A circulating MicroRNA profile is associated with late- stage neovascular age-related macular degeneration

Felix Grassmann; Peter G.A. Schoenberger; Caroline Brandl; Tina Schick; Daniele Hasler; Gunter Meister; Monika Fleckenstein; Moritz Lindner; Horst Helbig; Sascha Fauser; Bernhard H.F. Weber

doi:10.1371/journal.pone.0107461

A circulating MicroRNA profile is associated with late- stage neovascular age-related macular degeneration

Felix Grassmann, Peter G.A. Schoenberger, Caroline Brandl, Tina Schick, Daniele Hasler, Gunter Meister, Monika Fleckenstein, Moritz Lindner, Horst Helbig, Sascha Fauser, Bernhard H.F. Weber

Medical Sciences

Research output: Contribution to journal › Article › peer-review

63 Citations (Scopus)

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, p_corrected = 5.6∗10^-5, hsa-mir-361-5p, p_corrected = 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 (p_corrected<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.

Original language	English
Article number	e0107461
Journal	PloS ONE
Volume	9
Issue number	9
DOIs	https://doi.org/10.1371/journal.pone.0107461
Publication status	Published - 9 Sept 2014

Bibliographical note

Acknowledgments: We are grateful to the patients and control subjects for their participation in this study. We also want to thank Kerstin Meier for her excellent technical support.

Author Contributions: Conceived and designed the experiments: FG GM BHW. Performed the experiments: FG PGS. Analyzed the data: FG PGS. Contributed reagents/materials/analysis tools: PGS CB TS DH MF ML HH SF. Contributed to the writing of the manuscript: FG BHW. Recruited and phenotyped patients and control individuals: PGS CB TS MF ML HH SF.

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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.",

author = "Felix Grassmann and Schoenberger, {Peter G.A.} and Caroline Brandl and Tina Schick and Daniele Hasler and Gunter Meister and Monika Fleckenstein and Moritz Lindner and Horst Helbig and Sascha Fauser and Weber, {Bernhard H.F.}",

note = "Acknowledgments: We are grateful to the patients and control subjects for their participation in this study. We also want to thank Kerstin Meier for her excellent technical support. Author Contributions: Conceived and designed the experiments: FG GM BHW. Performed the experiments: FG PGS. Analyzed the data: FG PGS. Contributed reagents/materials/analysis tools: PGS CB TS DH MF ML HH SF. Contributed to the writing of the manuscript: FG BHW. Recruited and phenotyped patients and control individuals: PGS CB TS MF ML HH SF.",

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AU - Grassmann, Felix

AU - Schoenberger, Peter G.A.

AU - Brandl, Caroline

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AU - Hasler, Daniele

AU - Meister, Gunter

AU - Fleckenstein, Monika

AU - Lindner, Moritz

AU - Helbig, Horst

AU - Fauser, Sascha

AU - Weber, Bernhard H.F.

N1 - Acknowledgments: We are grateful to the patients and control subjects for their participation in this study. We also want to thank Kerstin Meier for her excellent technical support. Author Contributions: Conceived and designed the experiments: FG GM BHW. Performed the experiments: FG PGS. Analyzed the data: FG PGS. Contributed reagents/materials/analysis tools: PGS CB TS DH MF ML HH SF. Contributed to the writing of the manuscript: FG BHW. Recruited and phenotyped patients and control individuals: PGS CB TS MF ML HH SF.

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N2 - 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.

AB - 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.

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A circulating MicroRNA profile is associated with late- stage neovascular age-related macular degeneration

Abstract

Bibliographical note

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