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, IL12RB1 (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.01–1.01) and TNF (OR, 0.98; 95% CI, 0.97–0.99) exhibited therapeutic promise for oral ulcers, whereas CXCL10 (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.

中文翻译：

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遗传支持的药物靶点和牙齿特征：一项孟德尔随机化研究


目前对口腔/牙科疾病的干预严重依赖于手术/外科手术，而新药物靶点的发现可能使获得无创药物治疗成为可能。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，确定由遗传证据支持的口腔和牙齿疾病的潜在治疗靶点。通过对 31,684 个血液样本中的 4,302 个可成药基因与表达数量性状位点相交，我们确定了 2,580 个可成药靶点作为暴露。从 FinnGen R9、Gene-Lifestyle Interactions in Dental Endpoints 联盟和英国生物样本库中收集与牙科疾病/症状特征相关的单核苷酸多态性，作为发现和复制目的的结果。通过 MR 分析，我们确定了针对各种牙科疾病/症状特征的 43 个可成药靶点。为了评估这些靶标的可行性，我们使用循环蛋白质数量性状位点作为暴露复制了分析。此外，我们还进行了敏感性、共定位、基因本体论/京都基因和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牙齿性状相关的可成药基因表达。在这些目标中，IL12RB1 （比值比 [OR]，1.01;95% 置信区间 [CI]，1.01-1.01）和 TNF（OR，0.98;95% CI，0.97-0.99）显示出治疗口腔溃疡的前景，而 CXCL10 （OR，0.84;95% CI，0.76-0.91）则适用于牙周炎。通过严格的质量控制和验证流程，我们的研究为这些可成药靶点提供了令人信服的证据，这些靶点可能通过开发新药或重新利用现有靶点来增强临床预后。