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Nature Communications Jan 2024Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and...
Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.
Topics: Humans; Genome-Wide Association Study; Glaucoma, Open-Angle; Gene Expression Regulation; Causality; Glaucoma
PubMed: 38195602
DOI: 10.1038/s41467-023-44380-y -
Molecular Aspects of Medicine Dec 2023Glaucoma is a common irreversible vision loss disorder because of the gradual loss of retinal ganglion cells (RGCs) and the optic nerve axons. Major risk factors include... (Review)
Review
Glaucoma is a common irreversible vision loss disorder because of the gradual loss of retinal ganglion cells (RGCs) and the optic nerve axons. Major risk factors include elder age and high intraocular pressure (IOP). However, high IOP is neither necessary nor sufficient to cause glaucoma. Some non-IOP signaling cascades can mediate RGC degeneration. In addition, gender, diet, obesity, depression, or anxiety also contribute to the development of glaucoma. Understanding the mechanism of glaucoma development is crucial for timely diagnosis and establishing new strategies to improve current IOP-reducing therapies. The microbiota exerts a marked influence on the human body during homeostasis and disease. Many glaucoma patients have abnormal compositions of the microbiota (dysbiosis) in multiple locations, including the ocular surface, intraocular cavity, oral cavity, stomach, and gut. Here, we discuss findings in the last ten years or more about the microbiota and metabolite changes in animal models, patients with three risk factors (aging, obesity, and depression), and glaucoma patients. Antigenic mimicry and heat stress protein (HSP)-specific T-cell infiltration in the retina may be responsible for commensal microbes contributing to glaucomatous RGC damage. LPS-TLR4 pathway may be the primary mechanism of oral and ocular surface dysbiosis affecting glaucoma. Microbe-derived metabolites may also affect glaucoma pathogenesis. Homocysteine accumulation, inflammatory factor release, and direct dissemination may link gastric H. pylori infection and anterior chamber viral infection (such as cytomegalovirus) to glaucoma. Potential therapeutic protocols targeting microbiota include antibiotics, modified diet, and stool transplant. Later investigations will uncover the underlying molecular mechanism connecting dysbiosis to glaucoma and its clinical applications in glaucoma management.
Topics: Animals; Humans; Aged; Dysbiosis; Glaucoma; Retina; Microbiota; Obesity; Disease Models, Animal
PubMed: 37866106
DOI: 10.1016/j.mam.2023.101221 -
Proceedings of the National Academy of... Aug 2023Although the visual system extends through the brain, most vision loss originates from defects in the eye. Its central element is the neural retina, which senses light,...
Although the visual system extends through the brain, most vision loss originates from defects in the eye. Its central element is the neural retina, which senses light, processes visual signals, and transmits them to the rest of the brain through the optic nerve (ON). Surrounding the retina are numerous other structures, conventionally divided into anterior and posterior segments. Here, we used high-throughput single-nucleus RNA sequencing (snRNA-seq) to classify and characterize cells in six extraretinal components of the posterior segment: ON, optic nerve head (ONH), peripheral sclera, peripapillary sclera (PPS), choroid, and retinal pigment epithelium (RPE). Defects in each of these tissues are associated with blinding diseases-for example, glaucoma (ONH and PPS), optic neuritis (ON), retinitis pigmentosa (RPE), and age-related macular degeneration (RPE and choroid). From ~151,000 single nuclei, we identified 37 transcriptomically distinct cell types, including multiple types of astrocytes, oligodendrocytes, fibroblasts, and vascular endothelial cells. Our analyses revealed a differential distribution of many cell types among distinct structures. Together with our previous analyses of the anterior segment and retina, the data presented here complete a "Version 1" cell atlas of the human eye. We used this atlas to map the expression of >180 genes associated with the risk of developing glaucoma, which is known to involve ocular tissues in both anterior and posterior segments as well as the neural retina. Similar methods can be used to investigate numerous additional ocular diseases, many of which are currently untreatable.
Topics: Humans; Transcriptome; Endothelial Cells; Optic Disk; Glaucoma; Optic Nerve; Sclera
PubMed: 37566633
DOI: 10.1073/pnas.2306153120 -
Biomedicine & Pharmacotherapy =... Dec 2023Glaucoma is the world's leading irreversible blinding eye disease. Lowering intraocular pressure is currently the only effective clinical treatment. However, there is a... (Review)
Review
Glaucoma is the world's leading irreversible blinding eye disease. Lowering intraocular pressure is currently the only effective clinical treatment. However, there is a lack of long-acting IOP-lowering drugs, and some patients still experience retinal ganglion cell loss even with good intraocular pressure control. Currently, there is no effective method for neuroprotection and regeneration in clinical practice for glaucoma. In recent years, epigenetics has been widely researched and reported for its role in glaucoma's neuroprotection and regeneration. This article reviews the changes in histone modifications, DNA methylation, non-coding RNA, and m6A methylation in glaucoma, aiming to provide new perspectives for glaucoma management, protection of retinal ganglion cells, and axon regeneration by understanding epigenetic alterations.
