AccScience Publishing / GTM / Volume 1 / Issue 1 / DOI: 10.36922/gtm.v1i1.104

Identification of potential hub genes for the diagnosis and therapy of dilated cardiomyopathy with heart failure through bioinformatics analysis

Xinghui Zhuang1,2† Mengyue Tian3† Liming Li2,4 Shurong Xu5 Meiling Cai5 Xiaojie Yang2,4 Zhihuang Qiu1,2 Tianci Chai1,2,6 Liangwan Chen1,2*
Show Less
1 Department of Cardiovascular Surgery, Fujian Medical University Union Hospital, Fuzhou, China
2 Key Laboratory of Cardio-Thoracic Surgery (Fujian Medical University), Fujian Province University, Fuzhou, China
3 Key Laboratory of Ministry of Education for Gastrointestinal Caner, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
4 Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
5 Department of Nursing, Fujian Medical University Union Hospital, Fuzhou, China
6 Department of Anesthesiology, Xinyi People’s Hospital, Xuzhou, China
Global Translational Medicine 2022, 1(1), 104
Submitted: 20 May 2022 | Accepted: 16 June 2022 | Published: 28 June 2022
© 2022 by the Authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( )

Dilated cardiomyopathy (DCM) is a common cause of heart failure. However, genetic-level treatments are not available for this condition. In this study, we searched for biological markers and therapeutic targets for DCM from a genetic perspective. We chose microarray datasets of idiopathic DCM with heart failure tissues and normal function (NF) heart tissues, which were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were analyzed by the GEO2R tool. Gene ontology (GO) and gene set enrichment analysis were used to analyze the functions of DEGs and the pathways in which they are involved. Next, protein-protein interaction networks were built to filter out the hub genes from DEGs. The expression of hub gene was validated by other GEO datasets. Receiver operating characteristic (ROC) curves were plotted to verify the accuracy of the genetic diagnosis. In the end, the mRNA-miRNA-lncRNA network was built to find potentially correlative genes. Twenty-eight common DEGs in total were screened, and GO analysis showed that DEGs were mainly associated with neutrophil degranulation and activation, regulation of Wnt signaling pathway and the development of cardiac cell and tissue. Five hub genes (asporin [ASPN], osteoglycin [OGN], secreted frizzled-related protein 4 [SFRP4], membrane metalloendopeptidase [MME], and natriuretic peptide gene [NPPA]) were shown to be highly expressed in the validation sets and accurate in distinguish between DCM and NF by ROC curves. miRNA prediction of the hub genes revealed that hsa-mir-28b-5p was associated with SFRP4, ASPN, and MME. All of them may serve as biological diagnostic indicators and provide direction for treatment at the genetic level.

Dilated cardiomyopathy
Heart failure
Bioinformatics analysis
Differentially expressed genes
Hub genes
National Natural Science Foundation of China
Fujian Province Major Science and Technology Program

Yancy CW, Jessup M, Bozkurt B, et al., 2013 ACCF/AHA guideline for the management of heart failure: A report of the american college of cardiology foundation/American heart association task force on practice guidelines. J Am Coll Cardiol, 62: e147–e239.


Weintraub RG, Semsarian C, Macdonald P, 2017, Dilated cardiomyopathy. Lancet, 390: 400–414.


Bozkurt B, Colvin M, Cook J, et al., 2016, Current diagnostic and treatment strategies for specific dilated cardiomyopathies: A scientific statement from the American heart association. Circulation, 134: e579–e646.


Mahmaljy H, Yelamanchili VS, Singhal M, 2021, Dilated Cardiomyopathy. StatPearls, Treasure Island, FL.


Dec GW, Fuster V, 1994, Idiopathic dilated cardiomyopathy. N Engl J Med, 331: 1564–1575.


Merlo M, Cannatà A, Gobbo M, et al., 2018, Evolving concepts in dilated cardiomyopathy. Eur J Heart Fail, 20: 228–239. 


Cao Z, Jia Y, Zhu B, 2019, BNP and NT-proBNP as diagnostic biomarkers for cardiac dysfunction in both clinical and forensic medicine. Int J Mol Sci, 20: 1820.


Lakdawala NK, Winterfield JR, Funke BH, 2013, Dilated cardiomyopathy. Circ Arrhythm Electrophysiol, 6: 228–237.


Akalin PK, 2006, Introduction to bioinformatics. Mol Nutr Food Res, 50: 610–619.


Manfredi M, Brandi J, Di Carlo C, et al., 2019, Mining cancer biology through bioinformatic analysis of proteomic data. Expert Rev Proteom, 16: 733–747.


Edgar R, Domrachev M, Lash AE, 2002, Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res, 30: 207–210.


Cowen L, Ideker T, Raphael BJ, et al., 2017, Network propagation: a universal amplifier of genetic associations. Nat Rev Genet, 18: 551–562.


Salmena L, Poliseno L, Tay Y, et al., 2011, A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell, 146: 353–358.


Barrett T, Wilhite SE, Ledoux P, et al., 2013, NCBI GEO: archive for functional genomics data sets--update. Nucleic Acids Res, 41: D991–D995.


