Background Periodontitis drives irreparable destruction of periodontal tissue and possesses a tendency to aggravate inflammatory disorders. Systemic immunomodulation management remains an attractive approach in periodontal care within a context of “predictive, preventive, and personalized” periodontics. Leveraging a comprehensive Mendelian randomization (MR), the present study aims to evaluate the causal relationships between circulating immune cells and the risk of periodontitis.

Methods Genetic proxies for circulating immune cells and periodontitis were obtained from genome-wide association studies. We performed a two-sample bidirectional univariable Mendelian Randomization, followed by sensitivity testing, multivariable MR, subgroup analysis, and Bayesian model averaging (MR-BMA) to explore the causal association between them. The transcriptome-wide association study (TWAS) and colocalization analysis were further conducted to identify responsible genes as immunomodulation candidates for periodontal care.

Results MR study indicated that circulating neutrophils, Natural Killer T cells, and plasmacytoid Dendritic Cells were relative to a higher risk of periodontitis, with no evidence of heterogeneity or pleiotropy. The MR-BMA identified neutrophils as the primary factor responsible for periodontitis. The TWAS recognized five cross-trait genes to be involved in their interaction. Two high-confidence genes on 1q21.3, S100A9 and S100A12, could represent immunomodulation targets for neutrophils in periodontitis.

Conclusions The present study suggests the causative association between circulating immune cells and the risk of periodontitis. Our findings highlight the prospect of systemic immunomodulation management in periodontal care, which can be valuable for early diagnostics, risk assessment, targeted prevention, and personalized management of periodontitis. More research is required to comprehend the biological plausibility and clinical applicability of our findings.

Funding This work was supported by the Major Program of National Natural Science Foundation of China (No. 81991500 & 81991502), the Fundamental Research Funds for the Central Universities (No. 226-2023-00121 & 226-2022-00213), Zhejiang University Global Partnership Fund (No. 188170 & 194452307/004) and the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China (No. LHDMD23H300001)

The authors have declared no competing interest.

This work was supported by the Major Program of National Natural Science Foundation of China (No. 81991500 & 81991502), the Fundamental Research Funds for the Central Universities (No. 226-2023-00121 & 226-2022-00213), Zhejiang University Global Partnership Fund (No. 188170 & 194452307/004) and the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China (No. LHDMD23H300001)

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