{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:15:02Z","timestamp":1787026502630,"version":"build-2736575974"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T00:00:00Z","timestamp":1667260800000},"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. Genet."],"abstract":"<jats:p>\n                    <jats:bold>Background:<\/jats:bold>\n                    Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown etiology that is hard to diagnose early. Therefore, it is imperative to explore novel biomarkers that may contribute to the easy and early diagnosis of AS.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    Common differentially expressed genes between normal people and AS patients in GSE73754 and GSE25101 were screened by machine learning algorithms. A diagnostic model was established by the hub genes that were screened. Then, the model was validated in several data sets.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    <jats:italic>IL2RB<\/jats:italic>\n                    and\n                    <jats:italic>ZDHHC18<\/jats:italic>\n                    were screened using machine learning algorithms and established as a diagnostic model. Nomograms suggested that the higher the expression of\n                    <jats:italic>ZDHHC18<\/jats:italic>\n                    , the higher was the risk of AS, while the reverse was true for\n                    <jats:italic>IL2RB in vivo<\/jats:italic>\n                    . C-indexes of the model were no less than 0.84 in the validation sets. Calibration analyses suggested high prediction accuracy of the model in training and validation cohorts. The area under the curve (AUC) values of the model in GSE73754, GSE25101, GSE18781, and GSE11886 were 0.86, 0.84, 0.85, and 0.89, respectively. The decision curve analyses suggested a high net benefit offered by the model. Functional analyses of the differentially expressed genes indicated that they were mainly clustered in immune response\u2013related processes. Immune microenvironment analyses revealed that the neutrophils were expanded and activated in AS while some T cells were decreased.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusion:<\/jats:bold>\n                    <jats:italic>IL2RB<\/jats:italic>\n                    and\n                    <jats:italic>ZDHHC18<\/jats:italic>\n                    are potential blood biomarkers of AS, which might be used for the early diagnosis of AS and serve as a supplement to the existing diagnostic methods. Our study deepens the insight into the pathogenesis of AS.\n                  <\/jats:p>","DOI":"10.3389\/fgene.2022.1032010","type":"journal-article","created":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T01:51:11Z","timestamp":1667267471000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Novel peripheral blood diagnostic biomarkers screened by machine learning algorithms in ankylosing spondylitis"],"prefix":"10.3389","volume":"13","author":[{"given":"Jian","family":"Wen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijia","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xieping","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"20232","DOI":"10.1074\/jbc.M116.725762","article-title":"S-palmitoylation of a novel site in the \u03b22-adrenergic receptor associated with a novel intracellular itinerary","volume":"291","author":"Adachi","year":"2016","journal-title":"J. Biol. Chem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"11876","DOI":"10.1073\/pnas.1509929112","article-title":"Rapid and transient palmitoylation of the tyrosine kinase Lck mediates Fas signaling","volume":"112","author":"Akimzhanov","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B3","doi-asserted-by":"publisher","first-page":"155258","DOI":"10.1016\/j.cyto.2020.155258","article-title":"Interleukin-15 in autoimmunity","volume":"136","author":"Allard-Chamard","year":"2020","journal-title":"Cytokine"},{"key":"B4","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.bbamem.2010.01.002","article-title":"Palmitoylation of R-Ras by human DHHC19, a palmitoyl transferase with a CaaX box","volume":"1798","author":"Baumgart","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"B5","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1146\/annurev-immunol-032414-112110","article-title":"HLA-B27","volume":"33","author":"Bowness","year":"2015","journal-title":"Annu. Rev. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2672","DOI":"10.4049\/jimmunol.1002653","article-title":"Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis","volume":"186","author":"Bowness","year":"2011","journal-title":"J. Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1084\/jem.20190546","article-title":"IL2RB maintains immune harmony","volume":"216","author":"Campbell","year":"2019","journal-title":"J. Exp. