Abstract
Keratoconus (KC) is an etiologically heterogeneous corneal ectatic disorder. To systematically display the pathogenesis of keratoconus (KC), this study reviewed all the reported genes involved in KC, and performed an enrichment analysis of genes identified at the genome, transcription, and protein levels respectively. Combined analysis of multi-level results revealed their shared genes, gene ontology (GO), and pathway terms, to explore the possible pathogenesis of KC. After an initial search, 80 candidate genes, 2,933 transcriptional differential genes, and 947 differential proteins were collected. The candidate genes were significantly enriched in extracellular matrix (ECM) related terms, Wnt signaling pathway and cytokine activities. The enriched GO/pathway terms of transcription and protein levels highlight the importance of ECM, cell adhesion, and inflammatory once again. Combined analysis of multi-levels identified 13 genes, 43 GOs, and 12 pathways. The pathogenic relationships among these overlapping factors maybe as follows. The gene mutations/variants caused insufficient protein dosage or abnormal function, together with environmental stimulation, leading to the related functions and pathways changes in the corneal cells. These included response to the glucocorticoid and reactive oxygen species; regulation of various signaling (P13K-AKT, MAPK and NF-kappaB), apoptosis and aging; upregulation of cytokines and collagen-related enzymes; and downregulation of collagen and other ECM-related proteins. These undoubtedly lead to a reduction of extracellular components and induction of cell apoptosis, resulting in the loosening and thinning of corneal tissue structure. This study, in addition to providing information about the genes involved, also provides an integrated insight into the gene-based etiology and pathogenesis of KC.
Highlights
Keratoconus (KC) is a complex multifactor degenerative disorder of the cornea, characterized by corneal ectasia, thinning, and cone-shaped protrusion, leading to reduced vision, irregular astigmatism, and corneal scarring [1,2,3,4]
Based on results from studies that have investigated the genetic etiology, expression, and translation changes in the process of development, it is becoming increasingly clear that KC is a complex disease with a complex etiology or convergence of multiple disease pathways
We reviewed all the studies of KCrelated genes identified at the genome, transcription, and protein levels
Summary
Keratoconus (KC) is a complex multifactor degenerative disorder of the cornea, characterized by corneal ectasia, thinning, and cone-shaped protrusion, leading to reduced vision, irregular astigmatism, and corneal scarring [1,2,3,4]. KC at completion stage often has typical clinical sign, including Munson sign, a V-shape deformation of the lower eyelid in downward position; Fleischer ring, a hemosiderin arc or circle line around the cone base; Vogt’s striae, fine vertical lines produced by Descemet’s membrane compression [3, 4]. KC spontaneously or due to external forces such as eye rubbing, rupture of the posterior elastic layer of the cornea occurs, resulting in acute corneal edema and significant decline in visual acuity [3, 4]. Because of the unclear pathogenesis and limited availability of medical treatments, KC has become a significant clinical problem worldwide and a leading indication for corneal transplantation [5]
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