Identification of Key Gene Modules and Potential ceRNA Network in Progressive Coronary Artery Disease by Weighted Gene Co-Expression Network Analysis
Main Article Content
Abstract
Abstract
Coronary Artery Disease (CAD) is a global chronic inflammatory disease with high morbidity and mortality, seriously endangering human health and life quality. Therefore, exploring the critical molecular mechanisms and identifying potential signaling pathways in CAD progression is vital. We reanalyzed peripheral blood mRNA microarray expression data from the GSE34822 dataset and identified 15 gene co-expression modules using weighted gene co-expression network analysis (WGCNA). One of the modules was found to be closely associated with CAD progression, mediating pathways such as platelet degranulation, platelet activation, and platelet aggregation. Genes including NID2, PGRMC1, TSC22D1, LOC340508, KIAA1211, and SMIM3 were significantly correlated with CAD progression. Positive regulation of interleukin−13 production and regulation of monocyte differentiation were identified to be related to these six key genes. Specifically, we discovered that the SMIM3 gene was associated with monocyte infiltration and further developed a SMIM3-related competitive endogenous RNA (ceRNA) network. This suggests that SMIM3 plays a role in monocyte differentiation, contributing to plaque instability and accelerating CAD progression. In this study, we identified six key genes in the crucial module as potential biomarkers for diagnosing and treating progressive CAD. Additionally, we constructed a ceRNA network offering insights into CAD’s underlying regulatory mechanisms.
Downloads
Article Details
Copyright (c) 2025 Gao Z, et al.

This work is licensed under a Creative Commons Attribution 4.0 International License.
Licensing and protecting the author rights is the central aim and core of the publishing business. Peertechz dedicates itself in making it easier for people to share and build upon the work of others while maintaining consistency with the rules of copyright. Peertechz licensing terms are formulated to facilitate reuse of the manuscripts published in journals to take maximum advantage of Open Access publication and for the purpose of disseminating knowledge.
We support 'libre' open access, which defines Open Access in true terms as free of charge online access along with usage rights. The usage rights are granted through the use of specific Creative Commons license.
Peertechz accomplice with- [CC BY 4.0]
Explanation
'CC' stands for Creative Commons license. 'BY' symbolizes that users have provided attribution to the creator that the published manuscripts can be used or shared. This license allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author.
Please take in notification that Creative Commons user licenses are non-revocable. We recommend authors to check if their funding body requires a specific license.
With this license, the authors are allowed that after publishing with Peertechz, they can share their research by posting a free draft copy of their article to any repository or website.
'CC BY' license observance:
License Name |
Permission to read and download |
Permission to display in a repository |
Permission to translate |
Commercial uses of manuscript |
CC BY 4.0 |
Yes |
Yes |
Yes |
Yes |
The authors please note that Creative Commons license is focused on making creative works available for discovery and reuse. Creative Commons licenses provide an alternative to standard copyrights, allowing authors to specify ways that their works can be used without having to grant permission for each individual request. Others who want to reserve all of their rights under copyright law should not use CC licenses.
