The role of epigenetic modifications in cardiovascular disease: A systematic review

BACKGROUND: Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in processes underlying cardiovascular disease (CVD), including atherosclerosis, inflammation, hypertension and diabetes. METHODS: Eleven databases were searched for studies investigating the association between epigenetic marks (either global, site-specific or genome-wide methylation of DNA and histone modifications) and CVD. RESULTS: Of the 3459 searched references, 31 studies met our inclusion criteria (26 cross-sectional studies and 5 prospective studies). Overall, 12,648 individuals were included, with total of 4037 CVD events. The global DNA methylation assessed at long-interspersed nuclear element (LINE-1) was inversely associated with CVD, independent of established cardiovascular risk factors. Conversely, a higher degree of global DNA methylation measured at Alu repeats or by the LUMA method was associated with the presence of CVD. The studies reported epigenetic regulation of 34 metabolic genes (involved in fetal growth, glucose and lipid metabolism, inflammation, atherosclerosis and oxidative stress) in blood cells to be related with CVD. Among them, 5 loci were validated and methylation at F2RL3 was reported in two large prospective studies to predict cardiovascular disease beyond the traditional risk factors. CONCLUSIONS: Current evidence supports an association between genomic DNA methylation and CVD. However, this review highlights important gaps in the existing evidences including lack of large-scale epigenetic investigations, needed to reliably identify genomic loci where DNA methylation is related to risk of CVD.