Department of Critical Care Medicine, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan, China.
Kunming Medical University, Kunming, Yunnan, China.
Shock. 2024 Apr 1;61(4):577-584. doi: 10.1097/SHK.0000000000002334. Epub 2024 Feb 9.
Objective: The role of immune cells in sepsis remains unclear, and there is some controversy. Here, we aim to systematically assess whether distinct immune cell phenotypes impact the susceptibility to sepsis. Methods: In this study, we harnessed publicly available summary-level data from genome-wide association studies (GWASs). The selection of genetic variations strongly associated with 731 phenotypes of circulating immune cells served as instrumental variables (IVs). Using a two-sample Mendelian randomization (MR) analysis, we investigated the relationships between different immunophenotypes and the occurrence of sepsis, as well as the 28-day mortality. The MR study utilized the inverse variance weighting (IVW) method as the main analytical approach. In addition, we incorporated four other MR methods for supplementary causal inference, including weighted median (WME), MR-Egger regression, simple mode, and weighted mode. Furthermore, the robustness of the results was affirmed through multiple sensitivity analyses. Results: The results of the IVW method indicated that a total of 36 immunophenotypes are associated with the risk of sepsis. We also identified 34 immunophenotypes with a causal association with the 28-day mortality. Interestingly, before multiple testing corrections, 11 immunophenotypes were determined to have consistent causal relationships with both the occurrence of sepsis and the 28-day mortality. Notably, after false discovery rate (FDR) correction, four immunophenotypes were found to be significantly correlated with susceptibility to sepsis: CD45RA- CD4+ %CD4+ (odds ratio [OR], 1.355; 95% confidence interval [CI], 1.1391.611; P < 0.001, PFDR = 0.192), HLA DR on HLA DR+ NK (OR, 0.818; 95% CI, 0.7260.922; P = 0.001, PFDR = 0.192), IgD+ CD24+ %B cell (OR, 0.626; 95% CI, 0.4730.828; P = 0.001, PFDR = 0.192), and TD DN (CD4- CD8-) AC (OR, 0.655; 95% CI, 0.5100.840; P < 0.001, PFDR = 0.192). Following FDR correction, only one immunophenotype was confirmed to be negatively correlated with the 28-day mortality: CD39 on CD39+ CD8br (OR, 0.820; 95% CI, 0.737~0.912; P < 0.001, PFDR = 0.184). Conclusion: This study, for the first time, has uncovered indicative evidence of a causal relationship between circulating immune cell phenotypes and varying degrees of sepsis through genetic means. These findings underscore the significance of immune cells in the pathogenesis of sepsis.
免疫细胞在脓毒症中的作用仍不清楚，存在一些争议。在这里，我们旨在系统评估不同的免疫细胞表型是否会影响脓毒症的易感性。
本研究利用了全基因组关联研究（GWAS）的公开汇总水平数据。选择与循环免疫细胞的 731 种表型强烈相关的遗传变异作为工具变量（IVs）。使用两样本孟德尔随机化（MR）分析，我们研究了不同免疫表型与脓毒症发生以及 28 天死亡率之间的关系。MR 研究采用逆方差加权（IVW）方法作为主要分析方法。此外，我们还纳入了其他四种 MR 方法进行补充因果推断，包括加权中位数（WME）、MR-Egger 回归、简单模式和加权模式。此外，通过多种敏感性分析验证了结果的稳健性。
IVW 方法的结果表明，共有 36 种免疫表型与脓毒症风险相关。我们还确定了 34 种免疫表型与 28 天死亡率存在因果关系。有趣的是，在进行多次检验校正之前，有 11 种免疫表型被确定与脓毒症的发生和 28 天死亡率均存在一致的因果关系。值得注意的是，在经过错误发现率（FDR）校正后，有 4 种免疫表型与脓毒症的易感性显著相关：CD45RA- CD4+ %CD4+（比值比[OR]，1.355；95%置信区间[CI]，1.1391.611；P<0.001，PFDR=0.192）、HLA DR 上的 HLA DR+NK（OR，0.818；95%CI，0.7260.922；P=0.001，PFDR=0.192）、IgD+ CD24+ %B 细胞（OR，0.626；95%CI，0.4730.828；P=0.001，PFDR=0.192）和 TD DN（CD4-CD8-）AC（OR，0.655；95%CI，0.5100.840；P<0.001，PFDR=0.192）。在 FDR 校正后，只有一种免疫表型被证实与 28 天死亡率呈负相关：CD39 上的 CD39+ CD8br（OR，0.820；95%CI，0.737~0.912；P<0.001，PFDR=0.184）。
本研究首次通过遗传手段发现循环免疫细胞表型与不同程度脓毒症之间存在因果关系的指示性证据。这些发现强调了免疫细胞在脓毒症发病机制中的重要性。
