BACKGROUND Multiple sclerosis (MS) is a complex neurological disease and chronic inflammatory disease. Until now, observational studies have reported positive association between serum interleukin-6 (IL-6) levels and MS risk. In order to develop effective therapies, we should establish the causal link between IL-6 signaling and MS. However, it is currently unknown whether IL-6 signaling is causally associated with the risk of MS. METHODS Here, we selected the increased soluble IL-6R (s-IL-6R) levels as the indirect markers for reduced IL-6 signaling, and performed a Mendelian randomization (MR) study using the rs2228145 variant as the instrumental variable to evaluate and quantify the effect of IL-6 signaling on the risk of MS. To be a comparison, we also evaluated the causal association of IL-6 signaling with the risk of other three neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). RESULTS We found that the increased s-IL-6R levels (per 1 standard deviation) were significantly associated with decreased MS risk (OR = 0.96, 95% CI 0.94-0.98, P = 1.69E-04), but not associated with the risk of AD (OR = 1.01, 95% CI 0.92-1.11, P = 0.835), PD (OR = 0.94, 95% CI 0.84-1.05, P = 0.261), or ALS (OR = 1.00, 95% CI 0.92-1.10, P = 0.9411). CONCLUSION Our findings have the similar directional effects to an existing humanized anti-IL-6R monoclonal antibody Tocilizumab which could bind to the IL-6 binding site of human IL-6R and competitively inhibit IL-6 signaling. Hence, we provided genetic evidence that inhibiting the IL-6 signaling such as tocilizumab treatment might represent a novel therapy for MS.

中文翻译：

---

孟德尔随机化研究评估白细胞介素 6 信号传导对四种神经退行性疾病的影响。


背景技术多发性硬化症(MS)是一种复杂的神经系统疾病和慢性炎症性疾病。到目前为止，观察性研究已报告血清白细胞介素 6 (IL-6) 水平与 MS 风险之间呈正相关。为了开发有效的治疗方法，我们应该建立 IL-6 信号传导与 MS 之间的因果关系。然而，目前尚不清楚 IL-6 信号传导是否与 MS 风险存在因果关系。方法在这里，我们选择增加的可溶性 IL-6R (s-IL-6R) 水平作为 IL-6 信号传导减少的间接标志物，并使用 rs2228145 变体作为工具变量进行孟德尔随机化 (MR) 研究，以评估和评估量化 IL-6 信号传导对 MS 风险的影响。为了进行比较，我们还评估了 IL-6 信号传导与其他三种神经退行性疾病风险的因果关系，包括阿尔茨海默病 (AD)、帕金森病 (PD) 和肌萎缩侧索硬化症 (ALS)。结果 我们发现，s-IL-6R 水平升高（每 1 个标准差）与 MS 风险降低显着相关（OR = 0.96，95% CI 0.94-0.98，P = 1.69E-04），但与 MS 风险降低无关。 AD（OR = 1.01，95% CI 0.92-1.11，P = 0.835）、PD（OR = 0.94，95% CI 0.84-1.05，P = 0.261）或 ALS（OR = 1.00，95% CI 0.92-）的风险1.10，P = 0.9411）。结论我们的研究结果与现有的人源化抗IL-6R单克隆抗体托珠单抗具有相似的方向性作用，托珠单抗可以与人IL-6R的IL-6结合位点结合并竞争性抑制IL-6信号传导。因此，我们提供了遗传证据，表明抑制 IL-6 信号传导（例如托珠单抗治疗）可能是治疗多发性硬化症的一种新疗法。