Differential DNA methylation identified in the blood and retina of AMD patients

Abstract

Age-related macular degeneration (AMD) is a major cause of blindness in the western world. While genetic studies have linked both common and rare variants in genes involved in regulation of the complement system to increased risk of development of AMD, environmental factors, such as smoking and nutrition, can also significantly affect the risk of developing the disease and the rate of disease progression. Since epigenetics has been implicated in mediating, in part, the disease risk associated with some environmental factors, we investigated a possible epigenetic contribution to AMD. We performed genome-wide DNA methylation profiling of blood from AMD patients and controls. No differential methylation site reached genome-wide significance; however, when epigenetic changes in and around known GWASdefined AMD risk loci were explored, we found small but significant DNA methylation differences in the blood of neovascular AMD patients near age-related maculopathy susceptibility 2 (ARMS2), a top-ranked GWAS locus preferentially associated with neovascular AMD. The methylation level of one of the CpG sites significantly correlated with the genotype of the risk SNP rs10490924, suggesting a possible epigenetic mechanism of risk. Integrating genome-wide DNA methylation analysis of retina samples with and without AMD together with blood samples, we further identified a consistent, replicable change in DNA methylation in the promoter region of protease serine 50 (PRSS50). These methylation changes may identify sites in novel genes that are susceptible to non-genetic factors known to contribute to AMD development and progression.

Heritable DNA Methylation in CD4+ Cells among Complex Families Displays Genetic and Non-Genetic Effects

“…Depletion of MHC locus-related genes from the full GIC list (depleted of meQTL and meQTL-related genes) also did not remove GO term enrichment for T cell activation. One GIC region was the PRSS50 promoter, which was shown to be associated with age-related macular degeneration in both blood and retina samples [39]. Another site was around the LTB4R gene that encodes the leukotriene B4 receptor, and was shown to be the most epigenetically divergent human gene compared to other primates [40].…”

Unfolded protein response is activated in aged retinas

“…In addition, the CHOP could promote cell death by the induction of miR-708, which is known to regulate the expression of many genes, including the rhodopsin. Perhaps, the miR-708 is elevated in aged retinas, and might be responsible for the reduction in the RHO found in aged retinas in addition to age-related photoreceptor cell loss [31] and potential epigenetic changes [28, 40]. …”

Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions

“…Among these are oxidative and nitrosative stress associated with smoking, light exposure/phototoxicity, and impaired phagocytosis . Epigenetic modifications have also been implicated in AMD pathophysiology …”

“…[4][5][6][7][8][9][10][11] Epigenetic modifications have also been implicated in AMD pathophysiology. [12][13][14][15][16] Aging causes morphological changes in Bruch's membrane, including calcification and fragmentation due to the sub-RPE deposits of drusen that are associated with macular degeneration. 3,17 Nonenzymatic nitrosylation due to smoking affects the properties of Bruch's membrane by cross-linking collagens in all layers of the structure.…”