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

Verity F Oliver,Andrew E Jaffe,Jin Song,Guohua Wang,Pingwu Zhang,Kari E Branham,Anand Swaroop,Charles G Eberhart,Donald J Zack,Jiang Qian,Shannath L Merbs

doi:10.1080/15592294.2015.1060388

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 GWAS-defined 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.

Highlights

Age-related macular degeneration (AMD), the leading cause of irreversible loss of central vision in developed countries, is a multifactorial disease that occurs in the elderly
We did not identify any genome-wide significant differentially methylated probes in the blood study, when we focused on epigenetic changes in and around genetic loci already reported to be associated with AMD, we identified subtle but locally significant DNA methylation (DNAm) differences in the blood of NV patients near age-related maculopathy susceptibility 2 (ARMS2), a top-ranked Genome wide association studies (GWAS) risk locus,[5] which we replicated in an independent blood cohort from Baltimore
Much progress has been made identifying risk alleles and biological pathways that appear to be involved in the development of AMD,[5] yet a large proportion of disease is not explained by these genetic risk factors

Summary

Introduction

Age-related macular degeneration (AMD), the leading cause of irreversible loss of central vision in developed countries, is a multifactorial disease that occurs in the elderly. Early/intermediate AMD [Age-Related Eye Disease Study (AREDS) grades 2 and 3] is the most common and least severe form, characterized by pigmentary abnormalities in the macula and the accumulation of yellowish deposits called drusen beneath the macula.[2] Late. In NV, new capillaries from the choriocapillaris, the vascular bed below the retinal pigment epithelium (RPE), invade the RPE and retina, and leakage and bleeding from these new vessels can cause loss of vision. NV can be partially treated with inhibitors of vascular endothelial growth factor, this requires frequent intraocular injections.[3] In GA, retinal pigment epithelium and photoreceptor cells slowly degenerate and die, and no treatment option exists.[4]

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Conclusion