{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T05:09:47Z","timestamp":1784610587477,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T00:00:00Z","timestamp":1665360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universidad Santo Tom\u00e1s","award":["P7FM2021"],"award-info":[{"award-number":["P7FM2021"]}]},{"name":"Universidad Santo Tom\u00e1s","award":["Fondecyt 1220999"],"award-info":[{"award-number":["Fondecyt 1220999"]}]},{"name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","award":["P7FM2021"],"award-info":[{"award-number":["P7FM2021"]}]},{"name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","award":["Fondecyt 1220999"],"award-info":[{"award-number":["Fondecyt 1220999"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The characteristic epigenetic profile of periodontitis found in peripheral leukocytes denotes its impact on systemic immunity. In fact, this profile not only stands for periodontitis as a low-grade inflammatory disease with systemic effects but also as an important source of potentially valuable clinical biomarkers of its systemic effects and susceptibility to other inflammatory conditions. Thus, we aimed to identify relevant genes tested as epigenetic systemic biomarkers in patients with periodontitis, based on the DNA methylation patterns and RNA expression profiles in peripheral immune cells. A detailed protocol was designed following the Preferred Reporting Items for Systematic Review and Meta-analysis -PRISMA guideline. Only cross-sectional and case-control studies that reported potential systemic biomarkers of periodontitis in peripheral immune cell types were included. DNA methylation was analyzed in leukocytes, and gene expression was in polymorphonuclear and mononuclear cells. Hypermethylation was found in TLR regulators genes: MAP3K7, MYD88, IL6R, RIPK2, FADD, IRAK1BP1, and PPARA in early stages of periodontitis, while advanced stages presented hypomethylation of these genes. TGFB1I1, VNN1, HLADRB4, and CXCL8 genes were differentially expressed in lymphocytes and monocytes of subjects with poorly controlled diabetes mellitus, dyslipidemia, and periodontitis in comparison with controls. The DAB2 gene was differentially overexpressed in periodontitis and dyslipidemia. Peripheral blood neutrophils in periodontitis showed differential expression in 163 genes. Periodontitis showed an increase in ceruloplasmin gene expression in polymorphonuclears in comparison with controls. Several genes highlight the role of the epigenetics of peripheral inflammatory cells in periodontitis that could be explored in blood as a source of biomarkers for routine testing.<\/jats:p>","DOI":"10.3390\/ijms231912042","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T21:07:11Z","timestamp":1665436031000},"page":"12042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Biomarkers of Periodontitis and Its Differential DNA Methylation and Gene Expression in Immune Cells: A Systematic Review"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8497-9938","authenticated-orcid":false,"given":"Ang\u00e9lica","family":"C\u00e1rdenas","sequence":"first","affiliation":[{"name":"Faculty of Dentistry, Universidad Santo Tom\u00e1s, Bucaramanga 680001, Colombia"},{"name":"Doctoral Program in Dentistry, Faculty of Dentistry, Division of Health Sciences, Universidad Santo Tom\u00e1s, Carrera 27 Floridablanca Highway 80-395, Bucaramanga 680001, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Ardila","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry, Universidad Santo Tom\u00e1s, Bucaramanga 680001, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1391-320X","authenticated-orcid":false,"given":"Rolando","family":"Vernal","sequence":"additional","affiliation":[{"name":"Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samanta","family":"Melgar-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile"},{"name":"Department of Conservative Dentistry, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8479-6269","authenticated-orcid":false,"given":"Hern\u00e1n","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry, Universidad Santo Tom\u00e1s, Bucaramanga 680001, Colombia"},{"name":"Doctoral Program in Dentistry, Faculty of Dentistry, Division of Health Sciences, Universidad Santo Tom\u00e1s, Carrera 27 Floridablanca Highway 80-395, Bucaramanga 680001, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S162","DOI":"10.1111\/jcpe.12946","article-title":"Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions","volume":"45","author":"Papapanou","year":"2018","journal-title":"J. Clin. Periodontol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1111\/jcpe.12732","article-title":"Impact of the global burden of periodontal diseases on health, nutrition and wellbeing of mankind: A call for global action","volume":"44","author":"Tonetti","year":"2017","journal-title":"J. Clin. Periodontol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2146160","DOI":"10.1155\/2020\/2146160","article-title":"Global Prevalence of Periodontal Disease and Lack of Its Surveillance","volume":"2020","author":"Nazir","year":"2020","journal-title":"Sci. World J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.tim.2016.02.010","article-title":"Dancing with the Stars: How Choreographed Bacterial Interactions Dictate Nososymbiocity and Give Rise to Keystone Pathogens, Accessory Pathogens, and Pathobionts","volume":"24","author":"Hajishengallis","year":"2016","journal-title":"Trends Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/j.1600-0757.2006.00169.x","article-title":"Clinical relevance of the host responses of periodontitis","volume":"43","author":"Kinane","year":"2007","journal-title":"Periodontol. 