Luo Sumei, Yin Jianyin, Zhang Jie, Li Pan, Wen Tao, Li Ke, Tang Jing, Wang Xiaohong, Li Aiyuan, Chen Liang
Department of Anesthesiology, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, 410008, China.
Cell Mol Neurobiol. 2025 Jan 22;45(1):15. doi: 10.1007/s10571-025-01533-5.
Immune and metabolic factors play an important role in the onset and development of insomnia. This study aimed to investigate the causal relationship between insomnia and immune cells and metabolites. Data for 731 immune cell phenotypes, 1400 metabolites, and insomnia in this study were obtained from the GWAS open-access database. Two-way Mendelian randomization was used to (1) detect the causal relationship between immune cells and insomnia and (2) identify potential mediating metabolites. Mendelian randomization analysis identified eight immune cell phenotypes with a causal relationship to insomnia, and two immune cell phenotypes were protective factors for insomnia, namely CD8br %T cells and CD80 on CD62L + myeloid dendritic cells. The other six immune cell phenotypes were risk factors for insomnia, i.e., CD4/CD8br, CD16-CD56 on NKT, CCR2 on myeloid dendritic cells, CD40 on monocytes, CD38 on CD3-CD19-, and CD25 on CD45RA + CD4 not Treg. Further Mendelian randomization revealed 11 metabolites that were causally related to insomnia. Five metabolites were protective factors for insomnia, i.e., 3-hydroxy-3-methylglutarate, cholate, dodecanedioate, N-formylmethionine, and x-26054. Six metabolites were risk factors for insomnia, 3-amino-2-piperidone, 6-oxopiperdine-2-carboxylate, caffeine to theophylline ratio, leucine, maltose, and x-24736. In addition, our analysis showed that leucine mediated the association between CD4/CD8br and insomnia. From genetic information, we confirmed the causal relationship between insomnia, eight immune cell phenotypes, and eleven metabolite levels. Notably, we found a relationship between leucine-mediated CD4/CD8br and insomnia, providing evidence supporting the causal relationship between immune cell and insomnia, with plasma metabolites serving as mediators.
免疫和代谢因素在失眠的发生和发展中起重要作用。本研究旨在探讨失眠与免疫细胞及代谢物之间的因果关系。本研究中731种免疫细胞表型、1400种代谢物和失眠的数据来自全基因组关联研究（GWAS）开放获取数据库。采用双向孟德尔随机化方法：（1）检测免疫细胞与失眠之间的因果关系；（2）确定潜在的中介代谢物。孟德尔随机化分析确定了8种与失眠有因果关系的免疫细胞表型，其中2种免疫细胞表型是失眠的保护因素，即CD8br%T细胞和CD62L+髓样树突状细胞上的CD80。其他6种免疫细胞表型是失眠的危险因素，即CD4/CD8br、自然杀伤T细胞（NKT）上的CD16-CD56、髓样树突状细胞上的CCR2、单核细胞上的CD40、CD3-CD19-上的CD38以及CD45RA+CD4非调节性T细胞（Treg）上的CD25。进一步的孟德尔随机化分析揭示了11种与失眠有因果关系的代谢物。5种代谢物是失眠的保护因素，即3-羟基-3-甲基戊二酸、胆酸盐、十二烷二酸、N-甲酰甲硫氨酸和x-26054。6种代谢物是失眠的危险因素，即3-氨基-2-哌啶酮、6-氧代哌啶-2-羧酸盐、咖啡因与茶碱的比值、亮氨酸、麦芽糖和x-24736。此外，我们的分析表明亮氨酸介导了CD4/CD8br与失眠之间的关联。从遗传信息来看，我们证实了失眠、8种免疫细胞表型和11种代谢物水平之间的因果关系。值得注意的是，我们发现亮氨酸介导的CD4/CD8br与失眠之间存在关联，为免疫细胞与失眠之间的因果关系提供了证据，血浆代谢物起到了中介作用。
