Causal network between periodontitis and systemic inflammation: Triangulating evidence from Mendelian randomization...

Area of Science:

• Immunology
• Genetics
• Oral Health

Background:

• Periodontitis is an inflammatory disease driven by immune responses to oral pathogens.
• Gingival defects in periodontitis allow pathogen and inflammatory mediator entry into circulation, potentially causing systemic inflammation and disease.
• Systemic diseases can exacerbate periodontitis by increasing inflammation.

Purpose of the Study:

• To investigate the bidirectional relationship between periodontitis and blood immune cell phenotypes/circulating inflammation-associated proteins.
• To analyze the interplay between immune cells, inflammation proteins, and periodontitis.
• To validate findings using multi-omics and animal models.

Main Methods:

• Bidirectional Mendelian randomization (MR) was employed to assess causal links.
• Two-step mediation analysis explored the interplay between immune factors and periodontitis.
• Sensitivity analyses (MR-PRESSO, MR Egger, Cochran's Q, Steiger filter, leave-one-out) ensured robustness.
• Confounder-related instrumental variants were filtered using Open Targets Genetics.
• High-throughput sequencing and animal models provided supporting evidence.

Main Results:

• MR identified protective proteins (PD-L1, eotaxin, NRTN) and risk proteins (S100A12, CXCL11, SULT1A1) for periodontitis.
• Sixteen immunocyte phenotypes were causally linked to periodontitis.
• Periodontitis was associated with elevated CXCL 9/10/11 levels and altered immune cell profiles (Treg, T cell maturation, cDC).
• Single-cell/bulk-RNA sequencing and animal models confirmed these associations.

Conclusions:

• Periodontitis is closely connected to systemic inflammation, influencing immune cell phenotypes and circulating proteins.
• Findings support targeted immunotherapy for periodontitis and underscore its link to systemic diseases.
• Managing periodontitis necessitates considering the systemic inflammatory milieu, which may mediate links to other diseases.