Polymorphisms and gene expression of Notch4 in pulmonary tuberculosis.
Polymorphisms and gene expression of Notch4 in pulmonary tuberculosis.
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肺结核患者Notch4基因多态性及基因表达的研究
DOI：
10.3389/fimmu.2023.1081483
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发表时间：
2023
影响因子：
7.3
通讯作者：
Zheng, Ruijuan
中科院分区：
文献类型：
--
作者：
Fang, Weijun;Liu, Hua;Qin, Lianhua;Wang, Jie;Huang, Xiaochen;Pan, Sha;Zheng, Ruijuan
结核病（TB）是严重危害人类健康的公共卫生问题，但其发病机制至今仍不清楚。为了发现与结核病易感性相关的新的候选基因，我们进行了一项基于人群的病例对照研究，对来自中国的435名肺结核患者和375名健康献血员的21个基因的41个SNP进行了基因分型。Notch 4基因rs 206018和rs422951多态性与肺结核易感性相关。该关联在另一个独立队列中得到验证，该队列包括790名结核病患者和1，190名健康对照。此外，我们发现rs 206018 C等位基因与肺结核患者PBMC中Notch 4的高水平相关。此外，Notch 4在肺结核患者中的表达增加，并且Notch 4的高表达与肺结核的复发相关。最后，我们探讨了结核分枝杆菌（Mtb）感染时Notch 4表达调控的起源和信号通路。我们确定Mtb诱导Notch 4及其配体Jagged 1在巨噬细胞中的表达，Notch 4通过TLR 2/P38信号通路，Jagged 1通过TLR 2/ERK信号通路。我们的工作进一步证实了Notch 4增加了人类结核病的风险，并参与了结核病的发生和发展，这可能成为结核病宿主靶向治疗的新靶点。
Tuberculosis (TB) is a serious public health problem to human health, but the pathogenesis of TB remains elusive. To identify novel candidate genes associated with TB susceptibility, we performed a population-based case control study to genotype 41SNPs spanning 21 genes in 435 pulmonary TB patients and 375 health donors from China. We found Notch4 gene rs206018 and rs422951 polymorphisms were associated with susceptibility to pulmonary tuberculosis. The association was validated in another independent cohort including 790 TB patients and 1,190 healthy controls. Moreover, we identified that the rs206018 C allele was associated with higher level of Notch4 in PBMCs from pulmonary TB patients. Furthermore, Notch4 expression increased in TB patients and higher Notch4 expression correlated with the severer pulmonary TB. Finally, we explored the origin and signaling pathways involved in the regulation of Notch4 expression in response to Mycobacterium tuberculosis (Mtb) infection. We determine that Mtb induced Notch4 and its ligand Jagged1expression in macrophages, and Notch4 through TLR2/P38 signaling pathway and Jagged1 through TLR2/ERK signaling pathway. Our work further strengthens that Notch4 underlay an increased risk of TB in humans and is involved in the occurrence and development of TB, which could serve as a novel target for the host-targeted therapy of TB.
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影响因子：
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作者：
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