牙周炎潜在生物标志物和治疗靶点的鉴定
Identification of Potential Biomarkers and Therapeutic Targets for Periodontitis.
作者信息
Huoshen Wuda, Zhu Hanfang, Xiong Junkai, Chen Xinyu, Mou Yunjie, Hou Shuhan, Yang Bin, Yi Sha, He Yahan, Huang Haonan, Sun Chen, Li Chunhui
机构信息
Department of Periodontics and Oral Mucosal Diseases, The Affiliated Stomatology Hospital, Southwest Medical University, Luzhou, Sichuan, China; School of Stomatology, Southwest Medical University, Luzhou, Sichuan, China; Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatology Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Stomatology, Southwest Medical University, Luzhou, Sichuan, China; Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou City, Sichuan Province, China; Liangshan Minority Middle School, Liangshan, Sichuan, China.
Department of Periodontics and Oral Mucosal Diseases, The Affiliated Stomatology Hospital, Southwest Medical University, Luzhou, Sichuan, China; School of Stomatology, Southwest Medical University, Luzhou, Sichuan, China; Luzhou Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, The Affiliated Stomatology Hospital, Southwest Medical University, Luzhou, Sichuan, China; Institute of Stomatology, Southwest Medical University, Luzhou, Sichuan, China.
出版信息
Int Dent J. 2025 Apr;75(2):1370-1383. doi: 10.1016/j.identj.2024.10.006. Epub 2024 Nov 12.
BACKGROUND
Periodontitis is a chronic and multifactorial inflammatory disease. However, existing medications often lack sufficient therapeutic effects. The aim is to identify potential biomarkers and efficient therapeutic targets using Mendelian randomisation (MR) and single-cell analysis.
METHODS
MR analysis was conducted based on the cis-expression quantitative trait loci (cis-eQTLs) extracted from the eQTLGen Consortium and genome-wide association study (GWAS) data of periodontitis sourced from the Gene Lifestyle Interactions in Dental Endpoints (GLIDE) consortium (17,353 cases, 28,210 controls). Subsequently, colocalisation analysis was employed to detect whether genes and periodontitis shared the same casual variant. Finally, enrichment analysis, protein-protein interaction (PPI) networks, drug prediction, phenome-wide association study (PheWAS), molecular docking, and single-cell analysis were conducted to validate the significance of target genes.
RESULTS
Fourteen drug targets were significant related with periodontitis in MR analysis. Following the colocalisation and summary-data-based MR (SMR) analysis, 3 targets (S100A12, S100A9, and S100A8) were classified into tier 1 with strong evidence, 6 therapeutic targets (ADAM12, ADHFE1, BLK, HEBP1, SERPINE2, and TEK) were classified into tier 2 with moderate evidence, and 5 therapeutic targets (LY86, MMEL1, S100B, SPP1, and TRIB3) were classified into tier 3 with convincing evidence. PheWAS analysis showed that only TEK and SPP1 in tier 2 may induce side effects, including cardiometabolic and oncological issues. Molecular docking demonstrated strong binding between drugs and their respective protein targets. In the single-cell analysis, 5 target genes (HEBP1, LY86, S100A8, S100A9, and S100A12) exhibited enrichment in monocytes, while BLK and LY86 were primarily enriched in B cells.
CONCLUSION
The study identified 14 potential therapeutic targets for periodontitis. Among these, 3 therapeutic targets (S100A12, S100A9, and S100A8) demonstrated robust and well-supported results. Drugs designed to target these genes have a higher possibility of success in clinical trials, which are hopeful for prioritising periodontitis drug development.
背景
牙周炎是一种慢性多因素炎症性疾病。然而，现有药物往往缺乏足够的治疗效果。目的是利用孟德尔随机化（MR）和单细胞分析确定潜在的生物标志物和有效的治疗靶点。
方法
基于从eQTLGen联盟提取的顺式表达定量性状位点（cis-eQTLs）和来自牙齿终点基因生活方式相互作用（GLIDE）联盟（17353例病例，28210例对照）的牙周炎全基因组关联研究（GWAS）数据进行MR分析。随后，采用共定位分析来检测基因和牙周炎是否共享相同的因果变异。最后，进行富集分析、蛋白质-蛋白质相互作用（PPI）网络、药物预测、全表型关联研究（PheWAS）、分子对接和单细胞分析，以验证靶基因的重要性。
结果
在MR分析中，14个药物靶点与牙周炎显著相关。经过共定位和基于汇总数据的MR（SMR）分析，3个靶点（S100A12、S100A9和S100A8）被归类为证据充分的1级，6个治疗靶点（ADAM12、ADHFE1、BLK、HEBP1、SERPINE2和TEK）被归类为证据中等的2级，5个治疗靶点（LY8(6)、MMEL1、S100B、SPP1和TRIB3）被归类为证据确凿的3级。PheWAS分析表明，2级中只有TEK和SPP1可能会引起副作用，包括心脏代谢和肿瘤学问题。分子对接证明了药物与其各自蛋白质靶点之间有强结合。在单细胞分析中，5个靶基因（HEBP1、LY86、S100A8、S100A9和S100A12）在单核细胞中表现出富集，而BLK和LY86主要富集在B细胞中。
结论
该研究确定了14个潜在的牙周炎治疗靶点。其中，3个治疗靶点（S100A12、S100A9和S100A8）显示出有力且有充分支持的结果。针对这些基因设计的药物在临床试验中成功的可能性更高，有望为牙周炎药物开发确定优先顺序。
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