2000"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1600-0757.2007.00228.x","article-title":"Cellular and molecular susceptibility determinants for periodontitis","volume":"45","year":"2007","journal-title":"Periodontol. 2000"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/idh.12030","article-title":"The influence of epigenetics in relation to oral health","volume":"12","author":"Lod","year":"2014","journal-title":"Int. J. Dent. Hyg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2147\/JIR.S129027","article-title":"Epigenetics of chronic inflammatory diseases","volume":"12","author":"Stylianou","year":"2018","journal-title":"J. Inflamm. Res."},{"key":"ref_9","unstructured":"Patel, D., Lee, Y.J., Chauhan, B., Sidhu, L., Heck, D., and Duck, H. (2019). Epigenetics-Epidisease-Epidrug: A Key Context Folded inside of Periodontal Diseases. Enliven Dent. Periodont."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1007\/s40496-017-0156-9","article-title":"Current Concepts of Epigenetics and Its Role in Periodontitis","volume":"4","author":"Larsson","year":"2017","journal-title":"Curr. Oral Health Rep."},{"key":"ref_11","first-page":"e659","article-title":"Epigenetics and periodontics: A systematic review","volume":"24","year":"2019","journal-title":"Med. Oral Patol. Oral Cir. Bucal"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.humimm.2015.10.007","article-title":"Epigenetic characteristics in inflammatory candidate genes in aggressive periodontitis","volume":"77","author":"Schulz","year":"2016","journal-title":"Hum. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.imbio.2012.12.001","article-title":"Expression, polymorphism and methylation pattern of interleukin-6 in periodontal tissues","volume":"218","author":"Stefani","year":"2013","journal-title":"Immunobiology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/mi.2010.83","article-title":"Epigenetic regulation of human \u03b2-defensin 2 and CC chemokine ligand 20 expression in gingival epithelial cells in response to oral bacteria","volume":"4","author":"Yin","year":"2011","journal-title":"Mucosal Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/j.humimm.2013.04.037","article-title":"Hypermethylation and low transcription of TLR2 gene in chronic periodontitis","volume":"74","author":"Saraiva","year":"2013","journal-title":"Hum. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/prd.12231","article-title":"Targeting epigenetic mechanisms in periodontal diseases","volume":"78","author":"Barros","year":"2018","journal-title":"Periodontol. 2000"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1111\/jre.12868","article-title":"ZNF718, HOXA4, and ZFP57 are differentially methylated in periodontitis in comparison with periodontal health: Epigenome-wide DNA methylation pilot study","volume":"56","author":"Arboleda","year":"2021","journal-title":"J. Periodontal Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/prd.12103","article-title":"Personalized medicine: An update of salivary biomarkers for periodontal diseases","volume":"70","author":"Korte","year":"2016","journal-title":"Periodontol. 2000"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1186\/s13148-021-01179-2","article-title":"Association of peripheral blood DNA methylation level with Alzheimer\u2019s disease progression","volume":"13","author":"Li","year":"2021","journal-title":"Clin. Epigenetics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.2217\/epi-2017-0160","article-title":"Alzheimer\u2019s disease DNA methylome of pyramidal layers in frontal cortex: Laser-assisted microdissection study","volume":"10","author":"Zelaya","year":"2018","journal-title":"Epigenomics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"142","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":"ref_22","doi-asserted-by":"crossref","unstructured":"Bell, C.G., Teschendorff, A.E., Rakyan, V.K., Maxwell, A.P., Beck, S., and Savage, D.A. (2010). Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus. BMC Med. Genom., 3.","DOI":"10.1186\/1755-8794-3-33"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12033-009-9216-2","article-title":"DNA Methylation: An Introduction to the Biology and the Disease-Associated Changes of a Promising Biomarker","volume":"44","author":"Tost","year":"2010","journal-title":"Mol. Biotechnol."},{"key":"ref_24","first-page":"1","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13148-019-0614-4","article-title":"Epigenetic findings in periodontitis in UK twins: A cross-sectional study","volume":"11","author":"Kurushima","year":"2019","journal-title":"Clin. Epigenetics."