McCullough PA. Coronary artery disease. Clin J Am Soc Nephrol. 2007;2(3):611-6. Available from: https://doi.org/10.2215/cjn.03871106
Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005;111(25):3481-8. Available from: https://doi.org/10.1161/circulationaha.105.537878
Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114(12):1852-66. Available from: https://doi.org/10.1161/circresaha.114.302721
Popa LE, Petresc B, Cătană C, Moldovanu CG, Feier DS, Lebovici A, et al. Association between cardiovascular risk factors and coronary artery disease assessed using CAD-RADS classification: a cross-sectional study in Romanian population. BMJ Open. 2020;10(2):e031799. Available from: https://doi.org/10.1136/bmjopen-2019-031799
Head SJ, Milojevic M, Daemen J, Ahn JM, Boersma E, Christiansen EH, et al. Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a pooled analysis of individual patient data. Lancet. 2018;391(10124):939-48. Available from: https://doi.org/10.1016/s0140-6736(18)30423-9
Kadota A. The estimated absolute risk of coronary artery disease and subclinical atherosclerosis. J Atheroscler Thromb. 2021;28(12):1260-2. Available from: https://doi.org/10.5551/jat.ED177
Badimon L, Padró T, Vilahur G. Atherosclerosis, platelets and thrombosis in acute ischaemic heart disease. Eur Heart J Acute Cardiovasc Care. 2012;1(1):60-74. Available from: https://doi.org/10.1177/2048872612441582
Björkegren JLM, Lusis AJ. Atherosclerosis: recent developments. Cell. 2022;185(10):1630-45. Available from: https://doi.org/10.1016/j.cell.2022.04.004
Pasalic L, Wang SS, Chen VM. Platelets as biomarkers of coronary artery disease. Semin Thromb Hemost. 2016;42(3):223-33. Available from: https://doi.org/10.1055/s-0036-1572328
Mori H, Torii S, Kutyna M, Sakamoto A, Finn AV, Virmani R. Coronary artery calcification and its progression: what does it really mean? JACC Cardiovasc Imaging. 2018;11(1):127-42. Available from: https://doi.org/10.1016/j.jcmg.2017.10.012
Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559. Available from: https://doi.org/10.1186/1471-2105-9-559
Qi B, Chen JH, Tao L, Zhu CM, Wang Y, Deng GX, et al. Integrated weighted gene co-expression network analysis identified that TLR2 and CD40 are related to coronary artery disease. Front Genet. 2020;11:613744. Available from: https://doi.org/10.3389/fgene.2020.613744
Wang Y, Liu T, Liu Y, Chen J, Xin B, Wu M, Cui W. Coronary artery disease associated specific modules and feature genes revealed by integrative methods of WGCNA, MetaDE and machine learning. Gene. 2019;710:122-30. Available from: https://doi.org/10.1016/j.gene.2019.05.010
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545-50. Available from: https://doi.org/10.1073/pnas.0506580102
Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453-7. Available from: https://doi.org/10.1038/nmeth.3337
Nührenberg TG, Langwieser N, Binder H, Kurz T, Stratz C, Kienzle RP, et al. Transcriptome analysis in patients with progressive coronary artery disease: identification of differential gene expression in peripheral blood. J Cardiovasc Transl Res. 2013;6(1):81-93. Available from: https://doi.org/10.1007/s12265-012-9420-5
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47. Available from: https://doi.org/10.1093/nar/gkv007
Wang C, Song C, Liu Q, Zhang R, Fu R, Wang H, et al. Gene expression analysis suggests immunological changes of peripheral blood monocytes in the progression of patients with coronary artery disease. Front Genet. 2021;12:641117. Available from: https://doi.org/10.3389/fgene.2021.641117
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics. 2012;16(5):284-7. Available from: https://doi.org/10.1089/omi.2011.0118
Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics. 2011;12:77. Available from: https://doi.org/10.1186/1471-2105-12-77
Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife. 2015;4:e05005. Available from: https://doi.org/10.7554/elife.05005
