Kelly Kristen M, Smith Jennifer A, Mezuk Briana
Department of Epidemiology, School of Public Health, University of Michigan, United States; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, The Netherlands.
Department of Epidemiology, School of Public Health, University of Michigan, United States; Institute for Social Research, University of Michigan, United States.
Brain Behav Immun. 2021 Jul;95:106-114. doi: 10.1016/j.bbi.2021.02.019. Epub 2021 Feb 23.
A large body of research has reported associations between depression and elevated interleukin-6 (IL-6), a cytokine with several roles including pro-inflammatory signaling. The nature and directionality of this relationship are not yet clear. In this study we use Mendelian Randomization to examine the possibility of a causal relationship between IL-6 and depressive symptoms, and to explore multiple signaling pathways that could serve as mechanisms for this relationship.
This study uses a two-sample Mendelian Randomization design. Data come from the UK Biobank (n = 89,119) and published summary statistics from six existing GWAS analyses. The primary analysis focuses on the soluble interleukin-6 receptor (sIL-6R), which is involved in multiple signaling pathways. Exploratory analyses use C-reactive protein (CRP) and soluble glycoprotein 130 (sgp130) to further examine potential underlying mechanisms.
Results are consistent with a causal effect of sIL-6R on depression (PCA-IVW Odds Ratio: 1.023 (95% Confidence Interval: 1.006-1.039), p = 0.006). Exploratory analyses demonstrate that the relationship could be consistent with either decreased classical signaling or increased trans signaling as the underlying mechanism.
These results strengthen the body evidence implicating IL-6 signaling in depression. When compared with existing observational and animal findings, the direction of these results suggests involvement of IL-6 trans signaling. Further study is needed to examine whether IL6R genetic variants might influence IL-6 trans signaling in the brain, as well as to explore other potential pathways linking depression and inflammation.
大量研究报告了抑郁症与白细胞介素-6（IL-6）升高之间的关联，IL-6是一种具有多种作用（包括促炎信号传导）的细胞因子。这种关系的性质和方向性尚不清楚。在本研究中，我们使用孟德尔随机化方法来检验IL-6与抑郁症状之间因果关系的可能性，并探索可能作为这种关系机制的多种信号通路。
本研究采用两样本孟德尔随机化设计。数据来自英国生物银行（n = 89,119）以及六项现有全基因组关联研究（GWAS）分析已发表的汇总统计数据。主要分析集中在参与多种信号通路的可溶性白细胞介素-6受体（sIL-6R）上。探索性分析使用C反应蛋白（CRP）和可溶性糖蛋白130（sgp130）来进一步研究潜在的潜在机制。
结果与sIL-6R对抑郁症的因果效应一致（主成分分析逆方差加权比值比：1.023（95%置信区间：1.006 - 1.039），p = 0.006）。探索性分析表明，这种关系可能与经典信号传导减少或反式信号传导增加作为潜在机制一致。
这些结果加强了表明IL-6信号传导与抑郁症有关的证据。与现有的观察性和动物研究结果相比，这些结果的方向表明IL-6反式信号传导参与其中。需要进一步研究来检查IL6R基因变异是否可能影响大脑中的IL-6反式信号传导，以及探索将抑郁症和炎症联系起来的其他潜在途径。