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s13148-017-0385-8","article-title":"Epigenetic regulation of inflammation in localized aggressive periodontitis","volume":"9","author":"Shaddox","year":"2017","journal-title":"Clin. Epigenetics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1111\/j.1600-051X.2009.01446.x","article-title":"DNA methylation status of the IL8 gene promoter in oral cells of smokers and non-smokers with chronic periodontitis","volume":"36","author":"Oliveira","year":"2009","journal-title":"J. Clin. Periodontol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1111\/jre.12314","article-title":"Tumor necrosis factor-alpha gene promoter methylation in Japanese adults with chronic periodontitis and rheumatoid arthritis","volume":"51","author":"Kojima","year":"2016","journal-title":"J. Periodontal Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1902\/jop.2011.110356","article-title":"Interleukin-6 Gene Promoter Methylation in Rheumatoid Arthritis and Chronic Periodontitis","volume":"83","author":"Ishida","year":"2012","journal-title":"J. Periodontol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5775","DOI":"10.4049\/jimmunol.181.8.5775","article-title":"Periodontitis Associates with a Type 1 IFN Signature in Peripheral Blood Neutrophils","volume":"181","author":"Wright","year":"2008","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1902\/jop.2009.090092","article-title":"Ceruloplasmin Induces Polymorphonuclear Leukocyte Priming in Localized Aggressive Periodontitis","volume":"80","author":"Iwata","year":"2009","journal-title":"J. Periodontol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1902\/jop.2008.070309","article-title":"Blood cell gene expression profiling in subjects with aggressive periodontitis and chronic arthritis","volume":"79","author":"Sorensen","year":"2008","journal-title":"J. Periodontol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1007\/s00784-011-0634-8","article-title":"Expression and secretion levels of Th1 and Th2 cytokines in patients with aggressive periodontitis","volume":"16","author":"Gonzales","year":"2012","journal-title":"Clin. Oral Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.gene.2016.01.036","article-title":"RNA-sequencing study of peripheral blood monocytes in chronic periodontitis","volume":"581","author":"Liu","year":"2016","journal-title":"Gene"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8145","DOI":"10.1038\/s41598-020-65042-9","article-title":"Circulating lymphocytes and monocytes transcriptomic analysis of patients with type 2 diabetes mellitus, dyslipidemia and periodontitis","volume":"10","author":"Corbi","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1111\/jcpe.13361","article-title":"Dysregulation of genes and microRNAs in localized aggressive periodontitis","volume":"47","author":"Morford","year":"2020","journal-title":"J. Clin. Periodontol."},{"key":"ref_37","first-page":"1","article-title":"Integrative genomic and epigenomic analyses identified IRAK1 as a novel target for chronic inflammation-driven prostate tumorigenesis","volume":"2021","author":"Oseni","year":"2021","journal-title":"bioRxiv"},{"key":"ref_38","unstructured":"Oseni, S.O. (2021). Role of Interleukin-1 Receptor-Associated Kinases in Chronic Inflammation and Prostate Tumorigenesis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1177\/1099800414553463","article-title":"Epigenome variation in severe asthma","volume":"17","author":"Wysocki","year":"2015","journal-title":"Biol. Res. Nurs."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1530\/eje.0.1490601","article-title":"Sex hormones, inflammation and the metabolic syndrome: A population-based study","volume":"149","author":"Laaksonen","year":"2003","journal-title":"Eur. J. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Arathimos, R., Sharp, G.C., Granell, R., Tilling, K., and Relton, C.L. (2018). Associations of sex hormone-binding globulin and testosterone with genome-wide DNA methylation. BMC Genet., 19.","DOI":"10.1186\/s12863-018-0703-y"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1902\/jop.2013.120294","article-title":"Epigenetic regulation of TNFA expression in periodontal disease","volume":"84","author":"Zhang","year":"2013","journal-title":"J. Periodontol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/978-94-007-4525-4_27","article-title":"Role of epigenetics in inflammation-associated diseases","volume":"61","author":"Shanmugam","year":"2013","journal-title":"Subcell. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.biocel.2008.09.011","article-title":"Epigenetics and human disease","volume":"41","author":"Hirst","year":"2009","journal-title":"Int. J. Biochem. Cell Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/12042\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:49:20Z","timestamp":1760143760000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/19\/12042"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,10]]},"references-count":44,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms231912042"],"URL":"https:\/\/doi.org\/10.3390\/ijms231912042","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,10]]}}}