孟德尔随机化探究循环中免疫T细胞与克罗恩病之间的关系

Mendelian Randomization Investigating the Association between Circulating Immune T Cells and Crohn’s Disease

摘要: 目的：克罗恩病(Crohn’s disease, CD)是病因未明的慢性胃肠道炎症性疾病，免疫紊乱尤其是T细胞异常活化在其发病中起关键作用，通过两样本孟德尔随机化(Mendelian randomization, MR)方法，阐明特定循环免疫T细胞表型与克罗恩病之间的因果关系。方法：利用大型公共全基因组关联研究(Genome-Wide Association Study, GWAS)数据库，进行MR分析，以逆方差加权法(Inverse variance weighted, IVW)为主要方法，评估246种循环免疫T细胞表型与CD之间的关系，进行多效性与异质性检验，同时采用留一法敏感性分析以进一步验证结果的稳健性。结果：筛选出8种不同T细胞免疫表型与CD存在关联，CD45RA⁺ CD8⁺调节性T细胞绝对计数[IVW：比值比(odds ratio, OR) = 1.032，95%置信区间(confidence interval, CI): 1.001~1.603，P < 0.05]、效应记忆CD4⁻CD8⁻ T细胞比例(Effector Memory CD4⁻CD8⁻ T cell % CD4⁻CD8⁻ T cell) (IVW: OR = 1.054, 95% CI: 1.019~1.090, P < 0.05)、HLA DR⁺ T细胞上的CD3表达水平(CD3 on HLA DR⁺ T cell) (IVW: OR = 1.243, 95% CI: 1.083~1.427, P < 0.05)和终末分化CD8⁺ T细胞上的CD8表达水平(CD8 on Terminally Differentiated CD8⁺ T cell) (IVW: OR = 1.249, 95% CI: 1.029~1.516, P < 0.05)与CD风险增加存在因果关系；而终末分化CD4⁻CD8⁻ T细胞绝对计数(Terminally Differentiated CD4⁻CD8⁻ T cell Absolute Count) (IVW: OR = 0.947, 95% CI: 0.915~0.981, P < 0.05)、终末分化CD4⁻CD8⁻ T细胞比例(Terminally Differentiated CD4⁻CD8⁻ T cell % T cell) (IVW：OR = 0.950, 95% CI: 0.919~0.982, P < 0.05)、CD28⁻CD127⁻CD25⁺⁺ CD8⁺ T细胞绝对计数(IVW: OR = 0.798, 95% CI: 0.664~0.958, P < 0.05)和CD28⁻CD25⁺⁺ CD8⁺ T细胞绝对计数(IVW: OR = 0.840, 95% CI: 0.737~0.958, P < 0.05)与CD风险降低存在因果关系。结论：研究确定了八个与CD相关的循环免疫T细胞表型，需进一步研究验证这些发现并探索新的治疗途径。

Abstract: Objective: Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract with unknown etiology. Immune dysregulation, particularly abnormal T-cell activation, plays a key role in its pathogenesis. This study aimed to elucidate the causal relationship between specific circulating immune T-cell phenotypes and Crohn’s disease using a two-sample Mendelian randomization (MR) approach. Methods: Using data from large-scale public genome-wide association studies (GWAS), we performed MR analysis with inverse variance weighted (IVW) as the primary method to evaluate associations between 246 circulating immune T-cell phenotypes and CD. Pleiotropy and heterogeneity tests were conducted, and leave-one-out sensitivity analysis was performed to further validate the robustness of the results. Results: Eight distinct T-cell immune phenotypes were identified to be associated with CD. Absolute count of CD45RA⁺ CD8⁺ regulatory T cells (IVW: odds ratio [OR] = 1.032, 95% confidence interval [CI]: 1.001~1.603, P < 0.05), proportion of effector memory CD4⁻CD8⁻ T cells (Effector Memory CD4⁻CD8⁻ T cell % CD4⁻CD8⁻ T cell) (IVW: OR = 1.054, 95% CI: 1.019~1.090, P < 0.05), CD3 expression on HLA DR⁺ T cells (CD3 on HLA DR⁺ T cell) (IVW: OR = 1.243, 95% CI: 1.083~1.427, P < 0.05), and CD8 expression on terminally differentiated CD8⁺ T cells (CD8 on Terminally Differentiated CD8⁺ T cell) (IVW: OR = 1.249, 95% CI: 1.029~1.516, P < 0.05) were causally associated with an increased risk of CD. Conversely, absolute count of terminally differentiated CD4⁻CD8⁻ T cells (Terminally Differentiated CD4⁻CD8⁻ T cell Absolute Count) (IVW: OR = 0.947, 95% CI: 0.915~0.981, P < 0.05), proportion of terminally differentiated CD4⁻CD8⁻ T cells (Terminally Differentiated CD4⁻CD8⁻ T cell % T cell) (IVW: OR = 0.950, 95% CI: 0.919~0.982, P < 0.05), absolute count of CD28⁻CD127⁻CD25⁺⁺ CD8⁺ T cells (IVW: OR = 0.798, 95% CI: 0.664~0.958, P < 0.05), and absolute count of CD28⁻CD25⁺⁺ CD8⁺ T cells (IVW: OR = 0.840, 95% CI: 0.737~0.958, P < 0.05) were causally associated with a reduced risk of CD. Conclusion: This study identified eight circulating immune T-cell phenotypes associated with CD. Further studies are warranted to validate these findings and explore novel therapeutic avenues.