Whole-genome differentially hydroxymethylated DNA regions among twins discordant for cardiovascular death

Jun Dai, Ming Leung, Weihua Guan, Han Tian Guo, Ruth E. Krasnow, Thomas J. Wang, Wael El-rifai, Zhongming Zhao, Terry Reed

Research output: Contribution to journalArticlepeer-review

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. Hydroxymethyla-tion was quantified in buffy coat DNA collected in 1986–1987. The 1893 differentially hydroxymeth-ylated 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 ad-ditional 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 path-ways, phenotypes, and DNA motifs for these DhMRs or their subtypes, suggesting that hy-droxymethylation 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.

Original languageEnglish (US)
Article number1183
JournalGenes
Volume12
Issue number8
DOIs
StatePublished - Jul 29 2021

Bibliographical note

Funding Information:
This research was supported by the National Heart, Lung, and Blood Institute (NHLBI) 1R21 HL127368-01 (Dr. Dai), the Developmental Fund from the Vanderbilt University Medical Center Division of Epidemiology (Dr. Dai), the Des Moines University Start-up Research Fund (Dr. Dai), and NHLBI HL51429 (to the NHLBI Twin Study) and Vanderbilt University Clinical and Translational Science Awards (CTSA) grant UL1 TR000445 from the National Institutes of Health (NIH)/the National Center for Research Resource (NCRR). The primary work of Ming Leung was performed at the Department of Public Health, College of Health Sciences, Des Moines University, Des Moines, Iowa, U.S. The primary work of Han-Tian Guo was performed in Bioinformatics and Computational Biology Undergraduate Program, Iowa State University, Ames, Iowa, U.S. Jun Dai, Thomas J. Wang, Zhongming Zhao, and Wael El- Rifai conducted the primary work in the Division of Epidemiology at the Department of Medicine, the Division of Cardiovascular Medicine at the Department of Medicine, the Department of Biomedical Informatics, and the Department of Surgery and Cancer Biology in Vanderbilt University School of Medicine, Nashville, Tennessee, U.S., respectively. The whole-genome hy-droxymethylation (5hmC) profiling was performed at Peng Jin?s lab in the Department of Human Genetics at Emory University School of Medicine, Atlanta, Georgia, U.S.

Funding Information:
Funding: Funding/Support: This research was supported by the National Heart, Lung, and Blood Institute (NHLBI) 1R21 HL127368‐01 (Dr. Dai), the Developmental Fund from the Vanderbilt Uni‐ versity Medical Center Division of Epidemiology (Dr. Dai), the Des Moines University Start‐up Re‐ search Fund (Dr. Dai), and NHLBI HL51429 (to the NHLBI Twin Study) and Vanderbilt University Clinical and Translational Science Awards (CTSA) grant UL1 TR000445 from the National Institutes of Health (NIH)/the National Center for Research Resource (NCRR).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Cardiovascular disease
  • Dizygotic
  • Hydroxymethylation
  • Monozygotic
  • Twins

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