State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Department of Conservative Dentistry and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
J Dent Res. 2024 Nov;103(12):1271-1280. doi: 10.1177/00220345241272045. Epub 2024 Oct 6.
Current interventions for oral/dental diseases heavily rely on operative/surgical procedures, while the discovery of novel drug targets may enable access to noninvasive pharmacotherapy. Therefore, this study aims to leverage large-scale data and Mendelian randomization (MR) techniques, utilizing genetic variants as instruments, to identify potential therapeutic targets for oral and dental diseases supported by genetic evidence. By intersecting 4,302 druggable genes with expression quantitative trait loci from 31,684 blood samples, we identified 2,580 druggable targets as exposures. Single nucleotide polymorphisms associated with dental disease/symptom traits were collected from FinnGen R9, the Gene-Lifestyle Interactions in Dental Endpoints consortium, and the UK Biobank to serve as outcomes for both discovery and replication purposes. Through MR analysis, we identified 43 druggable targets for various dental disease/symptom traits. To evaluate the viability of these targets, we replicated the analysis using circulating protein quantitative trait loci as exposures. Additionally, we conducted sensitivity, colocalization, Gene Ontology/Kyoto Encyclopedia of Genes and Genomes annotation, protein-protein interaction analyses, and validated dental trait-associated druggable gene expression in animal models. Among these targets, (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.01-1.01) and (OR, 0.98; 95% CI, 0.97-0.99) exhibited therapeutic promise for oral ulcers, whereas (OR, 0.84; 95% CI, 0.76-0.91) was for periodontitis. Through a rigorous quality control and validation pipeline, our study yields compelling evidence for these druggable targets, which may enhance the clinical prognosis by developing novel drugs or repurposing existing ones.
目前针对口腔/牙齿疾病的干预措施主要依赖于手术/外科手术，而新药物靶点的发现可能使非侵入性药物治疗成为可能。因此，本研究旨在利用大规模数据和孟德尔随机化（MR）技术，利用遗传变异作为工具，通过遗传证据确定口腔和牙齿疾病的潜在治疗靶点。通过将 4302 个可成药基因与 31684 个血液样本中的表达数量性状基因座相交，我们确定了 2580 个可成药靶标作为暴露因素。从 FinnGen R9、基因-生活方式在口腔终点中的相互作用联盟以及英国生物银行收集与牙齿疾病/症状特征相关的单核苷酸多态性，作为发现和复制的结果。通过 MR 分析，我们确定了 43 个可用于各种牙齿疾病/症状特征的可成药靶标。为了评估这些靶标的可行性，我们使用循环蛋白数量性状基因座作为暴露因素复制了分析。此外，我们还进行了敏感性、共定位、基因本体论/京都基因与基因组百科全书注释、蛋白质-蛋白质相互作用分析，并在动物模型中验证了与牙齿特征相关的可成药基因表达。在这些靶标中，（比值比 [OR]，1.01；95%置信区间 [CI]，1.01-1.01）和（OR，0.98；95% CI，0.97-0.99）显示出对口腔溃疡的治疗潜力，而（OR，0.84；95% CI，0.76-0.91）则对牙周炎有治疗潜力。通过严格的质量控制和验证管道，我们的研究为这些可成药靶标提供了令人信服的证据，通过开发新的药物或重新利用现有的药物，可能会改善临床预后。
