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Systemic immunomodulatory management continues to be an attractive approach in periodontal care, particularly within the context of \u2018predictive, preventive, and personalized\u2019 periodontics. The present study incorporated genetic proxies identified through genome-wide association studies for circulating immune cells and periodontitis into a comprehensive Mendelian randomization (MR) framework. Univariable MR, multivariable MR, subgroup analysis, reverse MR, and Bayesian model averaging (MR-BMA) were utilized to investigate the causal relationships. Furthermore, transcriptome-wide association study and colocalization analysis were deployed to pinpoint the underlying genes. Consequently, the MR study indicated a causal association between circulating neutrophils, natural killer T cells, plasmacytoid dendritic cells, and an elevated risk of periodontitis. MR-BMA analysis revealed that neutrophils were the primary contributors to periodontitis. The high-confidence genes\n                    <jats:italic>S100A9<\/jats:italic>\n                    and\n                    <jats:italic>S100A12<\/jats:italic>\n                    , located on 1q21.3, could potentially serve as immunomodulatory targets for neutrophil-mediated periodontitis. These findings hold promise for early diagnosis, risk assessment, targeted prevention, and personalized treatment of periodontitis. Considering the marginal association observed in our study, further research is required to comprehend the biological underpinnings and ascertain the clinical relevance thoroughly.\n                  <\/jats:p>","DOI":"10.7554\/elife.92895","type":"journal-article","created":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T10:31:36Z","timestamp":1700735496000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.92895","source":"Crossref","is-referenced-by-count":23,"title":["Genetic associations between circulating immune cells and periodontitis highlight the prospect of systemic immunoregulation in periodontal care"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2300-6117","authenticated-orcid":true,"given":"Xinjian","family":"Ye","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00a2xv884","id-type":"ROR","asserted-by":"publisher"}],"name":"Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, 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