Yu Yuhui, Liu Qiang, Zhou Chen, Jiang Juan, Li Yanchun
Department of Ophthalmology, Second Affiliated Hospital, Shandong First Medical University, Shandong Academy of Medical Sciences, Taian, 271000, China.
School of International Education, Shandong First Medical University, Shandong Academy of Medical Sciences, Taian, 271000, China.
Mamm Genome. 2025 May 16. doi: 10.1007/s00335-025-10135-x.
This study aimed to identify key genes and immune features associated with keratoconus (KC), a progressive eye disorder, by integrating genomic and transcriptomic data using Mendelian randomization (MR) methods. We employed summary data-based Mendelian randomization (SMR) and inverse-variance weighted Mendelian randomization (IVW-MR) to analyze genetic variations from public databases. The study included expression quantitative trait loci (eQTL) data for 16,987 genes and GWAS summary statistics for 19,942 gene traits and 731 immune traits. We also utilized gene expression data from keratoconus patients and controls to validate findings and explore causal relationships. We identified 715 genes associated with KC, including 371 risk genes and 344 protective genes. Pathway over-representation analyses indicated that risk genes are involved in the regulation of the cytoskeleton, while protective genes are related to metabolic processes. Differential expression analysis showed significant overexpression of risk genes in KC samples. Additionally, we found 21 immune phenotypes with causal effects on KC, highlighting the role of immune cells in the disease's pathogenesis. The study revealed multiple risk and protective genes linked to KC, providing new insights into its pathophysiological mechanisms. The findings underscore the importance of cytoskeletal remodeling and immune regulation in KC and suggest potential targets for future diagnostic and therapeutic strategies. Further research is needed to validate these genes and immune traits' functions and their clinical application potential.
本研究旨在通过使用孟德尔随机化（MR）方法整合基因组和转录组数据，确定与圆锥角膜（KC，一种进行性眼部疾病）相关的关键基因和免疫特征。我们采用基于汇总数据的孟德尔随机化（SMR）和逆方差加权孟德尔随机化（IVW-MR）来分析来自公共数据库的基因变异。该研究纳入了16,987个基因的表达定量性状位点（eQTL）数据以及19,942个基因性状和731个免疫性状的全基因组关联研究（GWAS）汇总统计数据。我们还利用圆锥角膜患者和对照组的基因表达数据来验证研究结果并探索因果关系。我们确定了715个与KC相关的基因，包括371个风险基因和344个保护基因。通路过度表达分析表明，风险基因参与细胞骨架的调节，而保护基因与代谢过程相关。差异表达分析显示，风险基因在KC样本中显著过度表达。此外，我们发现21种免疫表型对KC有因果影响，突出了免疫细胞在该疾病发病机制中的作用。该研究揭示了与KC相关的多个风险和保护基因，为其病理生理机制提供了新的见解。这些发现强调了细胞骨架重塑和免疫调节在KC中的重要性，并为未来的诊断和治疗策略提出了潜在靶点。需要进一步研究来验证这些基因和免疫特征的功能及其临床应用潜力。
