title: The role of epigenetic modifications in cardiovascular disease: A systematic review.
abstract: 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.
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: t.muka@erasmusmc.nl.
authors.forename: Taulant
authors.initials: T
authors.lastname: Muka
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Fjorda
authors.initials: F
authors.lastname: Koromani
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Eliana
authors.initials: E
authors.lastname: Portilla
authors.affiliation: Research and Development, Metagenics, Inc., United States.
authors.forename: Annalouise
authors.initials: A
authors.lastname: O'Connor
authors.affiliation: Medical Library, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Wichor M
authors.initials: WM
authors.lastname: Bramer
authors.affiliation: Research and Development, Metagenics, Inc., United States.
authors.forename: John
authors.initials: J
authors.lastname: Troup
authors.affiliation: Department of Public Health & Primary Care, Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge CB1 8RN, United Kingdom.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chowdhury
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
mesh_terms: D020087:Alu Elements; D002318:Cardiovascular Diseases / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male
chemical_list: D006657:Histones
keywords: Cardiovascular disease; DNA methylation; Epigenetic; Histone modifications; LINE-1