MiR-146a, an effector mediator, targets Notch-1 and regulates the innate and adaptive immune systems response. Recently, we reported that Notch-1 signaling plays a key role in macrophage polarization and response during infection. We employed Mycobacterium avium paratuberculosis (MAP) infection in Crohn’s disease (CD) as a model to demonstrate the role of Notch-1/IL-6 signaling on MCL-1 based apoptosis and intracellular MAP infection and persistence. This study was designed to investigate the impact of polymorphisms in miR146a on the immune response and infection in our MAP-CD model. We determined the incidence of miR-146a rs2910164 G > C in 42 blood samples from clinical CD patients and controls. We also measured the effect of rs2910164 on expression of Notch-1 and IL-6, and plasma IL-6 protein levels in our study group. Finally, we analyzed the blood samples for MAP DNA and studied any correlation with miR-146a polymorphism. Samples were analyzed for statistical significance using unpaired tow-tailed t-test, unpaired two-tailed z-score and odds ratio. P < 0.05 considered significant. MiR-146a rs2910164 GC was detected at a higher incidence in CD (52.6%) compared to healthy controls (21.7%) rs2910164 GC Heterozygous polymorphism upregulated Notch-1 and IL-6, by 0.9 and 1.7-fold, respectively. As expected, MAP infection was detected more in CD samples (63%) compared to healthy controls (9%). Surprisingly, MAP infection was detected at a higher rate in samples with rs2910164 GC (67%) compared to samples with normal genotype (33%). The data clearly associates miR-146a rs2910164 GC with an overactive immune response and increases the risk to acquire infection. The study is even more relevant now in our efforts to understand susceptibility to SARS-CoV-2 infection and the development of COVID-19. This study suggests that genetic variations among COVID-19 patients may predict who is at a higher risk of acquiring infection, developing exacerbating symptoms, and possibly death. A high scale study with more clinical samples from different disease groups is planned.

中文翻译：

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MiR-146a rs2910164 G > C 多态性在感染过程中调节 Notch-1/IL-6 信号传导：克罗恩病的可能危险因素


MiR-146a 是一种效应介质，以 Notch-1 为靶标，调节先天性和适应性免疫系统反应。最近，我们报道了 Notch-1 信号在感染过程中巨噬细胞极化和反应中发挥关键作用。我们采用克罗恩病 (CD) 中的副结核分枝杆菌 (MAP) 感染作为模型，以证明 Notch-1/IL-6 信号传导对基于 MCL-1 的细胞凋亡以及细胞内 MAP 感染和持续性的作用。本研究旨在研究 miR146a 多态性对 MAP-CD 模型中免疫反应和感染的影响。我们确定了来自临床 CD 患者和对照的 42 份血液样本中 miR-146a rs2910164 G > C 的发生率。我们还测量了 rs2910164 对研究组中 Notch-1 和 IL-6 表达以及血浆 IL-6 蛋白水平的影响。最后，我们分析了血液样本中的 MAP DNA，并研究了与 miR-146a 多态性的相关性。使用不成对的双尾 t 检验、不成对的双尾 z 分数和比值比来分析样本的统计显着性。 P < 0.05 被视为显着。与健康对照 (21.7%) rs2910164 GC 杂合多态性相比，CD 中检测到的 MiR-146a rs2910164 GC 发生率更高 (52.6%)。杂合多态性使 Notch-1 和 IL-6 分别上调 0.9 倍和 1.7 倍。正如预期的那样，与健康对照 (9%) 相比，CD 样本 (63%) 中检测到更多 MAP 感染。令人惊讶的是，与具有正常基因型的样本（33%）相比，具有 rs2910164 GC 的样本中 MAP 感染的检测率更高（67%）。数据清楚地将 miR-146a rs2910164 GC 与过度活跃的免疫反应联系起来，并增加了感染的风险。 现在，这项研究对于我们了解 SARS-CoV-2 感染的易感性和 COVID-19 的发展的努力更加重要。这项研究表明，COVID-19 患者的遗传变异可以预测哪些人感染、出现症状加重甚至死亡的风险更高。计划对来自不同疾病组的更多临床样本进行大规模研究。