Chen Y, Wang X. miRDB: an online database for prediction of functional microRNA targets. Nucleic Acids Res. 2020;48(D1):D127-31. Available from: https://doi.org/10.1093/nar/gkz757
Li JH, Liu S, Zhou H, Qu LH, Yang JH. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2014;42(Database issue):D92-7. Available from: https://doi.org/10.1093/nar/gkt1248
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498-504. Available from: https://doi.org/10.1101/gr.1239303
Tousoulis D, Paroutoglou IP, Papageorgiou N, Charakida M, Stefanadis C. Recent therapeutic approaches to platelet activation in coronary artery disease. Pharmacol Ther. 2010;127(2):108-20. Available from: https://doi.org/10.1016/j.pharmthera.2010.05.001
Ali Sheikh MS, Alduraywish A, Almaeen A, Alruwali M, Alruwaili R, Alomair BM, et al. Therapeutic value of miRNAs in coronary artery disease. Oxid Med Cell Longev. 2021;2021:8853748. Available from: https://doi.org/10.1155/2021/8853748
Ebadi N, Ghafouri-Fard S, Taheri M, Arsang-Jang S, Parsa SA, Omrani MD. Dysregulation of autophagy-related lncRNAs in peripheral blood of coronary artery disease patients. Eur J Pharmacol. 2020;867:172852. Available from: https://doi.org/10.1016/j.ejphar.2019.172852
Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014;505(7483):344-52. Available from: https://doi.org/10.1038/nature12986
Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868-74. Available from: https://doi.org/10.1038/nature01323
Libby P, Lee RT. Matrix matters. Circulation. 2000;102(16):1874-6. Available from: https://doi.org/10.1161/01.cir.102.16.1874
Fox KAA, Metra M, Morais J, Atar D. The myth of 'stable' coronary artery disease. Nat Rev Cardiol. 2020;17(1):9-21. Available from: https://doi.org/10.1038/s41569-019-0233-y
Schrör K, Huber K. Platelets, inflammation and anti-inflammatory drugs in ACS and CAD. Thromb Haemost. 2015;114(3):446-8. Available from: https://doi.org/10.1160/th15-08-0632
Rolling CC, Barrett TJ, Berger JS. Platelet-monocyte aggregates: molecular mediators of thromboinflammation. Front Cardiovasc Med. 2023;10:960398. Available from: https://doi.org/10.3389/fcvm.2023.960398
Magrone T, Magrone M, Russo MA, Jirillo E. Platelets: angels and demons dancing on the immune stage. Nutrition conducts the orchestra. Endocr Metab Immune Disord Drug Targets. 2021;21(7):1196-1218. Available from: http://dx.doi.org/10.2174/1871530320666200901183119
Müller KA, Chatterjee M, Rath D, Geisler T. Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD. Thromb Haemost. 2015;114(3):498-518. Available from: http://dx.doi.org/10.2174/1871530320666200901183119
Abramowitz Y, Roth A, Keren G, Isakov O, Shomron N, Laitman Y, et al. Whole-exome sequencing in individuals with multiple cardiovascular risk factors and normal coronary arteries. Coron Artery Dis. 2016;27(4):257-66. Available from: https://doi.org/10.1097/mca.0000000000000357
Ghattas A, Griffiths HR, Devitt A, Lip GY, Shantsila E. Monocytes in coronary artery disease and atherosclerosis: where are we now? J Am Coll Cardiol. 2013;62(17):1541-51. Available from: https://doi.org/10.1016/j.jacc.2013.07.043
Pamukcu B, Lip GY, Devitt A, Griffiths H, Shantsila E. The role of monocytes in atherosclerotic coronary artery disease. Ann Med. 2010;42(6):394-403. Available from: https://doi.org/10.3109/07853890.2010.497767
Vanderlaan PA, Reardon CA. Thematic review series: the immune system and atherogenesis. The unusual suspects: an overview of the minor leukocyte populations in atherosclerosis. J Lipid Res. 2005;46(5):829-38. Available from: https://doi.org/10.1194/jlr.r500003-jlr200
Patino WD, Mian OY, Kang JG, Matoba S, Bartlett LD, Holbrook B, et al. Circulating transcriptome reveals markers of atherosclerosis. Proc Natl Acad Sci U S A. 2005;102(9):3423-8. Available from: https://doi.org/10.1073/pnas.0408032102
Tabibiazar R, Wagner RA, Deng A, Tsao PS, Quertermous T. Proteomic profiles of serum inflammatory markers accurately predict atherosclerosis in mice. Physiol Genomics. 2006;25(2):194-202. Available from: https://doi.org/10.1152/physiolgenomics.00240.2005