Department of Pathology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, P. R. China.
National Clinical Research Center for Infectious Disease, The Third People's Hospital of Shenzhen, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, Guangdong, P. R. China.
J Cell Mol Med. 2024 Oct;28(20):e70176. doi: 10.1111/jcmm.70176.
Neuroinflammation is increasingly recognized as a pivotal factor in the development and progression of neurodegenerative disorders. While correlations between inflammatory cytokines and these diseases are documented, the definitive causal dynamics remain to be elucidated. We explored the causal association between 91 circulating inflammatory cytokines and Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Parkinson's disease (PD) through Mendelian randomization analysis. Leveraging genetic variants from the most comprehensive genome-wide association studies (GWAS) available for these cytokines, AD, ALS, MS and PD, we sought to uncover the causality. Our study validated a causal influence of genetically determined cytokine levels on the susceptibility to AD, with notable cytokines including C-X-C motif chemokine 1 (OR = 0.9993, p = 0.0424), Interleukin-18 (OR = 0.9994, p = 0.0186), Leukaemia inhibitory factor receptor (OR = 0.9993, p = 0.0122) and Monocyte chemoattractant protein-1 (OR = 0.9992, p = 0.0026) in risk attenuation. Additionally, a positive causal relationship was identified between two cytokines-C-C motif chemokine 19 (OR = 1.0005, p = 0.0478) and Fms-related tyrosine kinase 3 ligand (OR = 1.0005, p = 0.0210)-and AD incidence. Conversely, transforming growth factor-alpha (OR = 0.8630, p = 0.0298), CD40L receptor (OR = 0.7737, p = 1.1265E-09) and Interleukin-12 subunit beta (OR = 0.8987, p = 0.0333) showed inverse associations with ALS, MS and PD, respectively. The consistency observed in various MR analyses, alongside sensitivity analysis, underscored the absence of horizontal pleiotropy, thus supporting our causal findings. This study reveals, for the first time, a genetically anchored causal nexus between levels of circulating inflammatory cytokines and the risk of neurodegenerative diseases.
神经炎症越来越被认为是神经退行性疾病发展和进展的关键因素。虽然已经记录了炎症细胞因子与这些疾病之间的相关性，但确切的因果动力学仍有待阐明。我们通过孟德尔随机化分析探讨了 91 种循环炎症细胞因子与阿尔茨海默病 (AD)、肌萎缩侧索硬化症 (ALS)、多发性硬化症 (MS) 和帕金森病 (PD) 之间的因果关系。利用这些细胞因子的最全面全基因组关联研究 (GWAS) 中的遗传变异，我们试图揭示因果关系。我们的研究验证了遗传决定的细胞因子水平对 AD 易感性的因果影响，显著的细胞因子包括 C-X-C 基序趋化因子 1 (OR=0.9993，p=0.0424)、白细胞介素 18 (OR=0.9994，p=0.0186)、白血病抑制因子受体 (OR=0.9993，p=0.0122) 和单核细胞趋化蛋白-1 (OR=0.9992，p=0.0026) 可降低患病风险。此外，还确定了两种细胞因子-C-C 基序趋化因子 19 (OR=1.0005，p=0.0478) 和 Fms 相关酪氨酸激酶 3 配体 (OR=1.0005，p=0.0210)-与 AD 发病率之间存在正因果关系。相反，转化生长因子-α (OR=0.8630，p=0.0298)、CD40L 受体 (OR=0.7737，p=1.1265E-09) 和白细胞介素 12 亚基β (OR=0.8987，p=0.0333) 分别与 ALS、MS 和 PD 呈负相关。各种 MR 分析的一致性，以及敏感性分析，都强调了不存在水平的横向多效性，从而支持了我们的因果发现。这项研究首次揭示了循环炎症细胞因子水平与神经退行性疾病风险之间存在遗传关联的因果关系。
