Understanding Age-Related Macular Degeneration and Epigenetic Regulation

Overview of Age-Related Macular Degeneration

Researchers are investigating the epigenetic regulation of genes in relation to age-related macular degeneration (AMD), a leading cause of blindness among individuals over 50 years old. AMD is a significant contributor to severe vision impairment in older adults, affecting approximately 2 million people globally, with an additional 7.3 million at high risk of vision loss. The condition primarily impacts the macula, a crucial part of the retina responsible for central vision, limiting the ability to see objects directly ahead, such as the hands of a clock while the peripheral numbers remain visible.

Forms of AMD: Dry and Wet

AMD manifests in two primary forms: dry AMD and wet AMD. The dry form, known as geographic atrophy, is more prevalent, affecting around 80% of AMD patients. In dry AMD, the macula gradually thins and degenerates with age. This degeneration is accompanied by the formation of tiny protein deposits called drusen behind the retina.

The clinical stages of AMD are classified by the size and quantity of drusen, with early AMD characterized by small drusen particles comparable to the width of a human hair. The size and number of drusen increase as the disease progresses. Importantly, not all early AMD patients transition to late AMD, and early stages are often asymptomatic, underscoring the necessity for regular eye examinations for adults over 50 years.

In contrast, wet AMD, or neovascular AMD, is characterized by the growth of new blood vessels near the retina, leading to fluid leakage, swelling, and damage to the macula.

Current Interventions for AMD

While several therapies exist for wet AMD aimed at preventing further vision loss, there are currently no treatments for the more common dry form. Although genome-wide studies have identified several genes linked to AMD, the causal factors and mechanisms behind the disease remain poorly understood.

Epigenetic Factors in AMD Development

Recent research indicates that epigenetic regulation may be impaired in retinal pigment epithelial cells of AMD patients. Epigenetic regulation involves the modification of gene expression through chemical changes to DNA or associated proteins, without altering the DNA sequence itself. DNA methylation is a common epigenetic modification, and studies suggest its involvement in AMD progression.

At the University of Liverpool, researchers conducted genome-wide studies on ocular tissue from human donors to explore the role of DNA methylation in AMD. Their findings, published in *Clinical Epigenetics*, involved retinal epithelial cells from 25 AMD donors and 19 control donors, primarily focusing on early to intermediate stages of AMD.

Key Findings of the Study

The study identified three genes with statistically significant differences in methylation status between normal and AMD samples, all exhibiting reduced gene expression in AMD patients. Two of these genes, SkI and GTF2H4, are associated with TGF beta signaling and DNA repair mechanisms, respectively. Notably, the TNXB gene, linked to previous studies on AMD, encodes the Tenascin-X protein, essential for connective tissue and extracellular matrix function. The diminished expression of TNXB in AMD patients suggests potential dysfunction in the extracellular matrix, highlighting a possible intervention point for treatment.

Led by Dr. Louise Porter, this research represents the largest genome-wide methylation study of human retinal epithelial cells to date, allowing for statistically significant results due to the larger sample size compared to previous studies.

Limitations and Future Research Directions

A noted limitation of this study is the variability introduced by the collection timeframe, as donor tissue was obtained 24-36 hours post-mortem. While DNA methylation is considered a stable modification, this time frame may affect results. Nevertheless, the identified genes provide a strong foundation for future therapeutic interventions.

Dr. Porter emphasized the need for addressing the unmet clinical needs in AMD, stating, “This work has identified new genes, providing us with novel targets for investigation in a disease in desperate need of therapies.”

References

Porter LF, Saptarshi N, Fang Y, Rathi S, den Hollander AI, de Jong EK, Clark SJ, Bishop PN, Olsen TW, Liloglou T, Chavali VRM, Paraoan L. Whole-genome methylation profiling of the retinal pigment epithelium of individuals with age-related macular degeneration reveals differential methylation of the SKI, GTF2H4, and TNXB genes. Clin Epigenetics. 2019 Jan 14;11(1):6.
https://www.aoa.org/patients-and-public/eye-and-vision-problems/glossary-of-eye-and-vision-conditions/macular-degeneration
https://eurekalert.org/pub_releases/2019-01/uol-sin012119.php