A Circulating MicroRNA Profile Is Associated with Late-Stage Neovascular Age-Related Macular Degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of severe vision impairment in Western populations over 55 years. A growing number of gene variants have been identified which are strongly associated with an altered risk to develop AMD. Nevertheless, gene-based biomarkers which could be dysregulated at defined stages of AMD may point toward key processes in disease mechanism and thus may support efforts to design novel treatment regimens for this blinding disorder. Circulating microRNAs (cmiRNAs) which are carried by nanosized exosomes or microvesicles in blood plasma or serum, have been recognized as valuable indicators for various age-related diseases. We therefore aimed to elucidate the role of cmiRNAs in AMD by genome-wide miRNA expression profiling and replication analyses in 147 controls and 129 neovascular AMD patients. We identified three microRNAs differentially secreted in neovascular (NV) AMD (hsa-mir-301-3p, pcorrected = 5.6*10−5, hsa-mir-361-5p, pcorrected = 8.0*10−4 and hsa-mir-424-5p, pcorrected = 9.6*10−3). A combined profile of the three miRNAs revealed an area under the curve (AUC) value of 0.727 and was highly associated with NV AMD (p = 1.2*10−8). To evaluate subtype-specificity, an additional 59 AMD cases with pure unilateral or bilateral geographic atrophy (GA) were analyzed for microRNAs hsa-mir-301-3p, hsa-mir-361-5p, and hsa-mir-424-5p. While we found no significant differences between GA AMD and controls neither individually nor for a combined microRNAs profile, hsa-mir-424-5p levels remained significantly higher in GA AMD when compared to NV (pcorrected<0.005). Pathway enrichment analysis on genes predicted to be regulated by microRNAs hsa-mir-301-3p, hsa-mir-361-5p, and hsa-mir-424-5p, suggests canonical TGFβ, mTOR and related pathways to be involved in NV AMD. In addition, knockdown of hsa-mir-361-5p resulted in increased neovascularization in an in vitro angiogenesis assay.

Circulating miRNAs as Potential Biomarkers of Age-Related Macular Degeneration

“…No significant differences were found between GA AMD and controls. These results indicate that the three miRNAs mentioned above may participate in wet AMD pathogenesis, whereas the exact mechanism remains unknown [17]. Ertekin et al analyzed some differently expressed miRNAs in AMD patients [18].…”

An Eye on Age-Related Macular Degeneration: The Role of MicroRNAs in Disease Pathology

“…Although some miRNAs were found in several studies, they do not necessarily agree on the orientation of the effect. For example, miR-424-5p was found to be dysregulated in two studies, one study found the miR-424-5p to be downregulated in patients with late-stage NV AMD ( p corrected = 9.6 × 10 −3 ) [51] and no significant differences between the expression of miR-424-5p in GA AMD patients and controls. The authors noted, however, that the miR-424-5p expression was significantly higher in GA AMD patients compared to NV AMD patients ( p corrected <0.005).…”

“…All words with an occurrence greater than 4 are plotted and their relative abundance is indicated by the size of the respective word. Figure was plotted with Tagxedo (http://www.tagxedo.com/app.html) using words from the abstracts of 21 publications related to miRNAs in AMD [51, 52, 56, 57, 71, 73–75, 77, 82, 89, 90, 99, 103–110] …”

MicroRNA Expression Patterns Involved in Amyloid Beta–Induced Retinal Degeneration

“…20 MicroRNAs are single-stranded short (21)(22)(23) nucleotides long) noncoding RNAs that are involved in posttranscriptional modulation. Each miRNA can specifically inhibit its target mRNA's function by binding to the complementary site.…”

“…20 Furthermore, the miRNA metabolism in neurons, such as photoreceptors, is higher than in other cell types. 22 Prior studies showed differential levels of secreted miRNAs (miR-301-3p, -361-5p, and -424-5p) in wet AMD patients, 23 and neurovascularization could be repressed by certain miRNA targets, including microRNA-24. 24 Kaneko et al 25 found that miRNA processing of the enzyme DICER1 was reduced in the RPE of humans with geographic atrophy (GA) and that conditional DICER1 ablation induced RPE degeneration.…”