{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T06:10:19Z","timestamp":1793686219723,"version":"4.5.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T00:00:00Z","timestamp":1673308800000},"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>Homeodomain-interacting protein kinase 3 (HIPK3) plays an important role in cell proliferation, apoptosis, and inflammation. Over-expression of HIPK3 in immune cells in rheumatoid arthritis (RA) has been reported. In this study, we investigated blood methylation levels and clinical characteristics of RA in a Chinese population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 235 patients with RA, 30 with osteoarthritis (OA), and 30 matched healthy controls were recruited. The methylation status of seven CpGs in the differentially methylated region of HIPK3 (cg05501357) was measured using targeted methylation-sequencing technology. The association between methylation haplotypes and the overall methylation status of HIPK3 with clinical characteristics was assessed using generalized linear regression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All seven CpGs showed hypomethylation status in RA blood compared with OA and normal individuals (overall p= 1.143\u00d710<jats:sup>-8<\/jats:sup> and FDR= 2.799\u00d710<jats:sup>-7<\/jats:sup>), which is consistent with the previously reported high expression of HIPK3 in RA immune cells. Among all seven CpGs, 33286785 showed the highest predictive power with an area under the curve (AUC) of 0.829; we received a higher AUC=0.864 when we combined HIPK3 with anti-citrullinated protein antibodies (ACPA -) and rheumatoid factor (RF +) in the prediction model, indicating that when a patient\u2019s ACPA is negative, HIPK3 can assist RF as a new clinical index for the diagnosis of RA. We also found that HIPK3 methylation levels were negatively correlated with C-reactive protein (CRP; r= -0.16, p= 0.01). Methylation haplotypes were analyzed, and the full methylation haplotype (FMH; r= 0.16, p= 0.01) and full non-methylation haplotype (FNH; r= 0.18, p= 0.0061) were negatively correlated with CRP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Circulating blood methylation levels in the protein region of HIPK3 can be utilized as a supportive diagnostic biomarker and CRP level indicator for RA.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1087279","type":"journal-article","created":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T22:23:30Z","timestamp":1673389410000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":18,"title":["DNA methylation change of HIPK3 in Chinese rheumatoid arthritis and its effect on inflammation"],"prefix":"10.3389","volume":"13","author":[{"given":"Ping","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingxia","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cen","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runrun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehua","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linshuai","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songtao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shicheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongsheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyi","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/s41584-020-00541-7","article-title":"Persistent inflammatory and non-inflammatory mechanisms in refractory rheumatoid arthritis","volume":"17","author":"Buch","year":"2021","journal-title":"Nat Rev Rheumatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)60826-4","article-title":"Rheumatoid arthritis","volume":"376","author":"Scott","year":"2010","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k1036","article-title":"Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications","volume":"361","author":"England","year":"2018","journal-title":"BMJ"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.838884","article-title":"MicroRNA-mediated epigenetic regulation of rheumatoid arthritis susceptibility and pathogenesis","volume":"13","author":"Chang","year":"2022","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/npp.2012.112","article-title":"DNA Methylation and its basic function","volume":"38","author":"Moore","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-018-0004-3","article-title":"DNA Methylation-based biomarkers and the epigenetic clock theory of ageing","volume":"19","author":"Horvath","year":"2018","journal-title":"Nat Rev Genet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2021.05.002","article-title":"Navigating the DNA methylation landscape of cancer","volume":"37","author":"Nishiyama","year":"2021","journal-title":"Trends Genet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1101\/gad.947102","article-title":"DNA Methylation patterns and epigenetic memory","volume":"16","author":"Bird","year":"2002","journal-title":"Genes Dev"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2487","article-title":"Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis","volume":"31","author":"Liu","year":"2013","journal-title":"Nat Biotechnol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.863703","article-title":"DNA Methylation of T lymphocytes as a therapeutic target: Implications for rheumatoid arthritis etiology","volume":"13","author":"Zhao","year":"2022","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e149538","DOI":"10.1172\/JCI149538","article-title":"Fibroblast pathology in inflammatory