Epigenetic Signatures of DNMTs and Retinal Structural Changes in Age-Related Macular Degeneration

Abstract

Introduction: Age-related macular degeneration (AMD) is one of the leading causes of irreversible visual loss in the elderly. Identifying effective biomarkers is essential due to the limited therapeutic options in the early stages. Epigenetic alterations, such as DNA methyltransferase (DNMT) expression, have been implicated in AMD pathogenesis; however, their association with structural changes in the choroid and GCL+IPL remains poorly understood.

Objective: To describe and correlate the genetic expression of epigenetic regulators (DNMT1, DNMT3A, DNMT3B) with choroidal and GCL+IPL thickness, assessed by SD-OCT, across different stages of AMD.

Methods: Cross-sectional study including 34 patients with early AMD (n=4), intermediate (n=13), atrophic (n=5), and neovascular (n=12). Gene expression of DNMTs was quantified in peripheral blood. Functional (BCVA) and structural (RNFL, GCL, GCL+IPL, CRT, choroid) parameters were assessed using SD-OCT.

Results: Atrophic AMD showed significant downregulation of DNMT1, DNMT3A, and DNMT3B compared with early, intermediate, and neovascular stages (p<0.05). In contrast, neovascular AMD exhibited a trend towards DNMT upregulation. In intermediate AMD, higher DNMT1 levels correlated positively with GCL and central GCL+IPL thickness (p<0.05), whereas DNMT3A and DNMT3B correlated negatively with central RNFL and BCVA (p<0.05). In neovascular AMD, DNMT1 expression correlated negatively with GCL and GCL+IPL thickness.

Conclusion: Advanced AMD phenotypes exhibit distinct epigenetic patterns, reflecting differentiated pathogenic mechanisms. Integrating epigenetic and imaging biomarkers may improve disease stratification. Larger longitudinal studies are warranted to validate these findings and to explore the potential of DNMTs as clinical biomarkers.