Chen Keyu, Cai Yuankun
Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan, China.
Brain Behav. 2025 Sep;15(9):e70699. doi: 10.1002/brb3.70699.
Tinnitus is a complex disease whose pathophysiological mechanisms are still not fully elucidated. Dysregulation of circulating inflammatory proteins and metabolites is thought to play a crucial role in tinnitus pathophysiology, but the causal relationships and specific biological pathways linking these factors to tinnitus persistence remain unestablished.
We performed a two-sample Mendelian randomization (MR) analysis using tinnitus genome-wide association study (GWAS) data from FinnGen biobanking and GWAS data from metabolites and circulating inflammatory factors in GWAS directories. For the identified key metabolites, we further investigated their mediating role in the effects on tinnitus using mediator MR. We explored potential mechanisms through protein-protein interaction and functional enrichment analyses.
MR analysis showed that Chemokine (C-C motif) Ligand 19 (CCL19) (OR = 1.071; 95% CI, 1.006-1.141; p = 0.032) was positively correlated with tinnitus. In addition, MR analysis identified 14 serum metabolites significantly associated with tinnitus. Among the metabolites, pantothenate (OR = 1.047; 95% CI, 1.012-1.082; p = 0.007) may play a critical mediating role in CCL19-induced tinnitus. Protein-protein interaction and functional enrichment analysis showed that CCL19 may promote tinnitus through extensive interactions with genes related to pantothenic acid metabolism, such as Toll-like receptor 4 (TLR4) and Scavenger Receptor Class B, Member 1 (SCARB1), by promoting oxidative stress and inflammation. And the downstream inflammation-related pathways of pantothenate (such as Toll-like receptor, NF-κB, etc.).
This first MR-based evidence establishes CCL19-pantothenate axis dysfunction as a causal driver of tinnitus, prioritizing these biomarkers for early detection. It also revealed the pivotal role of circulating inflammatory proteins and metabolic dysregulation in the pathogenesis of tinnitus. The findings provide new evidence-based medical support for specific circulating inflammatory proteins and metabolites as biomarkers for early tinnitus prediction and risk assessment. They also offer valuable insights for subsequent research on tinnitus pathophysiological mechanisms and precision medicine applications.
耳鸣是一种复杂的疾病，其病理生理机制仍未完全阐明。循环炎症蛋白和代谢物的失调被认为在耳鸣病理生理学中起关键作用，但将这些因素与耳鸣持续存在联系起来的因果关系和特定生物学途径仍未明确。
我们使用来自芬兰基因库生物样本库的耳鸣全基因组关联研究（GWAS）数据以及GWAS目录中代谢物和循环炎症因子的GWAS数据进行了两样本孟德尔随机化（MR）分析。对于鉴定出的关键代谢物，我们使用中介MR进一步研究了它们在耳鸣影响中的中介作用。我们通过蛋白质-蛋白质相互作用和功能富集分析探索了潜在机制。
MR分析表明，趋化因子（C-C基序）配体19（CCL19）（OR = 1.071；95%CI，1.006 - 1.141；p = 0.032）与耳鸣呈正相关。此外，MR分析鉴定出14种血清代谢物与耳鸣显著相关。在这些代谢物中，泛酸盐（OR = 1.047；95%CI，1.012 - 1.082；p = 0.007）可能在CCL19诱导的耳鸣中起关键中介作用。蛋白质-蛋白质相互作用和功能富集分析表明，CCL19可能通过与泛酸代谢相关基因（如Toll样受体4（TLR4）和清道夫受体B类成员1（SCARB1））广泛相互作用，通过促进氧化应激和炎症来促进耳鸣。以及泛酸盐的下游炎症相关途径（如Toll样受体、NF-κB等）。
这一基于MR的首个证据确立了CCL19 - 泛酸盐轴功能障碍是耳鸣的因果驱动因素，将这些生物标志物作为早期检测的重点。它还揭示了循环炎症蛋白和代谢失调在耳鸣发病机制中的关键作用。这些发现为特定循环炎症蛋白和代谢物作为耳鸣早期预测和风险评估的生物标志物提供了新的循证医学支持。它们也为耳鸣病理生理机制的后续研究和精准医学应用提供了有价值的见解。
