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J. P. SanGiovanni, C. M. Aderman, C. Rojas, T. E. Clemons, E. Chew, R. Uauy, D. R. Hoffman, L. E. Smith; Integrated Systems Approach to Study the Role of Omega-3 Long-Chain Polyunsaturated Fatty Acids in Health and Disease of the Retina. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2774.
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To apply an integrated analytic framework to examine the role of omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) in health and disease of the retina.
To determine the impact of omega-3 LCPUFA exposure on gene expression we compared microarray-based profiles of primary retinal tissue from: 1) mice fed an omega-3 LCPUFA rich diet (2% of total fatty acids) to omega-3 LCPUFA-free controls; and 2) ex vivo human explants with defined omega-3 LCPUFA exposure (27 µM for 14 days) to LCPUFA-free controls. We then filtered variants of the genes dysregulated by 2-or-more fold from a 100K SNP array used in a 12-year prospective follow-up of 503 people from the Age-Related Eye Disease Study (AREDS). We tested these variants in age- and sex-adjusted models for association with advanced age-related macular degeneration (AMD, neovascular AMD or geographic atrophy), relative to a cohort of elderly AMD-free people. We then used the AREDS GWAS data to examine functional clustering of omega-3 LCPUFA-regulated genes containing AMD-associated variants within ~500 gene sets, networks and pathways.
846 genes showed omega-3 LCPUFA-altered expression in our model systems (110 from mouse homologues and 756 in human explant). 6044 SNPs on the 100K array existed within these genes. Of these variants, 68 showed associations with advanced AMD at p-values ≤ 0.005; 3 SNPs from risk loci on chromosome 10q26 attained p-values < 0.003. SNPs of the LCPUFA- and AMD-associated genes were most likely to exist in networks functioning in cellular growth, proliferation, cell death, hematological system development, and humoral immune response. The most enriched canonical pathways were those driving leukocyte extravasation (p ≤ 0.002) and macrophage/chemokine signaling (Fc-gamma, p ≤ 0.002; CCR5, p ≤ 0.003; CXCR4/CD184, p ≤ 0.008).
Omega-3 LCPUFA exposure in model retinal systems alters expression of genes associated with advanced AMD. An integrated systems approach to the study of this topic suggests these nutrients may impact AMD risk by their action on immune and inflammatory processes.
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