Abstract
BackgroundAlterations in DNA methylation are demonstrated in atherosclerosis pathogenesis. However, changing rules of global DNA methylation and hydroxymethylation in peripheral blood leukocytes (PBLs) and different blood cell subtypes of coronary artery disease (CAD) patients are still inconclusive, and much less is known about mechanisms underlying.ResultsWe recruited 265 CAD patients and 270 healthy controls with genomic DNA from PBLs, of which 50 patients and 50 controls were randomly chosen with DNA from isolated neutrophils, lymphocytes and monocytes, and RNA from PBLs. Genomic 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) contents were quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) assay. Genomic 5-mC contents were negatively associated with the serum total cholesterol (TC) level (P = 0.010), age (P = 0.016), and PBL classifications (P = 0.023), explaining 6.8% individual variation in controls. Furthermore, genomic 5-mC contents were inversely associated with an increased risk of CAD (odds ratio (OR) = 0.325, 95% confidence interval (CI) = 0.237~0.445, P = 2.62 × 10− 12), independent of PBL counts and classifications, age, sex, histories of hyperlipidemia, hypertension, and diabetes. Within-individual analysis showed a general 5-mC decrease in PBL subtypes, but significant difference was found in monocytes only (P = 0.001), accompanied by increased 5-hmC (P = 3.212 × 10− 4). In addition, coincident to the reduced DNMT1 expression in patients’ PBLs, the expression level of DNMT1 was significantly lower (P = 0.022) in oxidized low-density lipoprotein (ox-LDL) stimulated THP-1-derived foam cells compared to THP-1 monocytes, with decreased genomic 5-mdC content (P = 0.038).ConclusionsGlobal hypomethylation of blood cells defined dominantly by the monocyte DNA hypomethylation is independently associated with the risk of CAD in Chinese Han population. The importance of monocytes in atherosclerosis pathophysiology may demonstrate via an epigenetic pathway, but prospective studies are still needed to test the causality.
Highlights
Alterations in DNA methylation are demonstrated in atherosclerosis pathogenesis
Genomic 5-mC contents were decreased in cases compared with controls Characteristics of the whole study population are presented in Table 1 (Additional file 1: Table S1–S4)
Genomic 5-mC contents were negatively related to age, total cholesterol (TC) levels, and peripheral blood leukocytes (PBLs) classifications in controls Since blood lipids, fasting blood glucose, and blood pressure are well-known established risk factors of coronary artery disease (CAD), we performed statistical analysis to evaluate correlations of DNA methylation with age, gender, TC, TG, high-density lipoprotein cholesterol (HDL-C), Table 1 Characteristics of cases and controls in association analysis
Summary
Alterations in DNA methylation are demonstrated in atherosclerosis pathogenesis. changing rules of global DNA methylation and hydroxymethylation in peripheral blood leukocytes (PBLs) and different blood cell subtypes of coronary artery disease (CAD) patients are still inconclusive, and much less is known about mechanisms underlying. Coronary artery disease (CAD) is the leading cause of death worldwide, counting for trillions of health care expenditure [1]. This situation will continue to deteriorate globally as risk factors continue increasing, such as hypertension, dyslipidemia, diabetes, and obesity. Since a large portion of 5-mC is found in repeat sequences and transposable elements, such as long interspersed nuclear element (LINE-1) and ALU [12,13,14], methylation of these repetitive elements has been used as a surrogate for the global methylation of the genome [15]. It could be directly detected using bisulfite sequencing or other methods primarily based on the digestion of genomic DNA by restriction enzymes, like Luminometric Methylation Assay, LUMA, and the [3H]-methyl acceptance-based method [16, 17]
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