陆军军医大学学报2026，Vol.48Issue(5)：543-550,8.DOI:10.16016/j.2097-0927.202512135
肉碱与犬尿氨酸驱动CD8+T细胞衰老:一项双向孟德尔随机化研究阐释尿毒症免疫紊乱新机制
Carnitine and kynurenine drive CD8+T cell senescence:a bidirectional Mendelian randomization study elucidates novel mechanisms of uremia-associated immune dysregulation
摘要
Abstract
Objective To systematically investigate the bidirectional causal relationship between 10 uremia-related toxins and metabolites and CD8+T cell senescence phenotypes using Mendelian randomization(MR).Methods A bidirectional MR analysis was performed using genome-wide association studies(GWAS)data to extract single nucleotide polymorphisms closely associated with 10 uremia-related toxins and metabolites and CD8+T cell senescence phenotypes as instrumental variables.The primary analytical method was inverse variance weighting(IVW),supplemented by MR-Egger,weighted median,simple mode,and weighted mode.The robustness and potential pleiotropy of the results were verified by sensitivity analyses including Cochran's Q test,MR-Egger intercept test,MR-PRESSO and leave-one-out analysis.Results MR analysis showed that carnitine level was positively associated with the proportion of terminally differentiated CD8+T cells(IVW:β=1.71,95%CI:0.59 to 2.83,P=0.003),the proportion of CD45RA+CD28⁻CD8+T cells(IVW:β=2.23,95%CI:0.65 to 3.80,P=0.006),and the proportion of CD28⁻CD8+T cells(IVW:β=1.13,95%CI:0.11 to 2.15,P=0.030).Kynurenine level also showed a significant positive association with the proportion of terminally differentiated CD8+T cells(IVW:β=1.69,95%CI:0.57 to 2.82,P=0.000 3),while IL-6 level presented a positive correlation with the proportion of CD28⁻CD8+T cells(IVW:β=0.28,95%CI:0.03 to 0.53,P=0.026)and the proportion of CD45RA+CD28⁻CD8+T cells(IVW:β=0.41,95%CI:0.02 to 0.79,P=0.04).N2,N2-dimethylguanosine level was positively correlated with CD45RA+CD28⁻CD8+T cell absolute count(IVW:β=2.53,95%CI:0.51 to 4.55,P=0.014).Reverse MR analysis revealed an increase in the absolute count of CD45RA+CD28⁻CD8+T cells was causally associated with a reduction in carnitine levels(IVW:β=-0.000 03,95%CI:-0.000 062 to 0.000 004,P=0.024).All sensitivity analyses supported the robustness of the main findings.Conclusion There are bidirectional causal associations between uremia-related toxins and metabolites and CD8+T cell senescence,providing novel causal insights and potential intervention targets for immune dysfunction in uremic patients.关键词
尿毒症相关毒素及代谢物/CD8+T细胞衰老/孟德尔随机化研究Key words
uremia-related toxins and metabolites/CD8+T cell senescence/Mendelian randomization analysis分类
医药卫生引用本文复制引用
孙跃文,蓝琦港,赵景宏..肉碱与犬尿氨酸驱动CD8+T细胞衰老:一项双向孟德尔随机化研究阐释尿毒症免疫紊乱新机制[J].陆军军医大学学报,2026,48(5):543-550,8.基金项目
国家自然科学基金重点项目(82030023,82530025) （82030023,82530025）
国家自然科学基金联合基金项目(U22A20279) （U22A20279）
重庆市研究生科研创新项目(CYB23281) Supported by the Key Program of National Natural Science Foundation of China(82030023 and 82530025),the Joint Fund of National Natural Science Foundation of China(U22A20279),and the Research and Innovation Project Graduate of Chongqing(CYB23281). （CYB23281）