Topics: Humans; Axons; Epigenesis, Genetic; Nerve Regeneration; Glaucoma; Intraocular Pressure
PubMed: 37806089
DOI: 10.1016/j.biopha.2023.115633 -
Frontiers in Immunology 2023Autoimmunity and inflammation are the main characteristics of rheumatic diseases and have both been found to be related to glaucoma. However, it remains unclear whether...
BACKGROUND
Autoimmunity and inflammation are the main characteristics of rheumatic diseases and have both been found to be related to glaucoma. However, it remains unclear whether rheumatic diseases increase the risk of glaucoma. Here, we performed a Mendelian randomization (MR) analysis to investigate the causal effects of six common rheumatic diseases on glaucoma.
METHODS
Six rheumatic diseases were included: ankylosing spondylitis (AS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sicca syndrome/Sjögren's sydrome (SS), dermatomyositis (DM), and gout. Glaucoma included primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). Genetic variants associated with these rheumatic diseases and glaucoma were extracted from the genome-wide association studies and FinnGen8 database, respectively. First, a two-sample MR was used to investigate the potential causal association. Then, a multivariable MR was conducted to further verify the results. Inverse-variance weighted MR analysis was used as the main method, together with several sensitivity analyses.
RESULTS
Two-sample MR suggests that AS is related to a higher risk of both POAG [odds ratio (OR): 1.28, 95% confidence interval (CI) 1.13-1.44; = 1.1 × 10] and PACG (OR: 1.55, 95% CI: 1.09-2.09, = 1.4 × 10). Multivariable MR shows a similar trend of the effect of AS on POAG (OR: 1.52, 95% CI: 1.22-1.90, = 1.9 × 10) and PACG (OR: 2.05, 95% CI: 1.06-3.95, = 3.2 × 10). No significant association was observed between the other five rheumatic diseases and glaucoma.
CONCLUSIONS
AS is related to an increased risk of POAG and PACG. We stress the importance of glaucoma screening for AS patients.
Topics: Humans; Glaucoma, Open-Angle; Genome-Wide Association Study; Mendelian Randomization Analysis; Glaucoma; Arthritis, Rheumatoid
PubMed: 37799717
DOI: 10.3389/fimmu.2023.1227138 -
Trends in Pharmacological Sciences Dec 2023Clinical evidence shows that intraocular hypertension is not the primary pathogenetic event of glaucoma, whereas early neurodegeneration of retinal ganglion cells (RGCs)... (Review)
Review
Clinical evidence shows that intraocular hypertension is not the primary pathogenetic event of glaucoma, whereas early neurodegeneration of retinal ganglion cells (RGCs) represents a key therapeutic target. Unfortunately, failure of clinical trials with neuroprotective agents, in particular those testing the anti-excitotoxic drug memantine, generated widespread skepticism regarding the possibility of counteracting neurodegeneration during glaucoma. New avenues for neuroprotective approaches to counteract glaucoma evolution have been opened by the identification of a programmed axonal degeneration (PAD) program triggered by increased nicotinamide mononucleotide (NMN)/NAD concentration ratio. Positive results of proof-of-concept clinical studies based on sustaining axonal NAD homeostasis facilitated the design of Phase 2/3 trials. Here, I share my opinion on how neurodegeneration in glaucoma should be put into context, together with an appraisal of the pharmacological rationale of NAD-supporting therapies for use during glaucoma progression.
Topics: Humans; Neuroprotection; NAD; Glaucoma; Neuroprotective Agents; Retinal Ganglion Cells
PubMed: 37880000
DOI: 10.1016/j.tips.2023.09.010 -
Ugeskrift For Laeger Nov 2023This review offers a summary of the current knowledge of pshychotropic drugs and glaucoma. If exposed to psychotropic drugs, some patients may develop angle-closure... (Review)
Review
This review offers a summary of the current knowledge of pshychotropic drugs and glaucoma. If exposed to psychotropic drugs, some patients may develop angle-closure glaucoma. Although rarely contraindicated, exposed predisposed and diagnosed patients should be followed-up by an ophthalmologist. It is still unclear if serotonin reuptake inhibitors increase the risk of angle-closure glaucoma. Tricyclic antidepressants and benzodiazepines should be used with caution in predisposed patients. The same applies to antipsychotic drugs, where first-generation antipsychotic drugs might have a smaller impact on the intraocular pressure than second-generation antipsychotic drugs.
Topics: Humans; Antipsychotic Agents; Glaucoma, Angle-Closure; Psychotropic Drugs; Glaucoma; Selective Serotonin Reuptake Inhibitors
PubMed: 38018726
DOI: No ID Found -
Medicine Dec 2023To assess ocular parameters and their association with anthropometric measurements in Indo-Trinidadians adults. This was a clinical, descriptive, cross-sectional study...
