Regulatory T cells-related gene in primary sclerosing cholangitis: evidence from Mendelian randomization and transcriptome data.

IF 5 3区 医学 Q1 GENETICS & HEREDITY
Jianlan Hu, Youxing Wu, Danxia Zhang, Xiaoyang Wang, Yaohui Sheng, Hui Liao, Yangpeng Ou, Zhen Chen, Baolian Shu, Ruohu Gui
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引用次数: 0

Abstract

The present study utilized large-scale genome-wide association studies (GWAS) summary data (731 immune cell subtypes and three primary sclerosing cholangitis (PSC) GWAS datasets), meta-analysis, and two PSC transcriptome data to elucidate the pivotal role of Tregs proportion imbalance in the occurrence of PSC. Then, we employed weighted gene co-expression network analysis (WGCNA), differential analysis, and 107 combinations of 12 machine-learning algorithms to construct and validate an artificial intelligence-derived diagnostic model (Tregs classifier) according to the average area under curve (AUC) (0.959) in two cohorts. Quantitative real-time polymerase chain reaction (qRT-PCR) verified that compared to control, Akap10, Basp1, Dennd3, Plxnc1, and Tmco3 were significantly up-regulated in the PSC mice model yet the expression level of Klf13, and Scap was significantly lower. Furthermore, immune cell infiltration and functional enrichment analysis revealed significant associations of the hub Tregs-related gene with M2 macrophage, neutrophils, megakaryocyte-erythroid progenitor (MEP), natural killer T cell (NKT), and enrichment scores of the autophagic cell death, complement and coagulation cascades, metabolic disturbance, Fc gamma R-mediated phagocytosis, mitochondrial dysfunction, potentially mediating PSC onset. XGBoost algorithm and SHapley Additive exPlanations (SHAP) identified AKAP10 and KLF13 as optimal genes, which may be an important target for PSC.

原发性硬化性胆管炎中的调节性 T 细胞相关基因:来自孟德尔随机化和转录组数据的证据。
本研究利用大规模全基因组关联研究(GWAS)汇总数据(731个免疫细胞亚型和3个原发性硬化性胆管炎(PSC)GWAS数据集)、荟萃分析和两个PSC转录组数据,阐明了Tregs比例失调在PSC发生中的关键作用。然后,我们采用加权基因共表达网络分析(WGCNA)、差异分析和12种机器学习算法的107种组合,在两个队列中根据平均曲线下面积(AUC)(0.959)构建并验证了人工智能诊断模型(Tregs分类器)。实时定量聚合酶链反应(qRT-PCR)证实,与对照组相比,PSC小鼠模型中的Akap10、Basp1、Dennd3、Plxnc1和Tmco3明显上调,但Klf13和Scap的表达水平明显降低。此外,免疫细胞浸润和功能富集分析表明,中枢Tregs相关基因与M2巨噬细胞、中性粒细胞、巨核细胞-红细胞祖细胞(MEP)、自然杀伤T细胞(NKT)有明显关联,自噬细胞死亡、补体和凝血级联、代谢紊乱、Fcγ R介导的吞噬作用、线粒体功能障碍的富集得分可能介导PSC发病。XGBoost算法和SHapley Additive exPlanations(SHAP)确定了AKAP10和KLF13为最佳基因,它们可能是PSC的重要靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Genes and immunity
Genes and immunity 医学-免疫学
CiteScore
8.90
自引率
4.00%
发文量
28
审稿时长
6-12 weeks
期刊介绍: Genes & Immunity emphasizes studies investigating how genetic, genomic and functional variations affect immune cells and the immune system, and associated processes in the regulation of health and disease. It further highlights articles on the transcriptional and posttranslational control of gene products involved in signaling pathways regulating immune cells, and protective and destructive immune responses.
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