The Genetic and Epigenetic Architecture of Keratoconus: Emerging Pathways and Clinical Implications

Genetic studies consistently implicate loci such as <i>ZNF469</i>, <i>COL5A1</i>, <i>LOX</i>, <i>HGF</i>, <i>FOXO1</i>, and <i>WNT10A</i>, alongside rare variants in Mendelian syndromes (e.g., brittle cornea syndrome, Ehlers-Danlos spectrum). Epigenetic research demonstrates altered DNA methylation, dysregulated microRNAs (e.g., MIR184, miR-143, miR-182), and aberrant lncRNA networks influencing extracellular matrix remodeling, collagen cross-linking, oxidative stress, and inflammatory signaling. Gene-environment interactions, particularly with eye rubbing and atopy, further shape disease expression. Translational progress includes polygenic risk scores, tear-based biomarkers, and early preclinical studies using RNA-based approaches (including siRNA and antisense oligonucleotides targeting matrix-degrading and profibrotic pathways) and proof-of-concept gene-editing strategies demonstrated in corneal cell and ex vivo models. <b>Conclusions</b>: Keratoconus arises from the convergence of inherited genomic risk, epigenetic dysregulation, and environmental stressors. Integrating multi-omic insights into clinical practice holds promise for earlier detection, precision risk stratification, and development of targeted therapies that move beyond biomechanical stabilization to disease modification.