{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T21:36:16Z","timestamp":1788212176343,"version":"build-2803163510"},"reference-count":44,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2019,1,31]],"date-time":"2019-01-31T00:00:00Z","timestamp":1548892800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"University of Washington School of Dentistry Elam M. and Georgina E. Hack Memorial Research Fund"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["JDR Clinical &amp; Translational Research"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction:<\/jats:title>\n                    <jats:p>Epigenetic changes are associated with various inflammatory diseases and are influenced by environmental factors. Recent data support an association between titanium dissolution products and peri-implantitis. We hypothesize that site-specific changes in gene methylation, a form of epigenetic regulation, around dental implants may be influenced by local environmental factors, such as titanium dissolution particles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives:<\/jats:title>\n                    <jats:p>The primary purpose of this study was to assess global methylation patterns related to the disease status of dental implants and the concentration of titanium particles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>We assessed peri-implantitis cases defined according to established definitions from a cross-sectional study that had implants in function for at least 2 y. Controls were sampled from the same population and had healthy implants. Peri-implant crevicular fluid samples were collected and prepared for immunohistochemical analysis of 5-methylcytosine (5mC), and submucosal plaque samples were collected and subjected to inductively coupled plasma mass spectrometry (ICP-MS) for measuring titanium. Data were analyzed via generalized estimating equation models to account for multiple implants per participant.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Forty participants were included; 21 implants with peri-implantitis and 24 healthy implants were included in the analysis. Epigenetic alterations in global gene methylation were significantly more pronounced in peri-implantitis cases as compared to controls ( P = 0.002). Adjustment for smoking status further strengthened the association ( P = 0.0079). Higher adjusted titanium quantities had significantly higher 5mC ( P &lt; 0.001).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Peri-implantitis cases exhibited increased levels of methylated DNA cytosine (5mC) as compared to controls, suggesting that peri-implantitis is associated with epigenetic alterations in the peri-implant tissues. In addition, the finding that titanium concentrations were associated with global methylation levels independent of peri-implantitis status suggests that methylation may be affected by titanium dissolution products. Collectively, these results support further investigations to determine if these associations are causal or ecological in nature.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Knowledge Transfer Statement:<\/jats:title>\n                    <jats:p>These are the first human data to elucidate the epigenetic regulation of gene transcription via hypermethylation as a potential mechanism involved in peri-implantitis. Furthermore, they identify titanium dissolution products as a potential environmental factor associated with this hypermethylation, which provides cues for novel therapeutic targets for peri-implantitis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/2380084418822831","type":"journal-article","created":{"date-parts":[[2019,1,31]],"date-time":"2019-01-31T12:50:05Z","timestamp":1548939005000},"page":"284-291","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":19,"title":["Association of Global DNA Methylation to Titanium and Peri-Implantitis: A Case-Control Study"],"prefix":"10.1177","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7307-4102","authenticated-orcid":false,"given":"D.M.","family":"Daubert","sequence":"first","affiliation":[{"name":"Department of Periodontics, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.E.","family":"Pozhitkov","sequence":"additional","affiliation":[{"name":"Department of Restorative Dentistry, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.M.","family":"Safioti","sequence":"additional","affiliation":[{"name":"Department of Periodontics, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.A.","family":"Kotsakis","sequence":"additional","affiliation":[{"name":"Department of Periodontics, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,1,31]]},"reference":[{"key":"bibr1-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1177\/0022034509335868"},{"key":"bibr2-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2009.00535.x"},{"key":"bibr3-2380084418822831","doi-asserted-by":"publisher","DOI":"10.5051\/jpis.2014.44.3.102"},{"key":"bibr4-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1111\/cid.12676"},{"key":"bibr5-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2014.140438"},{"key":"bibr6-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1186\/1868-7083-6-15"},{"key":"bibr7-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1007\/s12033-007-9010-y"},{"key":"bibr8-2380084418822831","doi-asserted-by":"publisher","DOI":"10.4161\/epi.7.1.18753"},{"key":"bibr9-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1111\/jcpe.12334"},{"key":"bibr10-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1016\/S1521-6616(03)00205-5"},{"key":"bibr11-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1177\/0022034517740560"},{"key":"bibr12-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-612-8_12"},{"key":"bibr13-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijom.2012.07.018"},{"key":"bibr14-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1126\/science.1063852"},{"key":"bibr15-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2016.150684"},{"key":"bibr16-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1016\/S0142-9612(02)00115-1"},{"key":"bibr17-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-051X.2010.01674.x"},{"key":"bibr18-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2014.140559"},{"key":"bibr19-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1177\/0022034510363675"},{"key":"bibr20-2380084418822831","doi-asserted-by":"publisher","DOI":"10.5051\/jpis.2013.43.3.111"},{"key":"bibr21-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1111\/idh.12030"},{"key":"bibr22-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1902\/jop.1967.38.6_part2.610"},{"key":"bibr23-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-380864-6.00001-8"},{"key":"bibr24-2380084418822831","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/2047-783X-15-S2-88","volume":"15","author":"Mierzwinska-Nastalska E","year":"2010","journal-title":"Eur J Med Res"},{"key":"bibr25-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0501.2012.02541.x"},{"key":"bibr26-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0501.2012.02542.x"},{"key":"bibr27-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1111\/jre.12479"},{"key":"bibr28-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2012.110757"},{"key":"bibr29-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2011.110392"},{"key":"bibr30-2380084418822831","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0140393"},{"key":"bibr31-2380084418822831","unstructured":"R Core Team. 2013. 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