Genetically Supported Drug Targets and Dental Traits: A Mendelian Randomization Study

Area of Science:

• Genetics and Bioinformatics
• Pharmacology
• Oral and Dental Medicine

Background:

• Current dental disease treatments often require surgery.
• Identifying novel drug targets can lead to noninvasive pharmacotherapy.
• Genetic evidence can support the discovery of therapeutic targets for oral diseases.

Purpose of the Study:

• To identify potential therapeutic targets for oral and dental diseases using genetic data and Mendelian randomization (MR).
• To leverage large-scale genetic datasets and druggable gene information for target discovery.
• To validate identified targets through replication and functional analyses.

Main Methods:

• Utilized Mendelian randomization (MR) with genetic variants as instrumental variables.
• Intersected 4,302 druggable genes with expression quantitative trait loci (eQTLs) from 31,684 blood samples.
• Collected single nucleotide polymorphisms (SNPs) for dental traits from large cohorts (FinnGen, GLIDE, UK Biobank) for discovery and replication.
• Performed sensitivity analyses, colocalization, pathway analysis (GO/KEGG), protein-protein interaction analysis, and animal model validation.

Main Results:

• Identified 43 druggable targets for various dental disease/symptom traits through MR analysis.
• Replicated findings using circulating protein quantitative trait loci (pQTLs) as exposures.
• IL12RB1 and TNF showed therapeutic potential for oral ulcers.
• CXCL10 demonstrated potential therapeutic relevance for periodontitis.

Conclusions:

• The study identified and validated several druggable genetic targets for oral and dental diseases.
• IL12RB1, TNF, and CXCL10 represent promising targets for novel drug development or repurposing.
• These findings may lead to noninvasive pharmacotherapy options, improving clinical outcomes for dental conditions.