{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T06:37:09Z","timestamp":1790318229317,"version":"4.1.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T00:00:00Z","timestamp":1734566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Calcific aortic valve disease (CAVD) is increasingly prevalent among the aging population, and there is a notable lack of drug therapies. Consequently, identifying novel drug targets will be of utmost importance. Given that type 2 diabetes is an important risk factor for CAVD, we identified key genes associated with diabetes - related CAVD via various bioinformatics methods, which provide further potential molecular targets for CAVD with diabetes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Three transcriptome datasets related to CAVD and two related to diabetes were retrieved from the Gene Expression Omnibus (GEO) database. To distinguish key genes, differential expression analysis with the \u201cLimma\u201d package and WGCNA was applied. Machine learning (ML) algorithms were employed to screen potential biomarkers. The receiver operating characteristic curve (ROC) and nomogram were then constructed. The CIBERSORT algorithm was utilized to investigate immune cell infiltration in CAVD. Lastly, the association between the hub genes and 22 types of infiltrating immune cells was evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>By intersecting the results of the \u201cLimma\u201d and WGCNA analyses, 727 and 190 CAVD - related genes identified from the GSE76717 and GSE153555 datasets were obtained. Then, through differential analysis and interaction, 619 genes shared by the two diabetes mellitus datasets were acquired. Next, we intersected the differential genes and module genes of CAVD with the differential genes of diabetes, and the obtained genes were used for subsequent analysis. ML algorithms and the PPI network yielded a total of 12 genes, 10 of which showed a higher diagnostic value. Immune cell infiltration analysis revealed that immune dysregulation was closely linked to CAVD progression. Experimentally, we have verified the gene expression differences of MFAP5, which has the potential to serve as a diagnostic biomarker for CAVD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In this study, a multi-omics approach was used to identify 10 CAVD-related biomarkers (COL5A1, COL5A2, THBS2, MFAP5, BTG2, COL1A1, COL1A2, MXRA5, LUM, CD34) and to develop an exploratory risk model. Western blot (WB) and immunofluorescence experiments revealed that MFAP5 plays a crucial role in the progression of CAVD in the context of diabetes, offering new insights into the disease mechanism.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1506663","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T05:10:38Z","timestamp":1734585038000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Identification and validation of the diagnostic biomarker MFAP5 for CAVD with type 2 diabetes by bioinformatics analysis"],"prefix":"10.3389","volume":"15","author":[{"given":"Qiang","family":"Shen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingyi","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuqiang","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengfeng","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongtao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nianguo","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,12,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.313248","article-title":"NFkappaB (Nuclear factor kappa-light-chain enhancer of activated B cells) activity regulates cell-type-specific and context-specific susceptibility to calcification in the aortic valve","volume":"40","author":"Gee","year":"2020","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.318503","article-title":"KPT-330 prevents aortic valve calcification via a novel C\/EBPbeta signaling pathway","volume":"128","author":"Dutta","year":"2021","journal-title":"Circ Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.jacbts.2022.03.002","article-title":"PTP1B inhibition improves mitochondrial dynamics to alleviate calcific aortic valve disease via regulating OPA1 homeostasis","volume":"7","author":"Liu","year":"2022","journal-title":"JACC Basic Transl Sci"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.116.307526","article-title":"Bone morphogenetic protein signaling is required for aortic valve calcification","volume":"36","author":"Gomez-Stallons","year":"2016","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14777","article-title":"Inhibition of microRNA-222 up-regulates TIMP3 to promotes osteogenic differentiation of MSCs from fracture rats with type 2 diabetes mellitus","volume":"24","author":"Jiang","year":"2020","journal-title":"J Cell Mol Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"3485","DOI":"10.1038\/ncomms4485","article-title":"Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction","volume":"5","author":"Sun","year":"2014","journal-title":"Nat Commun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-019-2328-6","article-title":"The effect of diabetes on burn patients: a retrospective cohort study","volume":"23","author":"Dolp","year":"2019","journal-title":"Crit Care"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.16937","article-title":"Aortic valve disease in diabetes: Molecular mechanisms and novel therapies","volume":"25","author":"Manduteanu","year":"2021","journal-title":"J Cell Mol Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"46","DOI":"10.4093\/dmj.2016.40.1.46","article-title":"Protective Effects of Ginger (Zingiber officinale) Extract against Diabetes-Induced Heart Abnormality in Rats","volume":"40","author":"Ilkhanizadeh","year":"2016","journal-title":"Diabetes Metab J"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvab142","article-title":"Role of oxidative stress in calcific aortic valve disease and its therapeutic