Current Management of Age-Related Macular Degeneration

Ung, Cindy; Miller, Joan W.; Kim, Ivana K.

doi:10.1007/978-3-030-66014-7_12

Cited by 10 publications

(11 citation statements)

References 121 publications

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“…Of the known previously associated AMD loci [1,10,57,63], none of them showed differential expression between disease states within the macular neural retina tissues.…”

Section: Discussionmentioning

confidence: 92%

“…Among genes demonstrated to be associated with AMD risk in previous studies [10,[56][57] and the GWAS conducted by the International AMD Genetics Consortium (IAMDGC) [1], expression was statistically significantly higher for ABCA4 S1). ARHGAP21, CCT3, HTRA1, and SRPK2 were also found to be up-regulated in the neural retina compared to the RPE/choroid, whereas NPLOC4, RAD51B, ROBO1, SKIV2L, and STON1-GTF2A1L…”

Section: Analysis Of Genes Previously Associated With Amdmentioning

confidence: 83%

“…Of the known previously associated AMD loci [1, 10, 57, 63], none of them showed differential expression between disease states within the macular neural retina tissues. Of the 34 GWAS loci [5], expression differences between disease states were observed for SPEF 2 (between AREDS3 vs. Neo RPE) and VTN (between Neo vs. normal RPE/choroid).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The intermediate form is a clinical biomarker that can increase the risk of either of the two advanced forms; neovascular AMD (also referred to as macular neovascularization, MNV) and geographic atrophy (GA). In either form, this condition involves progressive degradation of the central retina – the macula which can lead to visual disability, where the individual is unable to read, recognize faces, and drive [1]. Thus, the primary geographical region and the tissues that are affected by AMD include the macular retina and macular RPE/choroid, however, the precise mechanisms contributing to disease pathogenesis and why the disease is generally localized to the macular region remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Patterns of gene expression and allele-specific expression vary among macular tissues and clinical stages of Age-related Macular Degeneration

Zhang

Barr

Owen

et al. 2022

Preprint

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Age-related macular degeneration (AMD) is a complex neurodegenerative disease and is the leading cause of blindness in the aging community. AMD progresses, has an early and intermediate stages (both dry and two late stages, neovascular and geographic atrophy (GA). It is the late stages that are responsible for the majority of visual impairment and blindness. Available medicines are directed against the less common wet form and do not cure or reverse vision loss. Therefore, it is imperative to identify preventive and therapeutic targets. As the mechanism for AMD is unclear, one, way is to interrogate well characterized disease affected tissue in the appropriate geographic region that is the macular neural retina and macular retina pigment epithelium (RPE)/choroid. We investigated differential gene expression (DEG) across the clinical stages of AMD in the macula of the primary affected tissue compared to well characterized normal using a standardized published protocol (Owen et al., 2019). Donor eyes (n=27) were Caucasian with an age range of 60-94 and 63% were male, and tissue from the macula RPE/choroid and macula neural retina were taken from the same eye. Donor eyes were recovered within 6 hours post mortem interval time and phenotyped by ophthalmic experts using multi modal imaging (fundus photos and SD-OCT) to ensure maximal preservation of RNA quality and accuracy of diagnosis. Utilizing DESeq2, followed PCA, Benjamini Hockberg Analysis to control for the FDR, Bonferonni for the paired comparisons: a total of 26,650 genes were expressed in the macula RPE/choroid and/or macula retina with 1,204 genes found to be statistically different between neovascular AMD and normal eyes, 40 genes found between intermediate AMD (AREDS3) and normal eyes, and 1,194 genes found between intermediate AMD and neovascular AMD. A comparison of the DEGs from intermediate AMD with normal eyes and neovascular AMD with normal eyes showed an overlap of six genes: MTRNR2L1, CLEC2L, CCM2L, CYP4X1, GLDN, and SMAD7. The top pathways of DEGs identified through Ingenuity Pathway Analysis (IPA) for intermediate AMD with normal eyes were the interferon signaling and Th1 and Th2 activation pathways, while for neovascular AMD with normal eyes it was the phototransduction and SNARE signaling pathways. Allele specific expression (ASE) revealed known coding regions in previously reported GWAS loci demonstrated that significant ASE for C3 rs2230199 and CFH rs1061170 occurred in the macula RPE/choroid for normal, and intermediate AMD while ASE for CFH rs1061147 occurred in the macula RPE/choroid for normal, and intermediate and neovascular AMD. An investigation of previously identified GWAS loci (Fritsche et al., 2016) revealed that 76% of the 34 loci previously identified were significantly differentially expressed between normal macular RPE/choroid and macular neural retina, with 77% of these identified loci expressed higher in the RPE. Pathway analysis was conducted on these DEGs to reveal the involvement of pathways previously implicated in AMD as well as being the first study to assess ASE across the clinical spectrum of AMD. By utilizing a systems biology approach that integrates clinical, experimental, genomic, and phenotypic data to aid in the understanding of the pathogenesis of AMD.

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“…Of the known previously associated AMD loci [1,10,57,63], none of them showed differential expression between disease states within the macular neural retina tissues.…”

Section: Discussionmentioning

confidence: 92%