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Multilevel Analysis Reveals the Critical Role of Cell Death-Related Molecules and Drugs in Temporomandibular
Yuxin Zhang1, Xiaoyu Liao2, Dahe Zhang3
1Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology; Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China; Shanghai Key Laboratory of Orthopedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background:
Temporomandibular disorder (TMD) is the most common maxillofacial musculoskeletal disease involving various conditions such as chewing muscle disorders, disc displacement and osteoarthritis. However, its intricate pathogenesis remains unclear. Herein, by integrating evidence at the blood, tissue and cell levels, we aimed to investigate the association of cell death-related genes with TMD and predict potential target drugs.
Methods:
Summary-level data on methylation, expression and protein abundance levels of cell death-related genes were used to identify drug-targeted genes at the blood level. FUSION tool was employed to identify and validate associations at the tissue level. Single-cell analysis was utilised to determine whether TMD-associated cell death genes exhibited higher expression in specific cell types. Drug prediction and molecular docking was used to confirm drug-related effects of TMD-associated cell death genes.
Results:
Integrating the overlapping results of summary-data-based Mendelian randomisation of mQTL, eQTL and pQTL at the blood level with Bayesian co-localisation analysis, 3 cell death-related genes were identified as causally associated with TMD: TIE1 (Tier 1), IFI16 (Tier 1) and GATM (Tier 2). Based on tissue-level FUSION analysis, we validated the specific effects of TIE1 and GATM genes in muscle-skeletal histology. Meanwhile, single-cell data were utilised to further analyse the cell type-specific enrichment of the 3 target genes in TMD. Finally, drug prediction and molecular docking identified 5 pharmacokinetic associations of 3 TMD-associated cell death genes.
Conclusion:
Based on multilevel evidence of the blood, tissue and cell, we found that cell death-related genes TIE1, IFI16 and GATM were associated with TMD risk and predict potential target drugs such as fostamatinib. This study further elucidates the critical role of cell death-related molecules and drugs in TMD.
