title: 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.
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Grassmann
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Peter G A
authors.initials: PG
authors.lastname: Schoenberger
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, Germany; Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Brandl
authors.affiliation: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Schick
authors.affiliation: Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, Regensburg, Germany.
authors.forename: Daniele
authors.initials: D
authors.lastname: Hasler
authors.affiliation: Biochemistry Center Regensburg (BZR), Laboratory for RNA Biology, University of Regensburg, Regensburg, Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: Meister
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Fleckenstein
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Lindner
authors.affiliation: Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Helbig
authors.affiliation: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Fauser
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D055354:Exosomes / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008268:Macular Degeneration / Q000097:blood* / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D012306:Risk; D059467:Transcriptome / Q000235:genetics*
chemical_list: D015415:Biomarkers; D035683:MicroRNAs