Identification of novel therapeutic targets for Fuchs' endothelial corneal dystrophy based on gene bioinformatics analysis.

Chao Liu,Juan Li,Qi Zhou,Zi-Qing Gao,Kanhaiya Singh

doi:10.1371/journal.pone.0264018

Abstract

Fuchs’ endothelial corneal dystrophy (FECD) is a disease where progressive visual impairment occurs by the thickening of the Descemet’s membrane and the gradual degeneration and loss of corneal endothelial cells. This study aimed to investigate the key changes in gene expression associated with FECD and explore potential biomarkers and new therapeutic strategies for FECD. To explore the potential therapeutic targets of FECD, we downloaded the gene expression dataset GSE171830 from the Gene Expression Omnibus (GEO) database. A total of 303 differentially expressed genes (DEGs) were identified by the limma package. The enriched Gene Ontology (GO) annotations and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of DEGs mostly included the extracellular matrix organization, collagen-containing extracellular matrix, and the structural constituents of the extracellular matrix. Fifteen hub genes from the most significant module were ascertained by Cytoscape. Both collagen-containing extracellular matrix and extracellular matrix hit to ANXA1, VCAN, GPC3, TNC, IGFBP7, MATN3, and SPARCL1 genes in the GO cellular components. Among these genes, the expression of SPARCL1 was down-regulated in the FECD samples, whereas the expression of GPC3, MATN3, IGFBP7, TNC, VCAN, and ANXA1 was up-regulated in the FECD samples. Gene set enrichment analysis (GSEA) plots showed that among the 20,937 genes, SPARCL1 played an important role in three pathways, cytokine-cytokine receptor interaction, the TGF-beta signaling pathway, and antigen processing and presentation. The top three pathways enriched by the GPC3, MATN3, IGFBP7, TNC, VCAN, and ANXA1 genes were those for cytokine-cytokine receptor interaction, TGF-beta signaling, and RIG-I-like receptor signaling. In conclusion, the DEGs identified here might assist clinicians in understanding the pathogenesis of FECD. Furthermore, these identified biomarkers might serve as potential therapeutic targets for the treatment of FECD.

Highlights

Fuchs’ endothelial corneal dystrophy (FECD) is characterized by a bilateral progressive loss of the corneal endothelial cells
Hierarchical clustering demonstrated that the hub genes effectively differentiated the FECD samples from the unaffected samples (Fig 9B). Both collagen-containing extracellular matrix and extracellular matrix hit to ANXA1, VCAN, Glypican 3 (GPC3), TNC, IGFBP7, MATN3, and SPARCL1 genes in Gene Ontology (GO) cellular components (Fig 9C and Table 2)
FECD is characterized by morphological changes in the hexagonal mosaic, accelerated by the loss of endothelial cells, and a concomitant increase in the anomalous deposits of extracellular matrix on the Descemet membrane

Summary

Introduction

Fuchs’ endothelial corneal dystrophy (FECD) is characterized by a bilateral progressive loss of the corneal endothelial cells. The clinical signs of FECD include the formation of abnormal extracellular matrix material called guttata/guttae on the Descemet’s membrane [1]. The Reykjavik Eye Study revealed FECD in 11% female and 7% male residents older than 55 years in Reykjavik, Iceland [2]; the Kumejima Study found a prevalence of FECD in 4.1% of the individuals who were above 40 years [3]. The female-to-male ratio of the occurrence of FECD was found to be 2.5–3:1 [4]. The treatment for FECD requires surgical treatments (e.g., Descemet stripping endothelial keratoplasty, Descemet membrane endothelial keratoplasty, Descemetorhexis without endothelial keratoplasty, Rho-associated kinase inhibitors, and cell-based approaches), and non-surgical and pharmacological treatments (e.g., topical application of hypertonic 5% sodium chloride eye drops or ointments). The annual preparation of donor tissue is difficult and has unacceptable risks, including loss of donor tissue, financial losses, and cancellation of surgery; these limit the acceptance of corneal transplantation in patients

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Conclusion