Abstract
Epigenetics is a mechanism underlying cardiovascular disease. It is unknown whether DNA hydroxymethylation is prospectively associated with the risk for cardiovascular death independent of germline and common environment. Male twin pairs middle-aged in 1969–1973 and discordant for cardiovascular death through December 31, 2014, were included. Hydroxymethylation was quantified in buffy coat DNA collected in 1986–1987. The 1893 differentially hydroxymethylated regions (DhMRs) were identified after controlling for blood leukocyte subtypes and age among 12 monozygotic (MZ) pairs (Benjamini–Hochberg False Discovery Rate < 0.01), of which the 102 DhMRs were confirmed with directionally consistent log2-fold changes and p < 0.01 among additional 7 MZ pairs. These signature 102 DhMRs, independent of the germline, were located on all chromosomes except for chromosome 21 and the Y chromosome, mainly within/overlapped with intergenic regions and introns, and predominantly hyper-hydroxymethylated. A binary linear classifier predicting cardiovascular death among 19 dizygotic pairs was identified and equivalent to that generated from MZ via the 2D transformation. Computational bioinformatics discovered pathways, phenotypes, and DNA motifs for these DhMRs or their subtypes, suggesting that hydroxymethylation was a pathophysiological mechanism underlying cardiovascular death that might be influenced by genetic factors and warranted further investigations of mechanisms of these signature regions in vivo and in vitro.
Highlights
Gene expression plays a role in the development of cardiovascular disease [1]
Hydroxymethylated Regions (DhMRs) from Monozygotic (MZ) Twin Pairs Discordant for Cardiovascular Death (CVD-dMZ)
In phase 1, 1893 differentially hydroxymethylated regions (DhMRs) were statistically significant and directionally consistent among three regression models without and with subsequent controlling for blood leukocyte composition and age (B-H false discovery rate (FDR) < 0.01) (Table S2)
Summary
Gene expression plays a role in the development of cardiovascular disease [1]. Without changing genetic codes, DNA hydroxymethylation is one of the epigenetic mechanisms that regulate gene expression through the activation of genes and executes functions independent of methylation [1,2]. A prior case-control study of myocardial infarction in the Chinese elderly aged 70 to 88 years demonstrated a modest positive correlation between global 5hmC levels in peripheral mononuclear cells and coronary atherosclerosis measured with the Gensini severity score [7] Another case-control study of stable coronary heart disease and acute myocardial infarction showed the diagnostic and predictive property of 5hmC signature in circulating cell-free DNA for coronary heart disease [8]. Both case-control studies were retrospective and unable to control for potential genetic confounding It is unknown if circulating whole-genome 5hmC was prospectively associated with long-term cardiovascular death independent of genetic and shared environmental influences and blood leukocyte composition in humans. The paucity of this fundamental knowledge impedes the understanding of hydroxymethylation as an epigenetic mechanism underlying the development of cardiovascular disease
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