Dataset Information

Targeting of miR-33 ameliorates phenotypes linked to age-related macular degeneration.

ABSTRACT: Abnormal cholesterol/lipid homeostasis is linked to neurodegenerative conditions such as age-related macular degeneration (AMD), which is a leading cause of blindness in the elderly. The most prevalent form, termed "dry" AMD, is characterized by pathological cholesterol accumulation beneath the retinal pigment epithelial (RPE) cell layer and inflammation-linked degeneration in the retina. We show here that the cholesterol-regulating microRNA miR-33 was elevated in the RPE of aging mice. Expression of the miR-33 target ATP-binding cassette transporter (ABCA1), a cholesterol efflux pump genetically linked to AMD, declined reciprocally in the RPE with age. In accord, miR-33 modulated ABCA1 expression and cholesterol efflux in human RPE cells. Subcutaneous delivery of miR-33 antisense oligonucleotides (ASO) to aging mice and non-human primates fed a Western-type high fat/cholesterol diet resulted in increased ABCA1 expression, decreased cholesterol accumulation, and reduced immune cell infiltration in the RPE cell layer, accompanied by decreased pathological changes to RPE morphology. These findings suggest that miR-33 targeting may decrease cholesterol deposition and ameliorate AMD initiation and progression.

SUBMITTER: Gnanaguru G

PROVIDER: S-EPMC8261163 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeting of miR-33 ameliorates phenotypes linked to age-related macular degeneration.

Gnanaguru Gopalan G Wagschal Alexandre A Oh Justin J Saez-Torres Kahira L KL Li Tong T Temel Ryan E RE Kleinman Mark E ME Näär Anders M AM D'Amore Patricia A PA

Molecular therapy : the journal of the American Society of Gene Therapy 20210317 7

Abnormal cholesterol/lipid homeostasis is linked to neurodegenerative conditions such as age-related macular degeneration (AMD), which is a leading cause of blindness in the elderly. The most prevalent form, termed "dry" AMD, is characterized by pathological cholesterol accumulation beneath the retinal pigment epithelial (RPE) cell layer and inflammation-linked degeneration in the retina. We show here that the cholesterol-regulating microRNA miR-33 was elevated in the RPE of aging mice. Expressi ...[more]

PMID: 33744470

Similar Datasets

Project description:PurposeDemographic, environmental, and genetic risk factors for age-related macular degeneration (AMD) have been identified; however, a substantial portion of the variance in AMD disease risk and heritability remains unexplained. To identify AMD risk variants and generate hypotheses for future studies, we performed whole exome sequencing for 75 individuals whose phenotype was not well predicted by their genotype at known risk loci. We hypothesized that these phenotypically extreme individuals were more likely to carry rare risk or protective variants with large effect sizes.MethodsA genetic risk score was calculated in a case-control set of 864 individuals (467 AMD cases, 397 controls) based on 19 common (≥1% minor allele frequency, MAF) single nucleotide variants previously associated with the risk of advanced AMD in a large meta-analysis of advanced cases and controls. We then selected for sequencing 39 cases with bilateral choroidal neovascularization with the lowest genetic risk scores to detect risk variants and 36 unaffected controls with the highest genetic risk score to detect protective variants. After minimizing the influence of 19 common genetic risk loci on case-control status, we targeted single variants of large effect and the aggregate effect of weaker variants within genes and pathways. Single variant tests were conducted on all variants, while gene-based and pathway analyses were conducted on three subsets of data: 1) rare (≤1% MAF in the European population) stop, splice, or damaging missense variants, 2) all rare variants, and 3) all variants. All analyses controlled for the effects of age and sex.ResultsNo variant, gene, or pathway outside regions known to be associated with risk for advanced AMD reached genome-wide significance. However, we identified several variants with substantial differences in allele frequency between cases and controls with strong additive effects on affection status after controlling for age and sex. Protective effects trending toward significance were detected at two loci identified in single-variant analyses: an intronic variant in FBLN7 (the gene encoding fibulin 7) and at three variants near pyridoxal (pyridoxine, vitamin B6) kinase (PDXK). Aggregate rare-variant analyses suggested evidence for association at ASRGL1, a gene previously linked to photoreceptor cell death, and at BSDC1. In known AMD loci we also identified 29 novel or rare damaging missense or stop/splice variants in our sample of cases and controls.ConclusionsIdentified variants and genes may highlight regions important in the pathogenesis of AMD and are key targets for replication.

Project description:ImportanceSingle-nucleotide polymorphisms (SNPs) associated with the CFH, ARMS2, C3, LIPC, CFB, and C2 genes are associated with age-related macular degeneration (AMD); however, the association of these SNPs with angiographic features of neovascular AMD has been inconsistent in previous studies, and to date, no studies have addressed their association with features on optical coherence tomography.ObjectiveTo evaluate the influence of genotype of SNPs previously associated with AMD on the phenotype of neovascular lesions.Design, setting, and participantsParticipants for this cross-sectional study were recruited from the 1185 patients enrolled in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), a randomized clinical trial. Eligibility criteria for CATT specified that eyes have choroidal neovascularization and visual acuity between 20/25 and 20/320. A subgroup of 835 patients provided blood samples from July 2010 through September 2011 and were genotyped for the SNPs rs1061170 (CFH), rs10490924 (ARMS2),rs2230199 (C3), rs10468017 (LIPC), rs4151667 (CFB), rs547154 (C2) using TaqMan SNP genotyping assays. Data analysis was initiated in November 2013 and completed in January 2016.Main outcomes and measuresPretreatment ocular characteristics on fluorescein angiography (lesion type, area of neovascularization and total lesion, retinal angiomatous proliferation) and on time-domain optical coherence tomography (presence of intraretinal, subretinal, and subretinal pigment epithelium fluid; thickness at the foveal center of the retina, subretinal fluid, and subretinal tissue complex), visual acuity, and age.ResultsA total of 835 (73%) of 1150 CATT patients were genotyped. Mean age decreased with the number of risk alleles for CFH (P < .001), ARMS2 (P < .001), and C3 (P = .005). The following results were found as the number of risk alleles increased from 0 to 1 to 2. For CFH, mean total thickness decreased from 476 to 476 to 434 µm (P = .01; adjusted for age, sex, and smoking status). For ARMS2, the mean area of the total lesion increased from 2.0 to 2.8 to 2.4 mm2 (P = .03), the proportion with retinal angiomatous proliferation lesions increased from 8% to 10% to 12% (P = .05), and the proportion with intraretinal fluid increased from 72% to 71% to 82% (P = .008). For C3, the proportion with intraretinal fluid decreased from 78% to 69% to 64% (P = .001), and the mean retinal thickness decreased from 225 to 207 to 197 µm (P = .02).Conclusions and relevanceCFH, ARMS2, and C3 were associated with specific features of neovascularization at the time patients were enrolled in CATT. Previously identified associations of ARMS2 and CFH with type of choroidal neovascularization on fluorescein angiography were not confirmed. New associations with OCT features identified in CATT need confirmation to establish whether a true association exists.Trial registrationclinicaltrials.gov Identifier: NCT00593450.

Dataset Information

Targeting of miR-33 ameliorates phenotypes linked to age-related macular degeneration.

Publications

Targeting of miR-33 ameliorates phenotypes linked to age-related macular degeneration.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets