{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T15:51:51Z","timestamp":1788277911251,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T00:00:00Z","timestamp":1623456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT - Foundation for Science and Technology, I.P","award":["UIDB\/04585\/2020"],"award-info":[{"award-number":["UIDB\/04585\/2020"]}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["NIHR-INF-0387"],"award-info":[{"award-number":["NIHR-INF-0387"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Here, we assess the association between homocysteine (Hcy) serum levels and periodontal status in a large representative sample of the National Health and Nutrition Examination Survey (NHANES). Using the 2001\u20132002 and 2003\u20132004 NHANES databases, participants with a periodontal examination, medical self-reported data, blood pressure (BP) and blood samples to determine complete blood count, C-reactive protein (CRP) and Hcy levels. We then calculated the periodontal inflamed surface area (PISA) and the periodontal epithelial surface area (PESA). Multivariable regression analysis explored the association between Hcy, periodontal measures and BP. Mediation analysis was performed to understand the effect of PISA and PESA in the link between Hcy and BP. 4021 participants fulfilled the inclusion criteria. Hcy levels showed significant correlations with systolic BP, diastolic BP, PISA, PESA and age. PESA showed to be significantly associated with Hcy both for the crude and adjusted models (p &lt; 0.01), but not PISA (p &gt; 0.05). In the association of Hcy with systolic BP, PISA significantly mediated 17.4% and PESA 0.9%. In the association of Hcy with diastolic BP, PISA significantly mediated 16.3% and PESA 47.2%. In conclusion, Hcy and periodontitis are associated. Further, both PISA and PESA significantly mediated the association of Hcy with systolic BP and diastolic BP. Future studies shall deepen the mechanisms by which Hcy levels increase in a clinical situation of periodontitis.<\/jats:p>","DOI":"10.3390\/biom11060875","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T10:30:25Z","timestamp":1623666625000},"page":"875","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Periodontal Inflamed Surface Area Mediates the Link between Homocysteine and Blood Pressure"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1019-8263","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Botelho","sequence":"first","affiliation":[{"name":"Clinical Research Unit (CRU), Egas Moniz Interdisciplinary Research Center, Egas Moniz\u2013Cooperativa de Ensino Superior, 2829-511 Almada, Portugal"},{"name":"Evidence-Based Hub, Egas Moniz Interdisciplinary Research Center, Egas Moniz\u2013Cooperativa de Ensino Superior, 2829-511 Almada, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2503-260X","authenticated-orcid":false,"given":"Vanessa","family":"Machado","sequence":"additional","affiliation":[{"name":"Clinical Research Unit (CRU), Egas Moniz Interdisciplinary Research Center, Egas Moniz\u2013Cooperativa de Ensino Superior, 2829-511 Almada, Portugal"},{"name":"Evidence-Based Hub, Egas Moniz Interdisciplinary Research Center, Egas Moniz\u2013Cooperativa de Ensino Superior, 2829-511 Almada, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5027-7276","authenticated-orcid":false,"given":"Yago","family":"Leira","sequence":"additional","affiliation":[{"name":"Periodontology Unit, UCL Eastman Dental Institute and NIHR UCLH Biomedical Research Centre, University College London, London WC1E 6BT, UK"},{"name":"Periodontology Unit, Faculty of Medicine and Odontology, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain"},{"name":"Medical-Surgical Dentistry (OMEQUI) Research Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"},{"name":"Clinical Neurosciences Research Laboratory, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8482-5936","authenticated-orcid":false,"given":"Lu\u00eds","family":"Proen\u00e7a","sequence":"additional","affiliation":[{"name":"Evidence-Based Hub, Egas Moniz Interdisciplinary Research Center, Egas Moniz\u2013Cooperativa de Ensino Superior, 2829-511 Almada, Portugal"},{"name":"Quantitative Methods for Health Research (MQIS), Egas Moniz Interdisciplinary Research Center, Egas Moniz\u2013Cooperativa de Ensino Superior, 2829-511 Almada, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0167-4077","authenticated-orcid":false,"given":"Jos\u00e9 Jo\u00e3o","family":"Mendes","sequence":"additional","affiliation":[{"name":"Clinical Research Unit (CRU), Egas Moniz Interdisciplinary Research Center, Egas Moniz\u2013Cooperativa de Ensino Superior, 2829-511 Almada, Portugal"},{"name":"Evidence-Based Hub, Egas Moniz Interdisciplinary Research Center, Egas Moniz\u2013Cooperativa de Ensino Superior, 2829-511 Almada, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"\u0160kovierov\u00e1, H., Vidomanov\u00e1, E., Mahmood, S., Sopkov\u00e1, J., Drgov\u00e1, A., \u010cerve\u0148ov\u00e1, T., Hala\u0161ov\u00e1, E., and Lehotsk\u00fd, J. (2016). The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17101733"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"117957352096223","DOI":"10.1177\/1179573520962230","article-title":"Hyperhomocysteinemia: Clinical Insights","volume":"12","year":"2020","journal-title":"J. Cent. Nerv. Syst. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1373\/clinchem.2003.021634","article-title":"Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion","volume":"50","author":"Refsum","year":"2004","journal-title":"Clin. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s00726-006-0432-9","article-title":"Mechanisms of Homocysteine Toxicity in Humans","volume":"32","author":"Twardowski","year":"2007","journal-title":"Amino Acids"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1146\/annurev.nu.12.070192.001431","article-title":"Hyperhomocyst(e)Inemia as a Risk Factor for Occlusive Vascular Disease","volume":"12","author":"Kang","year":"1992","journal-title":"Annu. Rev. Nutr."},{"key":"ref_6","first-page":"477","article-title":"Chemical Pathology of Homocysteine I. Atherogenesis","volume":"23","author":"McCully","year":"1993","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1136\/bmj.39000.486701.68","article-title":"Folic Acid, Homocysteine, and Cardiovascular Disease: Judging Causality in the Face of Inconclusive Trial Evidence Evidence from Patients with Homocystinuria","volume":"333","author":"Wald","year":"2006","journal-title":"BMJ"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1161\/hc4601.098514","article-title":"Homocysteine Impairs the Nitric Oxide Synthase Pathway Role of Asymmetric Dimethylarginine","volume":"104","author":"Tsao","year":"2001","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Fournier, P., Fourcade, J., Roncalli, J., Salvayre, R., Galinier, M., and Causs\u00e9, E. (2015). Homocysteine in Chronic Heart Failure. Clin. Lab., 61.","DOI":"10.7754\/Clin.Lab.2015.141238"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1902\/annals.2001.6.1.48","article-title":"Candidate Genes as Potential Links between Periodontal and Cardiovascular Diseases","volume":"6","author":"Kornman","year":"2001","journal-title":"Ann. Periodontol.\/Am. Acad. Periodontol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nrmicro2337","article-title":"Periodontitis: A Polymicrobial Disruption of Host Homeostasis","volume":"8","author":"Darveau","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nri3785","article-title":"Periodontitis: From Microbial Immune Subversion to Systemic Inflammation","volume":"15","author":"Hajishengallis","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/j.0303-6979.2004.00432.x","article-title":"Poor Oral Health Is Associated with Coronary Heart Disease and Elevated Systemic Inflammatory and Haemostatic Factors","volume":"31","author":"Montebugnoli","year":"2004","journal-title":"J. Clin. Periodontol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1902\/jop.2010.100271","article-title":"Elevated Plasma Homocysteine Levels in Chronic Periodontitis: A Hospital-Based Case-Control Study","volume":"82","author":"Joseph","year":"2011","journal-title":"J. Periodontol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/jcpe.12374","article-title":"Effect of Non-Surgical Periodontal Therapy on Plasma Homocysteine Levels in Indian Population with Chronic Periodontitis: A Pilot Study","volume":"42","author":"Bhardwaj","year":"2015","journal-title":"J. Clin. Periodontol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1093\/cvr\/cvz201","article-title":"Periodontitis Is Associated with Hypertension: A Systematic Review and Meta-Analysis","volume":"116","author":"Suvan","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_17","unstructured":"(2021, March 06). NHANES Questionnaires, Datasets, and Related Documentation, Available online: https:\/\/wwwn.cdc.gov\/nchs\/nhanes\/."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lachat, C., Hawwash, D., Ock\u00e9, M.C., Berg, C., Forsum, E., H\u00f6rnell, A., Larsson, C., Sonestedt, E., Wirf\u00e4lt, E., and \u00c5kesson, A. (2016). Strengthening the Reporting of Observational Studies in Epidemiology\u2014Nutritional Epidemiology (STROBE-Nut): An Extension of the STROBE Statement. PLOS Med., 13.","DOI":"10.1371\/journal.pmed.1002036"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1902\/jop.2007.060210","article-title":"A Brief History of National Surveillance Efforts for Periodontal Disease in the United States","volume":"78","author":"Dye","year":"2007","journal-title":"J. Periodontol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1902\/jop.2012.110664","article-title":"Update of the Case Definitions for Population-Based Surveillance of Periodontitis","volume":"83","author":"Eke","year":"2012","journal-title":"J. Periodontol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1034\/j.1600-0765.2001.00011.x","article-title":"The Dentogingival Epithelial Surface Area Revisited","volume":"36","author":"Hujoel","year":"2001","journal-title":"J. Periodontal. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1111\/j.1600-051X.2008.01249.x","article-title":"Periodontal Inflamed Surface Area: Quantifying Inflammatory Burden","volume":"35","author":"Nesse","year":"2008","journal-title":"J. Clin. Periodontol."},{"key":"ref_23","unstructured":"(2020, November 10). NHANES 2001-2002 Data Documentation, Codebook, and Frequencies, Available online: https:\/\/wwwn.cdc.gov\/Nchs\/Nhanes\/2001-2002\/L06_2_B.htm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1093\/clinchem\/41.7.991","article-title":"Rapid, Fully Automated Measurement of Plasma Homocyst(e)Ine with the Abbott IMx Analyzer","volume":"41","author":"Shipchandler","year":"1995","journal-title":"Clin. Chem."},{"key":"ref_25","unstructured":"(2020, November 10). NHANES 2003-2004 Data Documentation, Codebook, and Frequencies, Available online: https:\/\/wwwn.cdc.gov\/Nchs\/Nhanes\/2003-2004\/L06MH_C.htm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1001\/jama.1995.03530130055028","article-title":"A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease. Probable Benefits of Increasing Folic Acid Intakes","volume":"274","author":"Boushey","year":"1995","journal-title":"JAMA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1093\/clinchem\/39.9.1764","article-title":"Total Homocysteine in Plasma or Serum: Methods and Clinical Applications","volume":"39","author":"Ueland","year":"1993","journal-title":"Clin. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1016\/S0895-4356(03)00085-4","article-title":"National Health and Nutrition Examination Survey 1999-2000: Effect of Observer Training and Protocol Standardization on Reducing Blood Pressure Measurement Error","volume":"56","author":"Ostchega","year":"2003","journal-title":"J. Clin. Epidemiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1097\/HJH.0000000000001940","article-title":"2018 ESC\/ESH Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Cardiology and the European Society of Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Cardiology and the European Society of Hypertension","volume":"36","author":"Williams","year":"2018","journal-title":"J. Hypertens"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1161\/CIRCULATIONAHA.115.018912","article-title":"Global Disparities of Hypertension Prevalence and Control: A Systematic Analysis of Population-Based Studies From 90 Countries","volume":"134","author":"Mills","year":"2016","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7093","DOI":"10.1038\/s41598-020-63700-6","article-title":"The 2018 Periodontitis Case Definition Improves Accuracy Performance of Full-Mouth Partial Diagnostic Protocols","volume":"10","author":"Botelho","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/S1286-4579(02)01586-1","article-title":"Correlation between Oral Malodor and Periodontal Bacteria","volume":"4","author":"Nakano","year":"2002","journal-title":"Microbes Infect."