Abstract
BACKGROUND: The association of overall cardiovascular health (CVH) with changes in DNA methylation (DNAm) has not been well characterized. METHODS: We calculated the American Heart Association's Life's Essential 8 (LE8) score to reflect CVH in five cohorts with diverse ancestry backgrounds. Epigenome-wide association studies (EWAS) for LE8 score were conducted, followed by bioinformatic analyses. DNAm loci significantly associated with LE8 score were used to calculate a CVH DNAm score. We examined the association of the CVH DNAm score with incident CVD, CVD-specific mortality, and all-cause mortality. RESULTS: We identified 609 CpGs associated with LE8 score at false discovery rate (FDR) < 0.05 in the discovery analysis and at Bonferroni corrected P < 0.05 in the multi-cohort replication stage. Most had low-to-moderate heterogeneity (414 CpGs [68.0%] with I(2) < 0.2) in replication analysis. Pathway enrichment analyses and phenome-wide association study (PheWAS) search associated these CpGs with inflammatory or autoimmune phenotypes. We observed enrichment for phenotypes in the EWAS 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 FDR < 0.05. For example, hypomethylation at cg20544516 (MIR33B; SREBF1) associated with 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, the reduction in risk of incident CVD, CVD mortality, and all-cause mortality per standard deviation increase in the DNAm score ranged from 19% to 32%, 28% to 40%, and 27% to 45%, respectively. CONCLUSIONS: We identified new DNAm signatures for CVH across diverse cohorts. Our analyses indicate that immune response-related pathways may be the key mechanism underpinning the association between CVH and clinical outcomes.