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Altered gene expression in dry age-related macular degeneration suggests early loss of choroidal endothelial cells.

ABSTRACT: Age-related macular degeneration (AMD) is a major cause of blindness in developed countries. The molecular pathogenesis of early events in AMD is poorly understood. We investigated differential gene expression in samples of human retinal pigment epithelium (RPE) and choroid from early AMD and control maculas with exon-based arrays.Gene expression levels in nine human donor eyes with early AMD and nine control human donor eyes were assessed using Affymetrix Human Exon ST 1.0 arrays. Two controls did not pass quality control and were removed. Differentially expressed genes were annotated using the Database for Annotation, Visualization and Integrated Discovery (DAVID), and gene set enrichment analysis (GSEA) was performed on RPE-specific and endothelium-associated gene sets. The complement factor H (CFH) genotype was also assessed, and differential expression was analyzed regarding high AMD risk (YH/HH) and low AMD risk (YY) genotypes.Seventy-five genes were identified as differentially expressed (raw p value <0.01; ?50% fold change, mean log2 expression level in AMD or control ? median of all average gene expression values); however, no genes were significant (adj. p value <0.01) after correction for multiple hypothesis testing. Of 52 genes with decreased expression in AMD (fold change <0.5; raw p value <0.01), 18 genes were identified by DAVID analysis as associated with vision or neurologic processes. The GSEA of the RPE-associated and endothelium-associated genes revealed a significant decrease in genes typically expressed by endothelial cells in the early AMD group compared to controls, consistent with previous histologic and proteomic studies. Analysis of the CFH genotype indicated decreased expression of ADAMTS9 in eyes with high-risk genotypes (fold change = -2.61; raw p value=0.0008).GSEA results suggest that RPE transcripts are preserved or elevated in early AMD, concomitant with loss of endothelial cell marker expression. These results are consistent with the notion that choroidal endothelial cell dropout or dedifferentiation occurs early in the pathogenesis of AMD.

SUBMITTER: Whitmore SS

PROVIDER: S-EPMC3834599 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Altered gene expression in dry age-related macular degeneration suggests early loss of choroidal endothelial cells.

Whitmore S Scott SS Braun Terry A TA Skeie Jessica M JM Haas Christine M CM Sohn Elliott H EH Stone Edwin M EM Scheetz Todd E TE Mullins Robert F RF

Molecular vision 20131116

<h4>Purpose</h4>Age-related macular degeneration (AMD) is a major cause of blindness in developed countries. The molecular pathogenesis of early events in AMD is poorly understood. We investigated differential gene expression in samples of human retinal pigment epithelium (RPE) and choroid from early AMD and control maculas with exon-based arrays.<h4>Methods</h4>Gene expression levels in nine human donor eyes with early AMD and nine control human donor eyes were assessed using Affymetrix Human E ...[more]

PMID: 24265543

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Project description:Age-related macular degeneration (AMD) is a multifactorial disease with genetic and environmental factors contributing to risk. Histopathologic changes underlying AMD are not fully understood, particularly the relationship between choriocapillaris (CC) dysfunction and phenotypic variability of this disease.To examine histopathologic changes in the CC of eyes with clinically documented AMD.The study was designed in 2011. Tissues were collected post mortem (2012-2016), and histopathological images were obtained from participants enrolled in AMD studies since 1988. Clinical records and images were collected from participants as standard protocol. Eyes without AMD (n?=?4) and eyes with early (n?=?9), intermediate (n?=?5), and advanced stages of AMD (geographic atrophy, n?=?5; neovascular disease, n?=?13) were evaluated. Choroidal vasculature was labeled using Ulex europaeus agglutinin lectin and examined using confocal microscopy.A standardized classification system was applied to determine AMD stage. Ocular records and images were reviewed and histopathologic analyses performed. Viability of the choroidal vasculature was analyzed for each AMD stage.All participants were white. Fourteen were male, and 16 were female. The mean age was 90.5 years among AMD patients and 88.5 years among control participants. Submacular CC dropout without retinal pigment eipthelial (RPE) loss was observed in all cases with early stages of AMD. Higher vascular area loss for each AMD stage was observed compared with control participants: 20.5% in early AMD (95% CI, 11.2%-40.2%; P?<?.001), 12.5% in intermediate AMD (95% CI, 2.9%-21.4%; P?=?.01), 39.0% loss in GA (95% CI, 32.1%-45.4%; P?<?.001), and 38.2% loss in neovascular disease where RPE remained intact (95% CI, 27.7%-47.9%; P?<?.001). Hypercellular, apparent neovascular buds were adjacent to areas of CC loss in 22.2% of eyes with early AMD and 40% of eyes with intermediate AMD.Retinal pigment epithelial atrophy preceded CC loss in geographic atrophy, but CC loss occurred in the absence of RPE atrophy in 2 of 9 eyes with early-stage AMD. Given the cross-sectional nature of this study and the small number of eyes evaluated, definitive conclusions regarding this progression cannot be determined with certainty. We speculate that neovascular buds may be a precursor to neovascular disease. Hypoxic RPE resulting from reduced blood supply might upregulate production of vascular endothelial growth factor, providing the stimulus for neovascular disease.

Dataset Information

Altered gene expression in dry age-related macular degeneration suggests early loss of choroidal endothelial cells.

Publications

Altered gene expression in dry age-related macular degeneration suggests early loss of choroidal endothelial cells.

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