Genetic Identification of Potential Drug Targets for Dental Caries: A Mendelian Randomization Study

Dental caries (DC), a chronic and multifactorial disease, affects billions of people globally, posing a significant public health challenge. Despite its prevalence, the molecular mechanisms underlying DC and effective pharmacological targets remain elusive. This study leverages Mendelian randomization (MR) and large-scale genomic data to identify potential drug targets for DC.

We utilized eQTL and genome-wide association studies (GWAS) data to identify genes whose expression is causally linked to DC risk. The eQTL data were extracted from the eQTLGen consortium, and the GWAS data were obtained from the IEU OpenGWAS database. We performed MR analysis using the R package TwoSampleMR and validated the results in the FinnGen cohort. We integrated phenome-wide association studies (PheWAS), gene ontology (GO), and protein-protein interaction (PPI) network construction to explore the potential roles of the identified genes. Molecular docking studies were conducted to identify potential therapeutic agents targeting TUBB.

We identified 32 genes whose expression is causally linked to DC risk. Further validation in the FinnGen cohort narrowed these down to nine key genes: EIF4G3, PREX1, ZFYVE19, TUBB, CBLL1-AS1, EDAR, ADRA2A, BBS10, and TCTN1. These genes were analyzed to explore their roles in dental caries. Molecular docking studies identified paclitaxel and mebendazole as potential therapeutic agents targeting TUBB, with binding energies as low as -9.2 kcal/mol, indicating strong binding affinity.

We identified nine novel candidate drug targets for DC through a comprehensive MR approach combined with multi-omics analyses. These findings highlight the potential of these genes as therapeutic targets and provide valuable insights into the genetic basis of dental caries. The findings provide insights into the genetic basis of DC and highlight targets for future therapeutic development, though experimental validation is required.