周期性歯周炎の薬物標的としてのCACNB4を特定する統合ヒトゲノムおよび薬理学的分析
Yixuan Jiang1,2, Zhengyu Guan1,2, Xiu Yao3,4
1Department of Stomatology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Aim:
Periodontitis currently lacks effective treatments to halt disease progression, as existing therapies focus solely on symptom management. Drug repurposing provides a promising strategy for rapidly identifying effective therapies.
Methods:
To identify therapeutic targets for periodontitis, we performed Mendelian randomization (MR) and colocalization analyses using the cis-expression quantitative trait loci (cis-eQTL) data of druggable genes and genome-wide association studies (GWAS) data. This approach allowed us to pinpoint druggable gene targets significantly associated with periodontitis, which were then validated by immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Next, we applied drug prediction and molecular docking to identify candidate drugs for the key druggable target. Finally, pharmacological analyses were conducted to evaluate the efficacy of these drugs in vitro and in vivo.
Results:
A total of six genes (CACNB4, PSMA4, GAA, FGF2, AURKAIP1, and ADAM12) were found to be causally associated with periodontitis in the MR analysis, of which two (CACNB4 and PSMA4) were further supported by colocalization analyses. CACNB4 was significant in both cohorts in MR analysis and supported by localization and experimental evidence. Moreover, the reliability of this target was confirmed in patient samples. We then identified drugs with repurposing potential that target CACNB4, namely verapamil and safinamide. Pharmacological analyses showed that both agents attenuated osteoclast differentiation, indicating therapeutic potential. Importantly, validation at the cellular level confirmed the activity of these candidate drug targets.
Conclusion:
Through MR analysis, we identified CACNB4 as a potential druggable gene for periodontitis. Among the drugs targeting CACNB4, verapamil and safinamide emerged as the most promising candidates for periodontitis treatment. Pharmacological studies further demonstrated that these agents may inhibit osteoclast differentiation by targeting CACNB4, thereby offering potential therapeutic options for periodontitis.