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13046-019-1033-2","article-title":"DHHC protein family targets different subsets of glioma stem cells in specific niches","volume":"38","author":"Chen","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B65","first-page":"14","article-title":"Introduction to machine learning, neural networks, and deep learning","volume":"9","author":"Choi","year":"2020","journal-title":"Transl. Vis. Sci. Technol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1111\/j.0105-2896.2009.00865.x","article-title":"From HLA-B27 to spondyloarthritis: A journey through the ER","volume":"233","author":"Colbert","year":"2010","journal-title":"Immunol. Rev."},{"key":"B64","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1111\/1756-185X.12779","article-title":"The ongoing quest for biomarkers in ankylosing spondylitis","volume":"18","author":"Danve","year":"2015","journal-title":"Int. J. Rheum. Dis."},{"key":"B10","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1093\/rheumatology\/ket387","article-title":"Global prevalence of ankylosing spondylitis","volume":"53","author":"Dean","year":"2014","journal-title":"Rheumatol. Oxf."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1084\/jem.20182015","article-title":"A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation","volume":"216","author":"Fernandez","year":"2019","journal-title":"J. Exp. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1189\/jlb.1112581","article-title":"CD4 T cell-intrinsic IL-2 signaling differentially affects Th1 and Th17 development","volume":"94","author":"Fujimura","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1002\/jcla.21768","article-title":"Neutrophil-lymphocyte ratio connected to treatment options and inflammation markers of ankylosing spondylitis","volume":"29","author":"G\u00f6kmen","year":"2015","journal-title":"J. Clin. Lab. Anal."},{"key":"B14","first-page":"401","article-title":"Anti-nuclear antibodies, anti-DNA and C4 complement evolution in rheumatoid arthritis and ankylosing spondylitis treated with TNF-alpha blockers","volume":"26","author":"Gonnet-Gracia","year":"2008","journal-title":"Clin. Exp. Rheumatol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1002\/art.39948","article-title":"Polymorphisms in the F pocket of HLA-B27 subtypes strongly affect assembly, chaperone interactions, and heavy-chain misfolding","volume":"69","author":"Guiliano","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.intimp.2018.02.008","article-title":"Relationship between monocytes to lymphocytes ratio and axial spondyloarthritis","volume":"57","author":"Huang","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"B61","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s12865-018-0280-x","article-title":"Anti-SIRT1 autoantibody is elevated in ankylosing spondylitis: A potential disease biomarker","volume":"19","author":"Hu","year":"2018","journal-title":"BMC Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"eabh2169","DOI":"10.1126\/sciadv.abh2169","article-title":"A single-cell type transcriptomics map of human tissues","volume":"7","author":"Karlsson","year":"2021","journal-title":"Sci. Adv."},{"key":"B60","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1111\/1756-185X.13475","article-title":"Serum miR-214 as a novel biomarker for ankylosing spondylitis","volume":"22","author":"Kook","year":"2019","journal-title":"Int. J. Rheum. Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"760214","DOI":"10.3389\/fimmu.2021.760214","article-title":"Platelet-to-Lymphocyte ratio as an independent factor was associated with the severity of ankylosing spondylitis","volume":"12","author":"Liang","year":"2021","journal-title":"Front. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/ni.2030","article-title":"Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages","volume":"12","author":"Liao","year":"2011","journal-title":"Nat. Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"490","DOI":"10.4049\/jimmunol.1100123","article-title":"Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis","volume":"187","author":"Lin","year":"2011","journal-title":"J. Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/s41584-021-00625-y","article-title":"Ankylosing spondylitis: An autoimmune or autoinflammatory disease?","volume":"17","author":"Mauro","year":"2021","journal-title":"Nat. Rev. Rheumatol."},{"key":"B22","doi-asserted-by":"crossref","first-page":"6665","DOI":"10.4049\/jimmunol.163.12.6665","article-title":"Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies","volume":"163","author":"Mear","year":"1999","journal-title":"J. Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1002\/jcla.21908","article-title":"The association between neutrophil\/lymphocyte ratio and disease activity in rheumatoid arthritis and ankylosing spondylitis","volume":"30","author":"Mercan","year":"2016","journal-title":"J. Clin. Lab. Anal."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1136\/annrheumdis-2021-221035","article-title":"Axial spondyloarthritis","volume":"80","author":"Navarro-Comp\u00e1n","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"B25","doi-asserted-by":"publisher","first-page":"4543","DOI":"10.1091\/mbc.E12-05-0336","article-title":"Analysis of substrate specificity of human DHHC protein acyltransferases using a yeast expression system","volume":"23","author":"Ohno","year":"2012","journal-title":"Mol. Biol. Cell."