diseases","volume":"131","author":"Wei","year":"2021","journal-title":"J Clin Invest"},{"key":"B12","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s12013-014-9913-8","article-title":"DNA Methylation: Roles in rheumatoid arthritis","volume":"70","author":"Yuan","year":"2014","journal-title":"Cell Biochem Biophys"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2012.06.074","article-title":"Homeodomain-interacting protein kinase regulates yorkie activity to promote tissue growth","volume":"22","author":"Chen","year":"2012","journal-title":"Curr Biol"},{"key":"B14","article-title":"Homeodomain-interacting protein kinases: Diverse and Complex Roles in Development and Disease","volume-title":"Curr Top Dev Biol.","author":"Blaquiere","year":"2017"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S166878","article-title":"The expression level and prognostic value of HIPK3 among non-small-cell lung cancer patients in China","author":"Liu","year":"2018","journal-title":"OTT"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2017.1393130","article-title":"HIPK3 modulates autophagy and HTT protein levels in neuronal and mouse models of huntington disease","volume":"14","author":"Fu","year":"2018","journal-title":"Autophagy"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.747274","article-title":"MicroRNA variants and HLA-miRNA interactions are novel rheumatoid arthritis susceptibility factors","volume":"12","author":"Guo","year":"2021","journal-title":"Front Genet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2010.138461","article-title":"2010 Rheumatoid arthritis classification criteria: an American college of Rheumatology\/European league against rheumatism collaborative initiative","volume":"69","author":"Aletaha","year":"2010","journal-title":"Ann Rheumatic Dis"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/imt2.36","article-title":"Sangerbox: A comprehensive, interaction-friendly clinical bioinformatics analysis platform","author":"Shen","year":"2022","journal-title":"iMeta"},{"key":"B20","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.berh.2008.08.002","article-title":"Current concepts in the pathogenesis of early rheumatoid arthritis","volume":"23","author":"Pratt","year":"2009","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2021.102797","article-title":"The pre-clinical phase of rheumatoid arthritis: From risk factors to prevention of arthritis","volume":"20","author":"Petrovsk\u00e1","year":"2021","journal-title":"Autoimmun Rev"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2019.102400","article-title":"The etiology of rheumatoid arthritis","volume":"110","author":"Scherer","year":"2020","journal-title":"J Autoimmun"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.903475","article-title":"SFRP1 negatively modulates pyroptosis of fibroblast-like synoviocytes in rheumatoid arthritis: A review","volume":"13","author":"Jiang","year":"2022","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/cells8090953","article-title":"DNA Methylation as a future therapeutic and diagnostic target in rheumatoid arthritis","volume":"8","author":"Ciechomska","year":"2019","journal-title":"Cells"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s13105-012-0216-5","article-title":"Inflammation and rheumatoid arthritis","volume":"69","author":"Shrivastava","year":"2013","journal-title":"J Physiol Biochem"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21155238","article-title":"Interleukin-6 in rheumatoid arthritis","volume":"21","author":"Pandolfi","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B27","article-title":"Increased interleukin-23 is associated with increased disease activity in patients with rheumatoid arthritis","volume":"126","author":"Guo","year":"2013","journal-title":"Chin Med J(Engl)"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.676105","article-title":"Relationship between inflammation and metabolism in patients with newly presenting rheumatoid arthritis","volume":"12","author":"Jutley","year":"2021","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.2174\/1381612820666140825122525","article-title":"Biomarkers for radiographic progression in rheumatoid arthritis","volume":"21","author":"Krabben","year":"2014","journal-title":"CPD"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22020686","article-title":"From rheumatoid factor to anti-citrullinated protein antibodies and anti-carbamylated protein antibodies for diagnosis and prognosis prediction in patients with rheumatoid arthritis","volume":"22","author":"Wu","year":"2021","journal-title":"IJMS"},{"key":"B31","doi-asserted-by":"publisher","first-page":"18001","DOI":"10.1038\/nrdp.2018.1","article-title":"Rheumatoid arthritis","volume":"4","author":"Smolen","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2019.1634945","article-title":"circHIPK3 modulates autophagy via MIR124-3p -STAT3-PRKAA\/AMPK\u03b1 signaling in STK11 mutant lung cancer","volume":"16","author":"Chen","year":"2020","journal-title":"Autophagy"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1087279\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T22:23:34Z","timestamp":1673389414000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1087279\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,10]]},"references-count":32,"alternative-id":["10.3389\/fimmu.2022.1087279"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1087279","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,10]]},"article-number":"1087279"}}