Pharmacovigilance-Based Identification and Mechanistic Exploration of Periodontitis-Related Drugs

Abstract

Background: Periodontitis is a common chronic inflammatory disease. However, drug-related risks and underlying molecular mechanisms remain underexplored from large real-world data.

Methods: We first mined the US Food and Drug Administration Adverse Event Reporting System (FAERS) database to identify drugs disproportionately associated with periodontitis, using four signal detection algorithms and logistic regression for confounder adjustment. Identified drugs were then mapped to their protein targets via DrugBank, followed by pathway enrichment and protein-protein interaction (PPI) network analysis to explore biological relevance. To assess potential causality, we conducted Mendelian randomisation (MR) using cis-pQTLs from UKB-PPP and deCODE cohorts. Finally, we used single-cell RNA sequencing (scRNA-seq) data from gingival tissue and peripheral blood of periodontitis patients to evaluate cell type-specific expression of candidate causal genes.

Results: Five drugs (actonel, aclasta, aredia, amlodipine and avastin) were significantly positively associated with periodontitis based on FAERS. VEGFA showed an association with disease risk (OR = 1.043, p = 0.049) after meta-analysis of two cohorts. scRNA-seq data identified high VEGFA expression in monocytes in both gingival and blood samples of periodontitis patients.

Conclusion: This study uncovered the association between drug and periodontitis and highlighted VEGFA as a potential molecular mediator. Further studies are needed to confirm causality.

Keywords: FAERS database; Mendelian randomisation; drug targets; periodontitis; single‐cell RNA sequencing.

FIGURE 1

Workflow chart of this study. EBGM, empirical Bayes geometric mean; GO, gene ontology; IC, information component; KEGG, Kyoto Encyclopedia of Genes and Genomes; PPI, protein–protein interaction; PRR, proportional reporting ratio; ROR, reporting odds ratio.

FIGURE 2

Forest plot of identified periodontitis‐related drugs after ROR, PRR, IC, EBGM, p‐value from Fisher's exact test and logistic regression analysis. CI, confidence interval; OR, odds ratio.

FIGURE 3

Results of enrichment and PPI analysis. (A) GO result of identified target genes from BP, CC and MF levels. (B) KEGG result of identified target genes. (C) PPI network of identified target genes. The genes with red circles are hub genes.

FIGURE 4

Single‐cell transcriptomic analysis of VEGFA expression in peripheral blood and gingival tissue. (A) Identified immune cell populations from single‐cell RNA sequencing (scRNA‐seq) of peripheral blood. (B, C) VEGFA expression levels across different cell clusters in peripheral blood. (D) Identified cell populations from scRNA‐seq of gingival tissue. (E, F) VEGFA expression levels across different cell clusters in gingival tissue.