Evidence of association of circulating epigenetic-sensitive biomarkers with suspected coronary heart disease evaluated by Cardiac Computed Tomography

PLoS One. 2019 Jan 23;14(1):e0210909. doi: 10.1371/journal.pone.0210909. eCollection 2019.


Circulating biomarkers available in clinical practice do not allow to stratify patients with coronary heart disease (CHD) prior the onset of a clinically relevant event. We evaluated the methylation status of specific genomic segments and gene expression in peripheral blood of patients undergoing Cardiac Computed Tomography (CCT) for CHD (n = 95). We choose to investigate cholesterol metabolism. Methylation and gene expression of low density lipoprotein receptor (LDLR), sterol regulatory element-binding factor 2 (SREBF2) and ATP-binding cassette transporter 1 (ABCA1) were evaluated by qRT-PCR. Calcium score (CACS), stenosis degree, total plaque volume (TPV), calcified plaque volume (CPV), non-calcified plaque volume (NCPV) and plaque burden (PB) were assessed in all CHD patients (n = 65). The percentage of methylation at the specific analyzed segment of LDLR promoter was higher in CHD patients vs healthy subjects (HS) (n = 30) (p = 0.001). LDLR, SREBF2 and ABCA1 mRNAs were up-regulated in CHD patients vs HS (p = 0.02; p = 0.019; p = 0.008). SREBF2 was overexpressed in patients with coronary stenosis ≥50% vs subjects with stenosis <50% (p = 0.036). After adjustment for risk factors and clinical features, ABCA1 (p = 0.005) and SREBF2 (p = 0.010) gene expression were identified as independent predictors of CHD and severity. ROC curve analysis revealed a good performance of ABCA1 on predicting CHD (AUC = 0.768; p<0.001) and of SREBF2 for the prediction of disease severity (AUC = 0.815; p<0.001). Moreover, adjusted multivariate analysis demonstrated SREBF2 as independent predictor of CPV, NCPV and TPV (p = 0.022; p = 0.002 and p = 0.006) and ABCA1 as independent predictor of NCPV and TPV (p = 0.002 and p = 0.013). CHD presence and characteristics are related to selected circulating transcriptional and epigenetic-sensitive biomarkers linked to cholesterol pathway. More extensive analysis of CHD phenotypes and circulating biomarkers might improve and personalize cardiovascular risk stratification in the clinical settings.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics
  • Aged
  • Biomarkers / blood
  • Case-Control Studies
  • Computed Tomography Angiography
  • Coronary Disease / blood*
  • Coronary Disease / diagnostic imaging
  • Coronary Disease / genetics*
  • DNA Methylation
  • Epigenesis, Genetic*
  • Female
  • Gene Expression
  • Genetic Markers
  • Humans
  • Male
  • Middle Aged
  • Plaque, Atherosclerotic / diagnostic imaging
  • Plaque, Atherosclerotic / genetics
  • Promoter Regions, Genetic
  • Receptors, LDL / genetics
  • Sterol Regulatory Element Binding Protein 2 / genetics


  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • Biomarkers
  • Genetic Markers
  • LDLR protein, human
  • Receptors, LDL
  • SREBF2 protein, human
  • Sterol Regulatory Element Binding Protein 2

Grant support

This study was supported by Italian Ministry of Health grants “Giovani Ricercatori 2011-12”, project code GR-2011-02349436 (TI) and “Ricerca Corrente 2013-15” (CN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.