Cheng Zina, Hao Jiahui, Cai Siying, Feng Pengfei, Chen Weiyi, Ma Xiaolu, Li Xiaona
Institute of Biomedical Engineering, College of Artificial Intelligence, Taiyuan University of Technology, Taiyuan, 030024, China.
Institute of Biomedical Engineering, College of Artificial Intelligence, Taiyuan University of Technology, Taiyuan, 030024, China.
Biochem Biophys Res Commun. 2025 Jan;742:151144. doi: 10.1016/j.bbrc.2024.151144. Epub 2024 Dec 5.
Keratoconus (KC) is an ectatic cornea disease with high prevalence and asymptomatic at early stage, leading to decreased visual acuity and even cornea transplantation. However, the etiology mechanism of keratoconus is still poorly understood. Oxidative stress (OS) and extracellular matrix (ECM) remodeling play critical roles in keratoconus development. Here, based on keratoconus datasets from GEO database, we obtained 454 differentially expressed genes (DEGs), which were further intersected with oxidative stress (OS) and extracellular matrix (ECM) genesets from MSigDB database. A total of 17 OS- and ECM-related DEGs (OEDEGs) were identified. Feature genes were screened by least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE) algorithms, and a six-gene (COL1A1, CYP1B1, MMP3, HMOX1, FOS and GDF15) classification model was developed utilizing Logistic regression (LR), Support Vector Machine (SVM) and Naïve Bayes (NB) algorithms respectively, which was further verified in internal and external cohort. Subsequently, a predictive nomogram was constructed for KC patients. Six signature genes showed a strong correlation with the infiltration level of macrophages M1, neutrophils and eosinophils. Additionally, in vitro qRT-PCR validated the decreased expression of signature genes in either keratoconus clinical samples or human cornea epithelial (HCE) cells grown on soft hydrogel substrate. Finally, we revealed that CYP1B1 and GDF15 regulate cellular proliferation and response to oxidative stress. In conclusion, the developed combined OS and ECM gene signature showed excellent performance for keratoconus prediction, providing beneficial perspectives for keratoconus pathogenesis.
圆锥角膜（KC）是一种扩张性角膜疾病，患病率高且早期无症状，可导致视力下降甚至角膜移植。然而，圆锥角膜的病因机制仍知之甚少。氧化应激（OS）和细胞外基质（ECM）重塑在圆锥角膜的发展中起关键作用。在此，基于来自GEO数据库的圆锥角膜数据集，我们获得了454个差异表达基因（DEG），并将其与来自MSigDB数据库的氧化应激（OS）和细胞外基质（ECM）基因集进一步交叉分析。共鉴定出17个与OS和ECM相关的DEG（OEDEG）。通过最小绝对收缩和选择算子（LASSO）和支持向量机递归特征消除（SVM-RFE）算法筛选特征基因，并分别利用逻辑回归（LR）、支持向量机（SVM）和朴素贝叶斯（NB）算法建立了一个六基因（COL1A1、CYP1B1、MMP3、HMOX1、FOS和GDF15）分类模型，并在内部和外部队列中进一步验证。随后，为圆锥角膜患者构建了一个预测列线图。六个特征基因与巨噬细胞M1、中性粒细胞和嗜酸性粒细胞的浸润水平密切相关。此外，体外qRT-PCR验证了圆锥角膜临床样本或在软水凝胶基质上生长的人角膜上皮（HCE）细胞中特征基因的表达降低。最后，我们发现CYP1B1和GDF15调节细胞增殖和对氧化应激的反应。总之，所建立的结合OS和ECM基因特征在圆锥角膜预测方面表现出色，为圆锥角膜发病机制提供了有益的见解。
