Liu Yi, Cao Yu
Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, People's Republic of China.
Inflamm Res. 2025 Jan 7;74(1):5. doi: 10.1007/s00011-024-01971-9.
A significant association between immune cells and sepsis has been suggested by observational studies. However, the precise biological mechanisms underlying this association remain unclear. Therefore, we employed a Mendelian randomization (MR) approach to investigate the causal relationship between immune cells and genetic susceptibility to sepsis, and to explore the potential mediating role of blood metabolites.
A large cohort based on publicly available genome-wide association study datasets from European populations was utilized for the MR study. The primary model employed was the inverse variance weighted (IVW) model, assessing heterogeneity and pleiotropy. Moreover, a two-step MR approach was adopted to evaluate the potential mediating role of factors in the causal effects between immune cells and sepsis.
Results from the IVW model indicated that the genetic prediction of CD62L on CD62L+ plasmacytoid dendritic cells (DC) (OR = 0.959, 95% CI [0.922-0.999], P = 0.043) was associated with a reduced risk of sepsis. Conversely, MR analysis with sepsis as the exposure and CD62L on CD62L+ plasmacytoid DC as the outcome did not demonstrate a significant causal relationship. Thus, mediation analysis was conducted, showing that the genetic prediction of CD62L on CD62L+ plasmacytoid DC (OR = 1.064, 95% CI [1.016-1.114], P = 0.008) was associated with increased levels of the metabolite N-palmitoyl-sphingadienine (d18:2/16:0). Similarly, MR analysis with N-palmitoyl-sphingadienine (d18:2/16:0) levels as the exposure and sepsis as the outcome found that the genetic prediction of N-palmitoyl-sphingadienine (d18:2/16:0) levels (OR = 0.843, 95% CI [0.748-0.950], p = 0.005) was associated with a reduced risk of sepsis. Furthermore, the results indicated that N-palmitoyl-sphingadienine (d18:2/16:0) levels mediated the causal impact of CD62L on CD62L+ plasmacytoid DC on sepsis, with a mediation proportion of 25.6% (95% CI [55.7%, - 4.51%]).
These findings support the evidence of a causal relationship between the genetic prediction of CD62L on CD62L+ plasmacytoid DC and a reduced risk of sepsis, with N-palmitoyl-sphingadienine (d18:2/16:0) levels playing a mediating role in this pathway. These insights may inform prevention strategies and interventions targeting sepsis. Future research should explore additional potential biological mechanisms.
观察性研究表明免疫细胞与脓毒症之间存在显著关联。然而，这种关联背后的确切生物学机制仍不清楚。因此，我们采用孟德尔随机化（MR）方法来研究免疫细胞与脓毒症遗传易感性之间的因果关系，并探讨血液代谢物的潜在中介作用。
基于来自欧洲人群的公开全基因组关联研究数据集的大型队列用于MR研究。采用的主要模型是逆方差加权（IVW）模型，评估异质性和多效性。此外，采用两步MR方法评估因素在免疫细胞与脓毒症因果效应中的潜在中介作用。
IVW模型的结果表明，CD62L对CD62L +浆细胞样树突状细胞（DC）的遗传预测（OR = 0.959，95%CI [0.922 - 0.999]，P = 0.043）与脓毒症风险降低相关。相反，以脓毒症为暴露因素、CD62L对CD62L +浆细胞样DC为结局的MR分析未显示出显著的因果关系。因此，进行了中介分析，结果显示CD62L对CD62L +浆细胞样DC的遗传预测（OR = 1.064，95%CI [1.016 - 1.114]，P = 0.008）与代谢物N-棕榈酰-鞘氨醇二烯（d18:2/16:0）水平升高相关。同样，以N-棕榈酰-鞘氨醇二烯（d18:2/16:0）水平为暴露因素、脓毒症为结局的MR分析发现，N-棕榈酰-鞘氨醇二烯（d18:2/16:0）水平的遗传预测（OR = 0.843，95%CI [0.748 - 0.950]，p = 0.005）与脓毒症风险降低相关。此外，结果表明N-棕榈酰-鞘氨醇二烯（d18:2/16:0）水平介导了CD62L对CD62L +浆细胞样DC对脓毒症的因果影响，中介比例为25.6%（95%CI [55.7%， - 4.51%]）。
这些发现支持了CD62L对CD62L +浆细胞样DC的遗传预测与脓毒症风险降低之间存在因果关系的证据，其中N-棕榈酰-鞘氨醇二烯（d18:2/16:0）水平在该途径中起中介作用。这些见解可能为脓毒症的预防策略和干预措施提供参考。未来的研究应探索其他潜在的生物学机制。