},{"key":"B26","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1007\/s11926-019-0856-3","article-title":"The pathogenesis of ankylosing spondylitis: An update","volume":"21","author":"Pedersen","year":"2019","journal-title":"Curr. Rheumatol. Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2017","DOI":"10.1007\/s11427-021-2048-2","article-title":"Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth","volume":"65","author":"Pei","year":"2022","journal-title":"Sci. China. Life Sci."},{"key":"B63","first-page":"9101964","article-title":"Serum sclerostin as a possible biomarker in ankylosing spondylitis: A case-control study","volume":"2018","author":"Perrotta","year":"2022","journal-title":"J. Immunol. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e20191247","DOI":"10.1084\/jem.20191247","article-title":"Effects of interleukin-2 in immunostimulation and immunosuppression","volume":"217","author":"Pol","year":"2020","journal-title":"J. Exp. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1189\/jlb.0605298","article-title":"Interleukin-15 enhances human neutrophil phagocytosis by a syk-dependent mechanism: Importance of the IL-15Ralpha chain","volume":"76","author":"Ratth\u00e9","year":"2004","journal-title":"J. Leukoc. Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"m4447","DOI":"10.1136\/bmj.m4447","article-title":"Axial spondyloarthritis: New advances in diagnosis and management","volume":"372","author":"Ritchlin","year":"2021","journal-title":"Bmj"},{"key":"B32","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1136\/ard.2010.133645","article-title":"The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general","volume":"70","author":"Rudwaleit","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"B33","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1136\/ard.2009.108233","article-title":"The development of assessment of SpondyloArthritis international society classification criteria for axial spondyloarthritis (part II): Validation and final selection","volume":"68","author":"Rudwaleit","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"B34","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1186\/s12859-018-2451-4","article-title":"SVM-RFE: Selection and visualization of the most relevant features through non-linear kernels","volume":"19","author":"Sanz","year":"2018","journal-title":"BMC Bioinforma."},{"key":"B35","doi-asserted-by":"publisher","first-page":"E1461","DOI":"10.3390\/biom10101461","article-title":"Understanding the pathogenesis of spondyloarthritis","volume":"10","author":"Sharip","year":"2020","journal-title":"Biomolecules"},{"key":"B36","doi-asserted-by":"publisher","first-page":"e109272","DOI":"10.15252\/embj.2021109272","article-title":"ZDHHC18 negatively regulates cGAS-mediated innate immunity through palmitoylation","volume":"41","author":"Shi","year":"2022","journal-title":"Embo J."},{"key":"B37","doi-asserted-by":"publisher","first-page":"15013","DOI":"10.1038\/nrdp.2015.13","article-title":"Axial spondyloarthritis","volume":"1","author":"Sieper","year":"2015","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B38","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/S0140-6736(16)31591-4","article-title":"Axial spondyloarthritis","volume":"390","author":"Sieper","year":"2017","journal-title":"Lancet"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v039.i05","article-title":"Regularization paths for cox's proportional hazards model via coordinate descent","volume":"39","author":"Simon","year":"2011","journal-title":"J. Stat. Softw."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1002\/eji.200737101","article-title":"IL-2Rbeta links IL-2R signaling with Foxp3 expression","volume":"37","author":"Soper","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1002\/acr.22831","article-title":"Global prevalence of spondyloarthritis: A systematic review and meta-regression analysis","volume":"68","author":"Stolwijk","year":"2016","journal-title":"Arthritis Care Res. Hob."},{"key":"B42","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/1471-2105-8-25","article-title":"Bias in random forest variable importance measures: Illustrations, sources and a solution","volume":"8","author":"Strobl","year":"2007","journal-title":"BMC Bioinforma."},{"key":"B62","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.cca.2019.11.028","article-title":"Serum Deoxyribonuclease 1-like 3 is a potential biomarker for diagnosis of ankylosing spondylitis","volume":"503","author":"Sun","year":"2020","journal-title":"Clin. Chim. Acta."