Identification of Potential Biomarkers for CAD Using Integrated Expression and Methylation Data

Abstract

DNA methylation plays an essential role in the pathogenesis of coronary artery disease (CAD) through regulating mRNA expressions. This study aimed to identify hub genes regulated by DNA methylation as biomarkers of CAD. Gene expression and methylation datasets of peripheral blood leukocytes (PBLs) of CAD were downloaded from the Gene Expression Omnibus (GEO) database. Subsequently, multiple computational approaches were performed to analyze the regulatory networks and to recognize hub genes. Finally, top hub genes were verified in a case-control study, based on their differential expressions and methylation levels between CAD cases and controls. In total, 535 differentially expressed-methylated genes (DEMGs) were identified and partitioned into 4 subgroups. TSS200 and 5 UTR were confirmed as high enrichment areas of differentially methylated CpGs sites (DMCs). The function of DEMGs is enriched in processes of histone H3-K27 methylation, regulation of post-transcription and DNAdirected RNA polymerase activity. Pathway enrichment showed DEMGs participated in the VEGF signaling pathway, adipocytokine signaling pathway, and PI3K-Akt signaling pathway. Besides, expressions of hub genes fibronectin 1 (FN1), phosphatase (PTEN), and tensin homolog and RNA polymerase III subunit A (POLR3A) were discordantly expressed between CAD patients and controls and related with DNA methylation levels. In conclusion, our study identified the potential biomarkers of PBLs for CAD, in which FN1, PTEN, and POLR3A were confirmed.

Role of DNA Methylation in Development of Cardiovascular Diseases, Resulting in a Sudden Cardiac Death (Review)

“…Lin et al [46] established an association of PLCB1 gene polymorphisms with the concentration of apolipoprotein B, total cholesterol, and high-density lipoprotein cholesterol in blood. Zhang et al in their recent study [47] identified potential IHD biomarkers (FN1, PTEN, POLR3A), the expression of which is associated with the level of DNA methylation and the risk of IHD. In people with SCD, type 2 diabetes mellitus, and preserved ejection fraction, the expression of the FN1 gene (fibronectin 1) is higher than in those who died from other causes.…”

“…Troponin subunit [33] PLA2G7 -phospholipase A2 group VII; 6p12.3 Degradation of platelet activating factor [35] MMP9 -matrix metallopeptidase 9; 20q13.12 Degradation of collagen of IV and V types Hypomethylation of the gene promoter is associated with IHD, higher levels of PTX3 protein in the blood plasma [28] The level of PTX3 protein in the blood plasma is higher in the group with fatal ACS related to coronary thrombosis as compared with the control group [29] as well as in persons with advanced endpoints (including cardiac death) related to the chronic heart failure [30] MMP9 -matrix metallopeptidase 9; 20q13.12 Gene methylation is associated with the risk of IHD, age when it started developing, IHD risk factors [24] The level of MMP-9 in the blood plasma is considered as a risk marker for SCD [39] FN1 -fibronectin 1; 2q35 Gene promoter hypermethylation is associated with IHD [47] Gene expression is higher in people with SCD, type 2 diabetes mellitus, and preserved left ventricular ejection fraction as compared with persons who died from another cause [48] F2RL3 -F2R like thrombin or trypsin receptor 3; 19p13.11 Gene methylation is associated with cardiovascular mortality in case of IHD [50] ABCB1 -ATP binding cassette subfamily B member 1; 7q21.12 Gene promoter methylation is associated with the risk of ischemic events (including cardiac death, myocardial infarction, ischemic stroke) in case of intracranial stenosis [52] FOXP3 -forkhead box P3; Xp11.23 Gene hypermethylation is associated with IHD [17]…”

Heterogeneous nuclear ribonucleoprotein U-actin complex derived from extracellular vesicles facilitates proliferation and migration of human coronary artery endothelial cells by promoting RNA polymerase II transcription

“…Pol II transcribes all protein-coding genes and many non-coding RNAs in eukaryotic genomes [ 31 ]. Furthermore, RNA Pol III subunit A is discordantly expressed in CAD individuals [ 32 ]. However, the mechanism of the hnRNPU-actin complex in regulating RNA Pol II transcription is rarely studied in HCAEC growth.…”

Construction and validation of molecular subtypes of coronary artery disease based on ferroptosis-related genes

“…With the development of microarray technology and high-throughput sequencing technology, it provides an opportunity to further understand the genetic and molecular basis of CAD [ 12 , 13 ]. However, most of the current studies focus on the differences between CAD and normal controls, and less attention is paid to the differences between different subtypes of CAD.…”