糖基化基因构建的IgA肾病风险预测模型及免疫细胞浸润分析
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1.南京医科大学附属南京医院(南京市第一医院)肾内科,江苏 南京 210006 ;2.南京医科大学附属江宁医院肾内科,江苏 南京 211100

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R692.3

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国家自然科学基金(82000693)


Risk prediction model of IgA nephropathy constructed by glycosylation genes and analysis of immune cell infiltration
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1.Department of Nephrology,the Affiliated Nanjing Hospital of Nanjing Medical University(Nanjing First Hospital), Nanjing 210006 ;2.Department of Nephrology,the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100 ,China

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    摘要:

    目的:筛选IgA肾病(IgA nephropathy,IgAN)糖基化相关基因并分析免疫细胞浸润情况。方法:基因表达综合数据库(Gene Expression Omnibus,GEO)中下载IgAN数据集,筛选糖基化相关差异基因并进行功能分析,通过最小绝对收缩和选择算子(least absolute shrinkage and selection operator,LASSO)、支持向量机递归特征消除(support vector machine recursive feature elimination,SVM-RFE)和随机森林树算法进一步筛选糖基化相关最优特征基因(the optimal feature gene,OFG),并运用免疫组织化学染色、Western blot和Nephroseq v5外部数据库验证OFG差异表达。基于OFG绘制IgAN预测列线图,分析免疫细胞浸润,构建ceRNA 网络。结果:经过筛选首次报道了3个OFG,α-N-乙酰神经氨酸 α-2,8-唾液酸转移酶 1(ST8 alpha-N-acetyl- neuraminide alpha-2,8-sialyltransferase 1,ST8SIA1)、硫酸软骨素合酶 1(chondroitin sulfate synthase 1,CHSY1)和磷脂酰肌醇 N-乙酰氨基葡萄糖转移酶亚基H(phosphatidylinositol N-acetylglucosaminyl transferase subunit H,PIGH),构建的列线图模型提示OFG对IgAN发生有较好的预测价值。免疫细胞浸润分析显示,和对照组相比,IgAN组CD8+ T细胞、CD4+ 幼稚T细胞、活化 CD4+ 记忆T细胞、静息树突状细胞以及静息肥大细胞等浸润显著增加,而幼稚B细胞、浆细胞、静息CD4+ 记忆T细胞、活化肥大细胞和中性粒细胞等浸润明显减少。OFG与活化CD4+ 记忆T细胞、静息CD4+ 记忆T细胞、CD4+ 幼稚T细胞、幼稚B细胞等相关。验证实验结果也表明与微小病变性肾病相比,IgAN 中CHSY1和PIGH 表达水平显著下降,而ST8SIA1表达水平显著增加。值得注意的是,糖尿病肾病和微小病变性肾病中OFG的表达水平差异无统计学意义。此外,成功构建了一个包含117个 lncRNA、67个miRNA和3个OFG的ceRNA网络。结论:ST8SIA1、CHSY1和PIGH可能是诊断和治疗IgAN的潜在靶点,结合浸润细胞免疫和ceRNA网络,为IgAN的研究提供了新的视角。

    Abstract:

    Objective:This study aimed to exploration of glycosylation-related genes and immune infiltration analysis of IgA nephropathy(IgAN). Methods:IgAN datasets were obtained from the GEO database. Then differentially expressed glycosylation-related genes and functional enrichment analyses were identified. Next,optimal feature genes(OFGs)were selected using least absolute shrinkage and selection operator(LASSO),support vector machine recursive feature elimination(SVM-RFE),and random forest algorithms. The expression of OFGs in IgAN were validated by immunohistochemistry staining,Western blot,and the Nephroseq v5 database. OFGs were further used to create a nomogram model,compare immune cell infiltration and construct a ceRNA network. Results:After screening,three OFGs of ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1(ST8SIA1),chondroitin sulfate synthase 1(CHSY1)and phosphatidylinositol N-acetylglucosaminyl transferase subunit H(PIGH)were first reported. The nomogram model showed that OFGs had good predictive value for IgAN occurrence. Compared to normal samples,IgAN showed increased infiltration of CD8+ T cells,naive CD4+ T cell,memory activated CD4+ T cells,resting dendritic cells,and resting mast cells,while naive B cells,plasma cells,memory resting CD4+ T,activated mast cells,and neutrophils were reduced. OFGs were associated with memory activated CD4+ T cells,memory resting CD4+ T cells,naive CD4+ T cell,naive B cells,etc. The validation experiments also revealed that the expression levels of CHSY1 and PIGH were significantly decreased,while the expression level of ST8SIA1 was significantly increased in IgAN compared with minimal change nephropathy. Of note,the expression levels of OFGs in diabetic nephropathy and minimal change nephropathy were not statistically different. A ceRNA network consisting of 117 lncRNAs,67 miRNAs,and 3 OFGs was constructed. Conclusion:ST8SIA1,CHSY1,and PIGH were identified as potential targets for diagnosis and treatment of IgAN. In conjunction with immune cell infiltration and ceRNA network,these results offer a novel perspective for future research on IgAN.

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陈梦星,宗慧敏,张洋.糖基化基因构建的IgA肾病风险预测模型及免疫细胞浸润分析[J].南京医科大学学报(自然科学版),2024,(12):1671-1681

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  • 收稿日期:2024-03-21
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  • 在线发布日期: 2024-12-16
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