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OA
Carnitine and kynurenine drive CD8+T cell senescence:a bidirectional Mendelian randomization study elucidates novel mechanisms of uremia-associated immune dysregulation
目的 通过应用孟德尔随机化(Mendelian randomization,MR)方法,系统探究10种尿毒症相关毒素及代谢物与CD8+T细胞衰老表型之间的双向因果关系.方法 采用双向MR方法,基于全基因组关联研究(genome-wide association studies,GWAS)数据库汇总数据,提取与10种尿毒症相关毒素及代谢物以及4种CD8+T细胞衰老表型显著相关的单核苷酸多态性位点作为工具变量.逆方差加权法(inverse variance weighting,IVW)作为主要分析方法,同时采用MR-Egger、加权中位数法、简单众数法及加权众数法进行补充分析.通过Cochran's Q检验、MR-Egger截距检验、MR-PRESSO及留一法等敏感性分析验证结果的稳健性与潜在多效性.结果 MR分析显示,肉碱水平与终末分化CD8+T细胞比例(IVW:β=1.71,95%CI:0.59～2.83,P=0.003)、CD45RA+CD28-CD8+T细胞比例(IVW:β=2.23,95%CI:0.65～3.80,P=0.006)、CD28-CD8+T细胞比例(IVW:β=1.13,95%CI:0.11～2.15,P=0.030)正相关.犬尿氨酸水平与终末分化CD8+T细胞比例正相关(IVW:β=1.69,95%CI:0.57～2.82,P=0.000 3),而白介 素-6 水 平 与 CD28-CD8+T 细 胞 比 例(IVW:β=0.28,95%CI:0.03～0.53,P=0.026)和CD45RA+CD28-CD8+T细胞比例(IVW:β=0.41,95%CI:0.02～0.79,P=0.04)正相关.N2,N2-二甲基鸟苷水平与CD45RA+CD28-CD8+T细胞绝对计数(IVW:β=2.53,95%CI:0.51～4.55,P=0.014)正相关.反向MR分析显示,CD45RA+CD28-CD8+T细胞绝对计数增加可降低肉碱水平(IVW:β=-0.00 003,95%CI:-0.000 062～-0.000 004,P=0.024).所有敏感性分析均支持主要结果的稳健性.结论 部分尿毒症相关毒素及代谢物与CD8+T细胞衰老之间存在双向因果关联,为尿毒症患者免疫功能紊乱的机制提供了新的因果证据与潜在干预靶点.
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.
孙跃文;蓝琦港;赵景宏
陆军军医大学(第三军医大学)第二附属医院肾内科,肾脏病防治重庆市重点实验室,重庆市肾病与泌尿系统疾病临床医学研究中心,重庆陆军军医大学(第三军医大学)第二附属医院肾内科,肾脏病防治重庆市重点实验室,重庆市肾病与泌尿系统疾病临床医学研究中心,重庆陆军军医大学(第三军医大学)第二附属医院肾内科,肾脏病防治重庆市重点实验室,重庆市肾病与泌尿系统疾病临床医学研究中心,重庆
医药卫生
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
uremia-related toxins and metabolitesCD8+T cell senescenceMendelian randomization analysis
《陆军军医大学学报》 2026 (5)
543-550,8
国家自然科学基金重点项目(82030023,82530025)国家自然科学基金联合基金项目(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).
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