Qiu Ruqing, Su Yana, Pan Lin, Fan Kangli, Sun Zhihui, Liang Yue, Lin Xiaoyue, Zhang Ying
Department of Neurology, The First Hospital of Jilin University, Changchun, China.
Sci Rep. 2025 Jul 10;15(1):24884. doi: 10.1038/s41598-025-11198-1.
Numerous studies have revealed a correlation between immune system dysfunction and Parkinson's disease (PD), yet the causal link between them remains unclear. To investigate the causal relationship between immune mediators and Parkinson's disease (PD), we conducted two independent Mendelian Randomization (MR) analyse using genetic variants associated with 731 immune cell phenotypes and 91 circulating inflammatory proteins as instrumental variables. The genetic variant data for immune cell phenotypes were derived from a genome-wide association study (GWAS) involving 3,757 individuals, while the genomic protein quantitative trait loci (pQTL) data for circulating inflammatory proteins were sourced from a GWAS dataset comprising 14,824 individuals of European descent. Additionally, we utilized PD risk data from a large meta-analysis of GWAS, which included 33,674 PD cases and 449,056 controls. Our primary analysis was conducted using the inverse-variance weighted (IVW) method, complemented by various Mendelian randomization (MR) approaches and sensitivity analyses to robustly assess the potential causal relationships between immune cell traits, inflammatory proteins, and PD risk. MR analysis reveals a significant causal link between 26 immune cell traits and the risk of PD. Of these, an increase in 15 traits, such as the proportion of resting CD4 regulatory T cells (OR = 1.039 [95% CI: 1.005-1.074], P = 0.024), is associated with a higher risk of PD. Conversely, an increase in 11 traits, such as the FSC-A of HLA DR + CD4 + T cells (OR = 0.934 [95% CI: 0.872-1.000], P = 0.0244), indicates a reduced risk of PD, a relationship that remains significant after false discovery rate (FDR) correction. Additionally, a significant causal relationship exists between four inflammatory proteins and PD risk, with two positively correlated and two negatively correlated with PD risk, all maintaining significance after FDR correction. This study reveals complex causal relationships between immune cells and inflammation-related proteins and the risk of Parkinson's disease (PD), emphasizing that even the same type of immune cell may play different roles at various stages of PD development.
众多研究揭示了免疫系统功能障碍与帕金森病（PD）之间的相关性，然而它们之间的因果关系仍不明确。为了研究免疫介质与帕金森病（PD）之间的因果关系，我们进行了两项独立的孟德尔随机化（MR）分析，使用与731种免疫细胞表型和91种循环炎症蛋白相关的基因变异作为工具变量。免疫细胞表型的基因变异数据来自一项涉及3757名个体的全基因组关联研究（GWAS），而循环炎症蛋白的基因组蛋白质定量性状位点（pQTL）数据则来自一个包含14824名欧洲血统个体的GWAS数据集。此外，我们利用了来自一项大型GWAS荟萃分析的PD风险数据，其中包括33674例PD病例和449056例对照。我们的主要分析采用逆方差加权（IVW）方法，并辅以各种孟德尔随机化（MR）方法和敏感性分析，以稳健地评估免疫细胞特征、炎症蛋白与PD风险之间的潜在因果关系。MR分析揭示了26种免疫细胞特征与PD风险之间存在显著的因果关系。其中，15种特征的增加，如静息CD4调节性T细胞的比例（OR = 1.039 [95% CI：1.005 - 1.074]，P = 0.024），与较高的PD风险相关。相反，11种特征的增加，如HLA DR + CD4 + T细胞的FSC - A（OR = 0.934 [95% CI：0.872 - 1.000]，P = 0.0244），表明PD风险降低，在错误发现率（FDR）校正后这种关系仍然显著。此外，四种炎症蛋白与PD风险之间存在显著的因果关系，其中两种与PD风险呈正相关，两种与PD风险呈负相关，在FDR校正后均保持显著。这项研究揭示了免疫细胞和炎症相关蛋白与帕金森病（PD）风险之间复杂的因果关系，强调即使是同一类型的免疫细胞在PD发展的不同阶段可能也发挥着不同的作用。
