Epigenetic Regulations in Age-related Macular Degeneration

Abstract

Purpose: : Age related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. Recent studies have demonstrated strong genetic associations between AMD and SNPs within genes including CFH, CFB, C2, C3, ARMS2, HTRA1, and APOE. However, we found monozygotic twins displayed discordant AMD pathology (one with disease, the other without disease), although they presumably share identical genetic background. In this study, we therefore explored the epigenetic mechanisms that control the pathogenesis of AMD.

Methods: : We recently identified two pairs of twins with phenotypic discordance of AMD. We obtained genomic DNA from their PBMCs and subjected them to DNA methylation-Chip analysis using NimbleGen Human 2.1M Deluxe Promoter Array (Roche-NimbleGen, Madison WI), which includes probes tiling through 7250 bp upstream and 3250 bp downstream of transcription start sites of all genes and microRNAs.

Results: : Analysis of microarray data identified ~1000 candidate genes within which promoters differential DNA methylation patterns were found. Among those 1000 genes, 256 genes were associated with hypomethylated CpG sites on their promoters only in twins with AMD, while 744 genes were associated with hypermethylated CpG sites on their promoters only in twins with AMD. One example locus of those differentially methylated loci is CCL22 locus. Hypermethylated CpG sites were only found in control but not AMD twins, indicating a potential role of CCL22 in AMD.

Conclusions: : Our study identified candidate DNA methylation sites on selected gene promoters, which can potentially serve as markers to distinguish AMD from non-disease samples. In addition, our results strongly suggested an epigenetic control of AMD pathogenesis.

Keywords: age-related macular degeneration • cytokines/chemokines • immunomodulation/immunoregulation