implications","volume":"118","author":"Greenberg","year":"2022","journal-title":"Cardiovasc Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehab757","article-title":"Calcific aortic valve disease: from molecular and cellular mechanisms to medical therapy","volume":"43","author":"Kraler","year":"2022","journal-title":"Eur Heart J"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2022.119360","article-title":"Weighted gene Co-expression network analysis (WGCNA) reveals a set of hub genes related to chlorophyll metabolism process in chlorella (Chlorella vulgaris) response androstenedione","volume":"306","author":"Yu","year":"2022","journal-title":"Environ pollut"},{"key":"B13","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s12938-018-0568-3","article-title":"Machine learning approaches for predicting high cost high need patient expenditures in health care","volume":"17","author":"Yang","year":"2018","journal-title":"BioMed Eng Online"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehae407","article-title":"Lumican promotes calcific aortic valve disease through H3 histone lactylation","volume":"45","author":"Huang","year":"2024","journal-title":"Eur Heart J"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000165064.31505.3B","article-title":"Effect of intensive glycemic control on levels of markers of inflammation in type 1 diabetes mellitus in the diabetes control and complications trial","volume":"111","author":"Schaumberg","year":"2005","journal-title":"Circulation"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-021-00551-9","article-title":"Autophagy in metabolic disease and ageing","volume":"17","author":"Kitada","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2022.801109","article-title":"Ambulophobia as a specific phobia-defining the problem among patients of long-term care facilities in Poland","volume":"10","author":"Gorski","year":"2022","journal-title":"Front Public Health"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-023-00845-7","article-title":"Calcific aortic valve disease: mechanisms, prevention and treatment","volume":"20","author":"Moncla","year":"2023","journal-title":"Nat Rev Cardiol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.2337\/dc22-2144","article-title":"Earlier age at type 2 diabetes diagnosis is associated with increased genetic risk of cardiovascular disease","volume":"46","author":"Lee","year":"2023","journal-title":"Diabetes Care"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.234138","article-title":"Calcific aortic valve stenosis: methods, models, and mechanisms","volume":"108","author":"Miller","year":"2011","journal-title":"Circ Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.091363","article-title":"Collagen V is a dominant regulator of collagen fibrillogenesis: dysfunctional regulation of structure and function in a corneal-stroma-specific Col5a1-null mouse model","volume":"124","author":"Sun","year":"2011","journal-title":"J Cell Sci"},{"key":"B22","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1161\/CIRCRESAHA.113.300155","article-title":"Molecular and cellular aspects of calcific aortic valve disease","volume":"113","author":"Towler","year":"2013","journal-title":"Circ Res"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/iub.131","article-title":"Lumican, a small leucine-rich proteoglycan","volume":"60","author":"Nikitovic","year":"2008","journal-title":"IUBMB Life"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.24100","article-title":"Small leucine-rich proteoglycans exhibit unique spatiotemporal expression profiles during cardiac valve development","volume":"243","author":"Dupuis","year":"2014","journal-title":"Dev Dyn"},{"key":"B25","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1186\/s10020-021-00413-0","article-title":"Microfibrillar-associated protein 5 regulates osteogenic differentiation by modulating the Wnt\/beta-catenin and AMPK signaling pathways","volume":"27","author":"Li","year":"2021","journal-title":"Mol Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/oby.21103","article-title":"MFAP5 is related to obesity-associated adipose tissue and extracellular matrix remodeling and inflammation","volume":"23","author":"Vaittinen","year":"2015","journal-title":"Obes (Silver Spring)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.jacbts.2020.11.008","article-title":"Proteomic architecture of valvular extracellular matrix: FNDC1 and MXRA5 are new biomarkers of aortic stenosis","volume":"6","author":"Bouchareb","year":"2021","journal-title":"JACC Basic Transl Sci"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12953","article-title":"MXRA5 is a TGF-beta1-regulated human protein with anti-inflammatory and anti-fibrotic properties","volume":"21","author":"Poveda","year":"2017","journal-title":"J Cell Mol Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.319644","article-title":"IMPROvE-CED trial: intracoronary autologous CD34+ Cell therapy for treatment of coronary endothelial dysfunction in patients with angina and nonobstructive coronary arteries","volume":"130","author":"Corban","year":"2022","journal-title":"Circ Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"6330","DOI":"10.3390\/ijms21176330","article-title":"Identification of CD34+\/PGDFRalpha+ Valve interstitial cells (VICs) in human aortic valves: association of their abundance, morphology and spatial organization with early calcific remodeling","volume":"21","author":"Lis","year":"2020","journal-title":"Int J Mol Sci"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1506663\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T05:10:41Z","timestamp":1734585041000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1506663\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,19]]},"references-count":30,"alternative-id":["10.3389\/fimmu.2024.1506663"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1506663","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,19]]},"article-number":"1506663"}}