The Role of DNA Methylation in Cardiovascular Risk and Disease

Abstract

Epidemiological studies have demonstrated that genetic, environmental, behavioral, and clinical factors contribute to cardiovascular disease (CVD) development. How these risk factors interact at the cellular level to cause CVD is not well known. Epigenetic epidemiology enables researchers to explore critical links between genomic coding, modifiable exposures, and manifestation of disease phenotype. One epigenetic link, DNA methylation, is potentially an important mechanism underlying these associations. In the past decade, there has been a significant increase in the number of epidemiological studies investigating cardiovascular risk factors and outcomes in relation to DNA methylation, but many gaps remain in our understanding of the underlying etiology and biological implications. In this review we provide a brief overview of the biology and mechanisms of DNA methylation and its role in CVD. In addition, we summarize the current evidence base in epigenetic epidemiology studies relevant to cardiovascular health and disease, and discuss the limitations, challenges, and future directions of the field. Finally, we provide guidelines for well-designed epigenetic epidemiology studies, with particular focus on methodological aspects, study design, and analytical challenges.

Epigenetics and Health Disparities

“…27–32 Higher exposure to air pollution has consistently been shown to be associated with DNA methylation changes. 24,30,33,34 For example, Wang et al reported that per interquartile range increase (26.78µg/m 3 ) in 24-hour exposure to fine particulate matter (PM 2.5 ), angiotensin-converting enzyme DNA methylation (%5mC) was 1.12% lower. 24 Breton et al recently found that first trimester prenatal exposure to multiple pollutants was associated with lower DNA methylation of a retrotransposon repetitive element found throughout the genome (long-interspersed nuclear element 1 [LINE1]) and that O 3 exposure later on in pregnancy was associated with higher LINE1 methylation levels.…”

Translational Perspective on Epigenetics in Cardiovascular Disease

“…Epigenomic research is now rapidly progressing from candidates epigenetic studies in a few individual cells towards the investigation of epigenomic variation in the population (93). Epigenome-wide association studies (EWAS) provide a systematic approach, comparable to GWAS, focused on uncovering epigenetic variants associated with diseases or phenotypes of interest by taking advantage of microarrays capable of measuring DNA methylation at up to 850,000 sites (93).…”

“…Epigenome-wide association studies (EWAS) provide a systematic approach, comparable to GWAS, focused on uncovering epigenetic variants associated with diseases or phenotypes of interest by taking advantage of microarrays capable of measuring DNA methylation at up to 850,000 sites (93). These EWAS have identified hundreds of CpGs, including HIF3A (hypoxia-inducible factor 3A), associated with body mass index (94–96), ABCG1 (ATP-binding cassette subfamily G member 1 , PHOSPHO1 (phosphoethanolamine/phosphocholine phosphatase), SOCS3 (suppressor of cytokine signaling-3) , SREBF1 (sterol regulatory element-binding protein 1), and TXNIP (thioredoxin-intereacting protein) with risk of future type 2 diabetes (97).…”

“…Key challenges include accounting for (or removing) variation in cellular composition, the potential confounding impact of genetic background, and resolving whether associations identified represent causal, consequential, or bystander effects. Although there are now well-validated approaches for taking the cell-type mixture into account in population-based studies on blood, proposed solutions for other tissues are unverified, and may remove both true and false signals (93,105). Quantitative assessment of the contribution of epigenetic factors to transcription, shows that cis-acting DNA sequence variation explains the majority of transcriptional variances for the majority of genes, with relatively few independent epigenetic influences for a small subset of biologically-relevant genes (106).…”

“…EWAS studies are beginning to explore this issue through robust analysis of tissue-specific, cell-specific, and cross-tissue variations in methylation (96). Integration of the EWAS with GWAS and Mendelian randomization analysis is also rapidly emerging as a tool for further understanding how genetics and epigenetics are linked (93,96). Longitudinal studies of changes in DNA methylation and their relationship to phenotypic pattern may also help to better understand casual relationships (96).…”