{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T13:10:47Z","timestamp":1779109847549,"version":"3.51.4"},"reference-count":50,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T00:00:00Z","timestamp":1751932800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["aap.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Periodontology"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Periodontitis, an inflammatory condition, results from the immune response to pathogenic microorganisms. Gingival defects from periodontitis enable these microorganisms, along with immune cells and inflammatory proteins, to enter the bloodstream, potentially causing systemic inflammation and contributing to systemic diseases. Conversely, systemic diseases can worsen periodontitis by inducing inflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, we investigated the connection between periodontitis and blood immune cell phenotypes\/circulating inflammation\u2010associated proteins using bidirectional Mendelian randomization (MR). We also analyzed the interplay between immune cells, inflammation proteins, and periodontitis through a two\u2010step mediation analysis. Besides, we utilized sensitivity analyses, including the MR\u2010PRESSO outlier test, MR Egger intercept, Cochran's\n                      <jats:italic>Q<\/jats:italic>\n                      statistic, Steiger filter, and leave\u2010one\u2010out analysis. Confounder\u2010related instrumental variants were filtered through the Open Targets Genetics. Additionally, the results were supported by triangulation of high\u2010throughput sequencing dataset analyses and animal models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MR analysis identified three proteins\u2014programmed cell death 1 ligand 1 (PD\u2010L1), eotaxin, and neurturin (NRTN)\u2014with protective roles against periodontitis, alongside three proteins\u2014protein S100\u2010A12 (S100A12), C\u2010X\u2010C motif chemokine ligand (CXCL) 11, and sulfotransferase 1A1 (SULT1A1)\u2014identified as risk factors. Furthermore, our study revealed 16 immunocyte phenotypes causally linked to periodontitis. Conversely, periodontitis was associated with heightened circulating levels of CXCL 9\/10\/11. Notably, periodontitis influenced the characteristics of circulating immune cells, particularly regulatory T cells (Treg), maturation stages of T cells, and conventional dendritic cells (cDC). Additionally, single\u2010cell and bulk\u2010RNA sequencing and animal models verified the above results.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study underscores the close connection between periodontitis and systemic inflammation, laying the groundwork for targeted immunotherapy against periodontitis and supporting the link between periodontitis and systemic diseases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Plain language summary<\/jats:title>\n                    <jats:p>This study explored the bidirectional causal relationship between periodontitis and systemic inflammation, demonstrating a causal relationship between periodontitis and specific circulating inflammatory proteins and immune cell phenotypes, indicating that the treatment of periodontitis needs to consider the systemic inflammatory state and that the systemic inflammatory state may be involved in the link between periodontitis and systemic diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jper.24-0382","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T14:58:11Z","timestamp":1751986691000},"page":"1432-1444","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Causal network between periodontitis and systemic inflammation: Triangulating evidence from Mendelian randomization and sequencing datasets"],"prefix":"10.1002","volume":"96","author":[{"given":"Guixin","family":"Zhu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Other Research Platforms West China Hospital of Stomatology, Sichuan University  Chengdu 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Other Research Platforms West China Hospital of Stomatology, Sichuan University  Chengdu China"},{"name":"Department of Prosthodontics West China Hospital of Stomatology, Sichuan University  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ran","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Other Research Platforms West China Hospital of Stomatology, Sichuan University  Chengdu China"},{"name":"Department of Prosthodontics West China Hospital of Stomatology, Sichuan University  Chengdu China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junchi","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases &amp; National Center for Stomatology &amp; National Clinical Research Center for Oral Diseases &amp; Other Research Platforms West China 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