Abstract：
Amyotrophic lateral sclerosis (ALS) represents a rare and potentially fatal neurodegenerative disease. Diverse T-cell subsets could potentially exert diametrically opposite impacts upon ALS development. A two-sample Mendelian randomization (MR) analysis was performed to investigate the correlation between 244 T-cell subsets and ALS risk. Genetic instrumental variables were procured from a standard genome-wide association study (GWAS) that encompassed 244 T-cell subsets in 3757 individuals of European lineage. ALS-related data were collected from a GWAS comprising 20,806 ALS instances and 59,804 European control participants. Multiple sensitivity analyses were performed to verify the robustness of the significant results. Reverse MR analysis was used for delineating the effects of ALS on the characteristics of T-cells. After multiple comparison corrections, 24 out of the 244 subtypes demonstrated a potential association with ALS risk. Significantly, 75% of these associations encompassed the expression of the CD3 on diverse T-cell subtypes, revealing a highly consistent inverse relation to ALS risk. The proportion of T regulatory cells (Tregs) in CD4+ T cells and secreting Tregs in CD4+ T cells demonstrated negative associations with the risk of ALS. CCR7 expression on naive CD4+ T cells and CCR7 expression on naive CD8+ T cells showed positive associations with ALS risk. Certain T-cell subsets, particularly those identified by CD3 expression on terminally differentiated CD8+ T cells, proportions of Tregs, and CCR7 expression, indicated an association with ALS risk. These findings harmonize with and extend previous observational studies investigating the involvement of T lymphocyte subset-induced immunological processes in ALS.
摘要：
肌萎缩侧索硬化症（ALS）是一种罕见且可能致命的神经退行性疾病。不同的T细胞亚群可能对ALS的发展产生截然相反的影响。进行了双样本孟德尔随机化（MR）分析，以研究244个T细胞亚群与ALS风险之间的相关性。遗传工具变量来自标准的全基因组关联研究（GWAS），该研究涵盖了3757名欧洲血统个体的244个T细胞亚群。ALS相关数据来自GWAS，包括20,806例ALS和59,804例欧洲对照参与者。进行了多个敏感性分析以验证重要结果的稳健性。反向MR分析用于描绘ALS对T细胞特征的影响。经过多次比较校正后，在244个亚型中，有24个亚型显示出与ALS风险的潜在关联。重要的是,这些关联的75％包括CD3在不同T细胞亚型上的表达，揭示了与ALS风险高度一致的反比关系。CD4+T细胞中调节性T细胞(Tregs)的比例和CD4+T细胞中分泌Tregs的比例与ALS的风险呈负相关。幼稚CD4+T细胞上的CCR7表达和幼稚CD8+T细胞上的CCR7表达与ALS风险呈正相关。某些T细胞亚群,特别是通过在终末分化的CD8+T细胞上的CD3表达鉴定的那些，Tregs的比例，和CCR7表达，表明与ALS风险相关。这些发现与先前的观察性研究相协调并扩展了研究T淋巴细胞亚群诱导的免疫过程在ALS中的参与。
