez-Plaza, M., Cole, S.A., Navas-Acien, A., Wang, M., Murabito, J.M., Heard-Costa, N.L., Prescott, B., Xanthakis, V., Mozaffarian, D., Levy, D., Ma, J. 2025. DNA methylation signatures of cardiovascular health provide insights into diseases. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.124.073181.
DOI: https://doi.org/10.1161/CIRCULATIONAHA.124.073181

Interpretive Summary: This study looked at how heart health is linked to changes in our DNA, specifically through a process called DNA methylation. Researchers used a heart health score called Life's Essential 8 (which includes things like diet, exercise, and blood pressure) in people from different backgrounds. They found over 600 places in the DNA that were closely tied to heart health. Many of these DNA changes were connected to inflammation and diseases like stroke and heart disease. Based on these findings, a new DNA-based score that reflects how Life's Essential 8 leads to changes in DNA, was created. This score predicted who was more likely to develop heart disease or die early more effectively than the original Life's Simple 8 score. People with better heart health had DNA patterns linked to lower risk of stroke, heart disease, and even death from any cause. This means that heart-healthy habits might help protect your DNA—and your life. This study shows how everyday lifestyle choices could have biological effects that enhance health, and could one day help identify who's at higher risk for heart disease earlier and more accurately. Overall, the importance of diet and other lifestyle factors in prevention is highlighted.

Technical Abstract: The association of overall cardiovascular health (CVH) with changes in DNA methylation (DNAm) has not been well characterized.We calculated the American Heart Association's Life's Essential 8 score to reflect CVH in 5 cohorts with diverse backgrounds (mean age 54 years, 55% women, and enrollment year ranging from 1989 to 2012). Epigenome-wide association studies (EWAS) for Life's Essential 8 score were conducted, followed by bioinformatic analyses. DNAm loci significantly associated with Life's Essential 8 score were used to calculate a CVH DNAm score. We examined the association of the CVH DNAm score with incident cardiovascular disease (CVD), cardiovascular disease-specific mortality, and all-cause mortality. We identified 609 cytosine-phosphate-guanines (CpGs) associated with Life's Essential 8 score at false discovery rate<0.05 in the discovery analysis and at Bonferroni-corrected P<0.05 in the multicohort replication stage. Most had low to moderate heterogeneity (414 CpGs [68.0%] with heterogeneity <0.2) in replication analysis. Pathway enrichment analyses and a phenome-wide association study search associated these CpGs with inflammatory or autoimmune phenotypes. We observed enrichment for phenotypes in the Epigenome-Wide Association Study Catalog, with 29-fold enrichment for stroke (P=2.4e-15) and 21-fold for ischemic heart disease (P=7.4e-38). Two-sample Mendelian randomization (MR) analysis showed significant association between 141 CpGs and ten phenotypes (261 CpG-phenotype pairs) at false discovery rate<0.05. For example, hypomethylation at cg20544516 (MIR33B [microRNA 33b] and SREBF1 [sterol regulatory element-binding transcription factor 1]) is associated with a lower risk of stroke (P=8.1e-6). In multivariable prospective analyses, the CVH DNAm score was consistently associated with clinical outcomes across participating cohorts. Per SD increase in the CVH DNAm score, the decrease in risk of incident cardiovascular disease, cardiovascular disease mortality, and all-cause mortality ranged from 19% to 32%, 28% to 40%, and 27% to 45%, respectively. We identified new DNAm signatures for CVH across diverse cohorts. Our analyses indicate that multiple biological pathways may be relevant to the observed association between CVH and clinical outcomes.