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1111\/j.1600-0757.2009.00327.x","article-title":"Comparison of Neutrophil Functions in Aggressive and Chronic Periodontitis","volume":"53","author":"Ryder","year":"2010","journal-title":"Periodontology 2000"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1902\/jop.1992.63.9.783","article-title":"Biochemical and Clinical Factors Influencing Oral Malodor in Periodontal Patients","volume":"63","author":"Yaegaki","year":"1992","journal-title":"J. Periodontol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.exphem.2020.10.001","article-title":"Periodontitis and Circulating Blood Cell Profiles: A Systematic Review and Meta-Analysis","volume":"93","author":"Botelho","year":"2021","journal-title":"Exp. Hematol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"17038","DOI":"10.1038\/nrdp.2017.38","article-title":"Periodontal Diseases","volume":"3","author":"Kinane","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"30317","DOI":"10.1074\/jbc.M212897200","article-title":"TDAG51 Is Induced by Homocysteine, Promotes Detachment-Mediated Programmed Cell Death, and Contributes to the Cevelopment of Atherosclerosis in Hyperhomocysteinemia","volume":"278","author":"Hossain","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"35867","DOI":"10.1074\/jbc.M100747200","article-title":"Homocysteine Induces Programmed Cell Death in Human Vascular Endothelial Cells through Activation of the Unfolded Protein Response","volume":"276","author":"Zhang","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Ganguly, P., and Alam, S.F. (2015). Role of Homocysteine in the Development of Cardiovascular Disease. Nutr. J., 14.","DOI":"10.1186\/1475-2891-14-6"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Velsko, I.M., Chukkapalli, S.S., Rivera, M.F., Lee, J.-Y., Chen, H., Zheng, D., Bhattacharyya, I., Gangula, P.R., Lucas, A.R., and Kesavalu, L. (2014). Active Invasion of Oral and Aortic Tissues by Porphyromonas Gingivalis in Mice Causally Links Periodontitis and Atherosclerosis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097811"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1177\/0022034517701901","article-title":"Poor Response to Periodontal Treatment May Predict Future Cardiovascular Disease","volume":"96","author":"Holmlund","year":"2017","journal-title":"J. Dent. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1111\/jcpe.13276","article-title":"The Effect of the Systemic Folic Acid Intake as an Adjunct to Scaling and Root Planing on Clinical Parameters and Homocysteine and C-Reactive Protein Levels in Gingival Crevicular Fluid of Periodontitis Patients: A Randomized Placebo-Controlled Clinical t","volume":"47","author":"Keceli","year":"2020","journal-title":"J. Clin. Periodontol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"H2649","DOI":"10.1152\/ajpheart.00548.2005","article-title":"Mechanisms of Homocysteine-Induced Oxidative Stress","volume":"289","author":"Tyagi","year":"2005","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"910","DOI":"10.3389\/fphys.2017.00910","article-title":"Oxidative Stress and Antioxidant System in Periodontitis","volume":"8","author":"Wang","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_45","first-page":"145","article-title":"Partial Recording Protocols Performance on the Assessment of Periodontitis Severity and Extent: Bias Magnitudes, Sensibility, and Specificity","volume":"59","author":"Machado","year":"2018","journal-title":"Rev. Port. De Estomatol. Med. Dent. E Cir. Maxilofac."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/6\/875\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:13:40Z","timestamp":1760163220000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/6\/875"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,12]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["biom11060875"],"URL":"https:\/\/doi.org\/10.3390\/biom11060875","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.02.02.21251010","asserted-by":"object"}]},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,12]]}}}