To assess ocular parameters and their association with anthropometric measurements in Indo-Trinidadians adults. This was a clinical, descriptive, cross-sectional study of ocular parameters and anthropometry in adults Trinidadians of South Asian descent (Indo-Trinidadian). Ocular parameters were measured using optical coherence tomography, intraocular lens master biometer, and an autorefractor. Weight, height, and body mass index (BMI) were measured by anthropometry. Univariable and multivariable linear regressions were used to determine the association between demographic variables, anthropometric and ocular parameters. A total of 149 participants (298 eyes) comprising of 90 females (60.6%) and 59 males (39.4%). Aged 18 to 67 participated in the study. Males were taller, heavier, and had longer axial lengths than females which were statistically significant (P < .05). Age was negatively correlated with central corneal thickness (CCT) (r = -0.353, P = .044) and retinal nerve fiber layer thickness (r = -0.348, P = .047) but positively correlated with lens thickness (R = 0.881, P < .001). Education level was positively associated with CCT (R = 0.408, P = .018) but negatively associated with lens thickness (r = -0.521, P = .002). Weight was negatively correlated with corneal topography (r = -0.427, P = .013). Height was negatively correlated with cup-to-disc ratio (r = -0.410, P = .018), CCT (r = -0.382, P = .028), and corneal topography (r = -0.453, P = .008). There was no correlation between BMI, ocular parameters and CCT. There was a significant difference in the ocular parameters between males and females of South Asian descent in Trinidad and Tobago. Weight was negatively associated with the corneal topography. Height was negatively associated with the cup-to-disc ratio, central corneal thickness, and corneal topography. BMI had no statistically significant association with the ocular parameters investigated.
Topics: Adult; Female; Humans; Male; Anthropometry; Caribbean People; Cornea; Cross-Sectional Studies; Intraocular Pressure; Ocular Hypertension; Tomography, Optical Coherence; Adolescent; Young Adult; Middle Aged; Aged
PubMed: 38206703
DOI: 10.1097/MD.0000000000036763 -
Nature Genetics Jul 2023Glaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the...
Glaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the most common form, primary open-angle glaucoma. Two key glaucoma-associated traits also show high heritability: intraocular pressure and optic nerve head excavation damage quantified as the vertical cup-to-disc ratio. Here, since much of glaucoma heritability remains unexplained, we conducted a large-scale multitrait genome-wide association study in participants of European ancestry combining primary open-angle glaucoma and its two associated traits (total sample size over 600,000) to substantially improve genetic discovery power (263 loci). We further increased our power by then employing a multiancestry approach, which increased the number of independent risk loci to 312, with the vast majority replicating in a large independent cohort from 23andMe, Inc. (total sample size over 2.8 million; 296 loci replicated at P < 0.05, 240 after Bonferroni correction). Leveraging multiomics datasets, we identified many potential druggable genes, including neuro-protection targets likely to act via the optic nerve, a key advance for glaucoma because all existing drugs only target intraocular pressure. We further used Mendelian randomization and genetic correlation-based approaches to identify novel links to other complex traits, including immune-related diseases such as multiple sclerosis and systemic lupus erythematosus.
Topics: Humans; Genome-Wide Association Study; Glaucoma, Open-Angle; Glaucoma; Intraocular Pressure; Optic Nerve; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 37386247
DOI: 10.1038/s41588-023-01428-5 -
Turkish Journal of Ophthalmology Aug 2023Pseudoexfoliation syndrome (PES) is one of the most common causes of open-angle glaucoma, with a higher risk of vision loss, a higher maximum and mean intraocular... (Review)
Review
Pseudoexfoliation syndrome (PES) is one of the most common causes of open-angle glaucoma, with a higher risk of vision loss, a higher maximum and mean intraocular pressure (IOP) at diagnosis, and a wider range of IOP fluctuation compared to primary open-angle glaucoma. Patients with this syndrome have a ten-fold higher risk of developing glaucoma than the normal population. A definite diagnosis can be made by the observation of pseudoexfoliation material (PEM) on the anterior lens surface, ciliary processes, zonules, and iris. PEM deposits on the zonules may explain the clinically observed zonular weakness and lens subluxation or dislocation. An increased incidence of cataract development is also associated with PES. There is growing evidence for systemic associations of PES with peripheral, cardiovascular, and cerebrovascular system diseases, Alzheimer's disease, hearing loss, and increased plasma homocysteine levels. Indications for surgery are markedly more common in patients with pseudoexfoliation glaucoma than primary open-angle glaucoma. The goal of this article is to review the latest perspectives on the clinical features, therapy, and systemic associations of this clinically and biologically challenging disease.
Topics: Humans; Cataract; Exfoliation Syndrome; Glaucoma; Glaucoma, Open-Angle; Lens Subluxation
PubMed: 37602651
DOI: 10.4274/tjo.galenos.2023.76300