Transcriptome Analysis on Monocytes from Patients with Neovascular Age-Related Macular Degeneration

Area of Science:

• Ophthalmology
• Immunology
• Genetics

Background:

• Mononuclear phagocytes (MPs), including monocytes and macrophages, are implicated in age-related macular degeneration (AMD) pathogenesis.
• Previous studies indicated altered gene expression and chemokine receptor signatures in peripheral blood mononuclear cells and monocytes of AMD patients.

Purpose of the Study:

• To comprehensively understand the involvement of MPs in the peripheral circulation of AMD patients.
• To perform global gene expression analysis in monocytes from treatment-naïve neovascular AMD (nvAMD) patients and age-matched controls.

Main Methods:

• Monocytes were isolated from nvAMD patients (n=14) and controls (n=15) for microarray and bioinformatics analysis.
• Quantitative real-time PCR was used for validation in larger cohorts of nvAMD (n=25), atrophic AMD (n=21), and controls (n=28).
• Functional annotation (DAVID, TANGO), gene set enrichment analysis (GSEA), ISMARA, MEME, and SAGE data-mining were employed.

Main Results:

• Identified 2,165 differentially-expressed genes (P<0.05), with 79 genes showing a log2 fold change ≥1.5 between nvAMD and controls.
• Functional annotation revealed significant immune response alterations in AMD monocytes (FDR-P <0.05), validated by randomized data comparison (P<0.0001).
• Gene expression signatures were enriched in non-classical versus classical monocyte subsets and found to be enriched in the retina.

Conclusions:

• Global gene expression analysis of monocytes in AMD reveals a distinct, altered immune-related signature.
• These findings further implicate systemic mononuclear phagocyte activation as a significant factor in the pathogenesis of age-related macular degeneration.