Abstract
BackgroundStudies on DNA methylation have the potential to discover mechanisms of cardiovascular disease (CVD) risk. However, the role of DNA methylation in CVD etiology remains unclear.ResultsWe performed an epigenome-wide association study (EWAS) on CVD in a longitudinal sample of Swedish twins (535 individuals). We selected CpGs reaching the Bonferroni-corrected significance level (2 times 10–7) or the top-ranked 20 CpGs with the lowest P values if they did not reach this significance level in EWAS analysis associated with non-stroke CVD, overall stroke, and ischemic stroke, respectively. We further applied a bivariate autoregressive latent trajectory model with structured residuals (ALT-SR) to evaluate the cross-lagged effect between DNA methylation of these CpGs and cardiometabolic traits (blood lipids, blood pressure, and body mass index). Furthermore, mediation analysis was performed to evaluate whether the cross-lagged effects had causal impacts on CVD. In the EWAS models, none of the CpGs we selected reached the Bonferroni-corrected significance level. The ALT-SR model showed that DNA methylation levels were more likely to predict the subsequent level of cardiometabolic traits rather than the other way around (numbers of significant cross-lagged paths of methylation → trait/trait → methylation were 84/4, 45/6, 66/1 for the identified three CpG sets, respectively). Finally, we demonstrated significant indirect effects from DNA methylation on CVD mediated by cardiometabolic traits.ConclusionsWe present evidence for a directional association from DNA methylation on cardiometabolic traits and CVD, rather than the opposite, highlighting the role of epigenetics in CVD development.
Highlights
Studies on Deoxyribonucleic acid (DNA) methylation have the potential to discover mechanisms of cardiovascular disease (CVD) risk
Two hundred and twelve individuals were diagnosed with non-stroke CVD in the registry database, 108 were diagnosed with stroke regardless of subtype, and 85 of them were diagnosed with ischemic stroke
In the gene sets related to overall stroke or ischemic stroke in our study, we identified ABP1, known as AOC1, which has been associated with High-density lipoprotein cholesterol (HDL) [17], Total triglyceride (TG) [18], and body mass index (BMI) [19]
Summary
Studies on DNA methylation have the potential to discover mechanisms of cardiovascular disease (CVD) risk. CVD is a global public health concern, many risk factors have been associated with CVD, and new factors emerge with the development of omics technologies, such as genetic variation and epigenetic modifications. DNA methylation is a type of epigenetic process where a methyl group is added to the 5′-position of a cytosine, forming 5-methylcytosine. It is mostly found in regions containing a large number of cytosine 5′ to guanine dinucleotides (CpGs) in promoters. Due to the advances of new technologies to detect DNA methylation in the last decades [2], especially array-based approaches, it is feasible to assess hundreds of thousands of CpGs along the genome in the population
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