Ye Xinjian, Chen Tan, Cheng Jiuhao, Song Yue, Ding Peihui, Wang Zhiyong, Chen Qianming
Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, 166th Qiutao Road, Hangzhou, 310000, China.
Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, 166th Qiutao Road, Hangzhou, 310000, China..
Int Immunopharmacol. 2025 Jan 10;144:113642. doi: 10.1016/j.intimp.2024.113642. Epub 2024 Nov 22.
Oral manifestations function as precursors to potential systemic pathologies, signaling early indicators of underlying health complications or immunological dysfunctions. Within these dynamics, circulating inflammatory proteins are recognized as critical mediators in immunopharmacology, bridging holistic health, immune response, and oral health.
We employed genetic data from genome-wide association studies to perform comprehensive Mendelian randomization (MR) analyses on 91 circulating inflammatory proteins and 17 oral phenotypes. Six MR algorithms and five auxiliary control measures were utilized to estimate the causal effects. Subsequently, the MR-Bayesian model averaging (MR-BMA) approach was conducted to elucidate the priorities in host-oral communication, followed by network analyses to explore the interactions among phenotypes.
After multiple corrections, MR identified five genetically predicted proteins associated with oral phenotypes. Specifically, FGF21 was correlated with Nteeth and DMFS; hGDNF with gingival pain; CCL4 with stomatitis; and S100A12 with denture use. The causal associations remained robust in sensitivity analyses. Nine protein-phenotype clusters were prioritized using MR-BMA. Among these, S100A12, FGF19, FGF21, and CCL4 exhibited extensive correlations with various oral phenotypes.
Our study offers novel genetic insights into the causal relationships, prioritizations, and connections between circulating inflammatory proteins and oral phenotypes. These findings comprehensively depict immune-mediated proteomic profiles underlying the host-oral axis, providing significant implications for clinical practice, public health, and immunopharmacology.
口腔表现是潜在全身病理状况的先兆，是潜在健康并发症或免疫功能障碍的早期指标。在这些动态变化中，循环炎症蛋白被认为是免疫药理学中的关键介质，连接着整体健康、免疫反应和口腔健康。
我们利用全基因组关联研究的遗传数据，对91种循环炎症蛋白和17种口腔表型进行全面的孟德尔随机化（MR）分析。采用六种MR算法和五种辅助对照措施来估计因果效应。随后，采用MR-贝叶斯模型平均（MR-BMA）方法来阐明宿主与口腔沟通中的优先事项，接着进行网络分析以探索表型之间的相互作用。
经过多次校正后，MR鉴定出五种与口腔表型相关的基因预测蛋白。具体而言，成纤维细胞生长因子21（FGF21）与恒牙数（Nteeth）和恒牙龋失补牙面数（DMFS）相关；人胶质细胞源性神经营养因子（hGDNF）与牙龈疼痛相关；趋化因子配体4（CCL4）与口腔炎相关；钙结合蛋白A12（S100A12）与义齿使用相关。在敏感性分析中，因果关联仍然稳健。使用MR-BMA对九个蛋白-表型簇进行了优先级排序。其中，S100A12、成纤维细胞生长因子19（FGF19）、FGF21和CCL4与多种口腔表型表现出广泛的相关性。
我们的研究为循环炎症蛋白与口腔表型之间的因果关系、优先级排序和联系提供了新的遗传学见解。这些发现全面描绘了宿主-口腔轴潜在的免疫介导蛋白质组学特征，对临床实践、公共卫生和免疫药理学具有重要意义。