Huang DW, Sherman BT, Lempicki RA, 2009, Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc, 4: 44–57.


Szklarczyk D, Gable AL, Lyon D, et al., 2019, STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res, 47: D607– D613.


Zhou G, Soufan O, Ewald J, et al., 2019, NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis. Nucleic Acids Res, 47: W234–W241.


Li JH, Liu S, Zhou H, et al., 2014, StarBase v2.0: Decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res, 42: D92–D97.


Kumar R, Indrayan A, 2011, Receiver operating characteristic (ROC) curve for medical researchers. Indian Pediatr, 48: 277–287.


McNally EM, Mestroni L, 2017, Dilated Cardiomyopathy: Genetic Determinants and Mechanisms. Circ Res, 121: 731–748.


Taylor MR, Carniel E, Mestroni L, 2006, Cardiomyopathy, familial dilated. Orphanet J Rare Dis, 1: 27. 


Reichart D, Magnussen C, Zeller T, et al., 2019, Dilated cardiomyopathy: from epidemiologic to genetic phenotypes: A translational review of current literature. J Intern Med, 286: 362–372.


Gerull B, Gramlich M, Atherton J, et al., 2002, Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet, 30: 201–204.


van Berlo JH, de Voogt WG, van der Kooi AJ, et al., 2005, Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: Do lamin A/C mutations portend a high risk of sudden death? J Mol Med (Berl), 83: 79–83.


Verdonschot JA, Hazebroek MR, Ware JS, et al., 2019, Role of targeted therapy in dilated cardiomyopathy: The challenging road toward a personalized approach. J Am Heart Assoc, 8: e012514.


Kaneko M, Hashikami K, Yamamoto S, et al., 2016, phospholamban ablation using CRISPR/Cas9 system improves mortality in a murine heart failure model. PLoS One, 11: e0168486. 


Greenberg B, Butler J, Felker GM, et al., 2016, Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): A randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet, 387: 1178-1186.


Muchir A, Wu W, Choi JC, et al., 2012, Abnormal p38α mitogen-activated protein kinase signaling in dilated cardiomyopathy caused by lamin A/C gene mutation. Hum Mol Genet, 21: 4325–4333.


Henry SP, Takanosu M, Boyd TC, et al., 2001, Expression pattern and gene characterization of asporin. A newly discovered member of the leucine-rich repeat protein family. J Biol Chem, 276: 12212–12221.


Li XL, Yu F, Li BY, et al., 2019, The protective effects of grape seed procyanidin B2 against asporin mediates glycated low-density lipoprotein induced-cardiomyocyte apoptosis and fibrosis. Cell Biol Int, 44: 268-277.


Zuo C, Li X, Huang J, et al., 2018, Osteoglycin attenuates cardiac fibrosis by suppressing cardiac myofibroblast proliferation and migration through antagonizing lysophosphatidic acid 3/matrix metalloproteinase 2/ epidermal growth factor receptor signalling. Cardiovasc Res, 114: 703–712.


Deckx S, Heggermont W, Carai P, et al., 2018, Osteoglycin prevents the development of age-related diastolic dysfunction during pressure overload by reducing cardiac fibrosis and inflammation. Matrix Biol, 66: 110–124.


Jazbutyte V, Fiedler J, Kneitz S, et al., 2013, MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age (Dordr), 35: 747–762.


Cai R, Jiang J, 2020, LncRNA ANRIL silencing alleviates high glucose-induced inflammation, oxidative stress, and apoptosis via upregulation of MME in podocytes. Inflammation, 43: 2147–2155.


de Bold AJ, Bruneau BG, de Bold ML, 1996, Mechanical and neuroendocrine regulation of the endocrine heart. Cardiovasc Res, 31: 7–18.


Cheng C, Liu H, Tan C, et al., 2019, Mutation in causes atrial fibrillation by activating inflammation and cardiac fibrosis in a knock-in rat model. FASEB J, 33: 8878–8891.


Li J, Zhu J, Ren L, et al., 2002, Association between NPPA promoter methylation and hypertension: Results from Gusu cohort and replication in an independent sample. Clin Epigenetics 12: 133. 


Zeng W, Cao Y, Jiang W, et al., 2019, Knockdown of Sfrp4 attenuates apoptosis to protect against myocardial ischemia/ reperfusion injury. J Pharmacol Sci, 140: 14–19.


Tang CM, Zhang M, Huang L, et al., 2017, CircRNA_000203 enhances the expression of fibrosis-associated genes by derepressing targets of miR-26b-5p, Col1a2 and CTGF, in cardiac fibroblasts. Sci Rep, 7: 40342.


Qi J, Luo X, Ma Z, et al., 2002, Downregulation of miR-26b-5p, miR-204-5p, and miR-497-3p expression facilitates exercise-induced physiological cardiac hypertrophy by augmenting autophagy in rats. Front Genet, 11: 78.

Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Back to top
Global Translational Medicine, Electronic ISSN: 2811-0021 Published by AccScience Publishing