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

Journal of dental research Pub Date : 2024-11-01 Epub Date: 2024-10-06 DOI:10.1177/00220345241272045
L Liu, T Wang, C Duan, S Mao, B Wu, Y Chen, D Huang, Y Cao
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Abstract

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.

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基因支持药物靶点与牙齿特征:孟德尔随机化研究。
目前对口腔/牙科疾病的干预在很大程度上依赖于手术/外科手术,而新型药物靶点的发现则可能使人们获得非侵入性的药物治疗。因此,本研究旨在利用大规模数据和孟德尔随机化(Mendelian randomization,MR)技术,以基因变异为工具,找出有基因证据支持的口腔和牙科疾病潜在治疗靶点。通过将 31,684 份血液样本中的 4,302 个可用药基因与表达定量性状位点相交叉,我们确定了 2,580 个可用药靶点作为暴露因子。与牙科疾病/症状特征相关的单核苷酸多态性是从 FinnGen R9、牙科终点基因与生活方式相互作用联盟和英国生物库中收集的,作为发现和复制的结果。通过磁共振分析,我们确定了 43 个可用于治疗各种牙科疾病/症状特征的靶点。为了评估这些靶点的可行性,我们使用循环蛋白定量性状位点作为暴露因子进行了重复分析。此外,我们还进行了灵敏度、共定位、基因本体/京都基因和基因组百科全书注释、蛋白-蛋白相互作用分析,并在动物模型中验证了与牙齿性状相关的可药用基因的表达。在这些靶点中,IL12RB1(几率比 [OR],1.01;95% 置信区间 [CI],1.01-1.01)和 TNF(OR,0.98;95% CI,0.97-0.99)对口腔溃疡有治疗前景,而 CXCL10(OR,0.84;95% CI,0.76-0.91)则对牙周炎有治疗前景。通过严格的质量控制和验证流程,我们的研究为这些可药用靶点提供了令人信服的证据,这些靶点可通过开发新型药物或重新利用现有药物来改善临床预后。
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