Identification of Potential Biomarkers and Therapeutic Targets for Periodontitis.

Background: Periodontitis is a chronic and multifactorial inflammatory disease. However, existing medications often lack sufficient therapeutic effects. The aim is to identify potential biomarkers and efficient therapeutic targets using Mendelian randomisation (MR) and single-cell analysis.

Methods: MR analysis was conducted based on the cis-expression quantitative trait loci (cis-eQTLs) extracted from the eQTLGen Consortium and genome-wide association study (GWAS) data of periodontitis sourced from the Gene Lifestyle Interactions in Dental Endpoints (GLIDE) consortium (17,353 cases, 28,210 controls). Subsequently, colocalisation analysis was employed to detect whether genes and periodontitis shared the same casual variant. Finally, enrichment analysis, protein-protein interaction (PPI) networks, drug prediction, phenome-wide association study (PheWAS), molecular docking, and single-cell analysis were conducted to validate the significance of target genes.

Results: Fourteen drug targets were significant related with periodontitis in MR analysis. Following the colocalisation and summary-data-based MR (SMR) analysis, 3 targets (S100A12, S100A9, and S100A8) were classified into tier 1 with strong evidence, 6 therapeutic targets (ADAM12, ADHFE1, BLK, HEBP1, SERPINE2, and TEK) were classified into tier 2 with moderate evidence, and 5 therapeutic targets (LY86, MMEL1, S100B, SPP1, and TRIB3) were classified into tier 3 with convincing evidence. PheWAS analysis showed that only TEK and SPP1 in tier 2 may induce side effects, including cardiometabolic and oncological issues. Molecular docking demonstrated strong binding between drugs and their respective protein targets. In the single-cell analysis, 5 target genes (HEBP1, LY86, S100A8, S100A9, and S100A12) exhibited enrichment in monocytes, while BLK and LY86 were primarily enriched in B cells.

Conclusion: The study identified 14 potential therapeutic targets for periodontitis. Among these, 3 therapeutic targets (S100A12, S100A9, and S100A8) demonstrated robust and well-supported results. Drugs designed to target these genes have a higher possibility of success in clinical trials, which are hopeful for prioritising periodontitis drug development.