},{"key":"B43","doi-asserted-by":"publisher","first-page":"795","DOI":"10.3389\/fimmu.2018.00795","article-title":"A reappraisal on the potential ability of human neutrophils to express and produce IL-17 family members in vitro: Failure to reproducibly detect it","volume":"9","author":"Tamassia","year":"2018","journal-title":"Front. Immunol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1056\/NEJMc1609622","article-title":"Ankylosing spondylitis and axial spondyloarthritis","volume":"374","author":"Taurog","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"B45","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1002\/art.1780270401","article-title":"Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria","volume":"27","author":"van der Linden","year":"1984","journal-title":"Arthritis Rheum."},{"key":"B46","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1111\/imm.13242","article-title":"New developments in our understanding of ankylosing spondylitis pathogenesis","volume":"161","author":"Voruganti","year":"2020","journal-title":"Immunology"},{"key":"B47","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/nri1901","article-title":"The biology of interleukin-2 and interleukin-15: Implications for cancer therapy and vaccine design","volume":"6","author":"Waldmann","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1186\/s12891-021-03973-8","article-title":"The role of lymphocyte-monocyte ratio on axial spondyloarthritis diagnosis and sacroiliitis staging","volume":"22","author":"Wang","year":"2021","journal-title":"BMC Musculoskelet. Disord."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.1002\/art.41042","article-title":"2019 update of the American College of rheumatology\/spondylitis association of America\/spondyloarthritis research and treatment network recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis","volume":"71","author":"Ward","year":"2019","journal-title":"Arthritis Rheumatol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1080\/14397595.2018.1564165","article-title":"Neutrophil lymphocyte ratio in patients with ankylosing spondylitis: A systematic review and meta-analysis","volume":"30","author":"Xu","year":"2020","journal-title":"Mod. Rheumatol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"34643","DOI":"10.1038\/srep34643","article-title":"Inhibition of complement retards ankylosing spondylitis progression","volume":"6","author":"Yang","year":"","journal-title":"Sci. Rep."},{"key":"B52","doi-asserted-by":"publisher","first-page":"E2126","DOI":"10.3390\/ijms17122126","article-title":"A possible role of intestinal microbiota in the pathogenesis of ankylosing spondylitis","volume":"17","author":"Yang","year":"","journal-title":"Int. J. Mol. Sci."},{"key":"B53","doi-asserted-by":"publisher","first-page":"600368","DOI":"10.3389\/fcell.2020.600368","article-title":"Protein palmitoylation in leukocyte signaling and function","volume":"8","author":"Yang","year":"2020","journal-title":"Front. Cell. Dev. Biol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"4016802","DOI":"10.1155\/2017\/4016802","article-title":"Targeted delivery of the HLA-B(\u2217)27-Binding peptide into the endoplasmic reticulum suppresses the IL-23\/IL-17 Axis of immune cells in spondylarthritis","volume":"2017","author":"Yu","year":"2017","journal-title":"Mediat. Inflamm."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1084\/jem.20182304","article-title":"Human interleukin-2 receptor \u03b2 mutations associated with defects in immunity and peripheral tolerance","volume":"216","author":"Zhang","year":"2019","journal-title":"J. Exp. Med."},{"key":"B56","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.pnpbp.2017.10.003","article-title":"Integrating genome-wide association study and expression quantitative trait locus study identifies multiple genes and gene sets associated with schizophrenia","volume":"81","author":"Zhao","year":"2018","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"B57","doi-asserted-by":"publisher","first-page":"e12125","DOI":"10.7717\/peerj.12125","article-title":"Identification of immune related cells and crucial genes in the peripheral blood of ankylosing spondylitis by integrated bioinformatics analysis","volume":"9","author":"Zheng","year":"2021","journal-title":"PeerJ"},{"key":"B58","first-page":"3178","article-title":"Transcriptome network analysis reveals potential candidate genes for ankylosing spondylitis","volume":"17","author":"Zhu","year":"2013","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1093\/rheumatology\/kei047","article-title":"The current concept of spondyloarthritis with special emphasis on undifferentiated spondyloarthritis","volume":"44","author":"Zochling","year":"2005","journal-title":"Rheumatol. Oxf."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.1032010\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T16:26:42Z","timestamp":1678465602000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.1032010\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,1]]},"references-count":65,"alternative-id":["10.3389\/fgene.2022.1032010"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.1032010","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,1]]},"article-number":"1032010"}}