Genetic analysis of primary open-angle glaucoma-related risk alleles in a Korean population: the GLAU-GENDISK study

2020 ◽  
pp. bjophthalmol-2020-316089
Author(s):  
Yong Woo Kim ◽  
Yun Hwan Lee ◽  
Jin-Soo Kim ◽  
Jinho Lee ◽  
Yu Jeong Kim ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Coiled Coil ◽  
Korean Population ◽  
Bhlh Transcription Factor ◽  
Nucleotide Polymorphisms ◽  
Open Angle ◽  
Risk Alleles

AimTo validate six previously known primary open-angle glaucoma (POAG)-related loci in a Korean population.MethodsRepresentative POAG-related single-nucleotide polymorphisms (SNPs) from six loci (cyclin-dependent kinase 4 inhibitor B antisense RNA 1 (CDKN2B)-AS1, sineoculis homeobox homolog 1/sineoculis homeobox homolog 6(SIX1/SIX6), atonal BHLH transcription factor 7 (ATOH7), cell division cycle 7-transforming growth factor beta receptor 3, CAV1, transmembrane and coiled-coil domain family 1 (TMCO1) were selected and genotyped from discovery (POAG=309, heathy=5400) and replication cohorts (POAG=310, healthy=5612 and POAG=221, healthy=6244, respectively). Data were analysed using logistic regression to calculate the OR for POAG risk associated with SNP.ResultsFrom the discovery cohort, rs1900004 in ATOH7 (OR=1.29, p=0.0024); rs1063192 (OR=0.69, p=0.0006), rs2157719 (OR=0.63, p=0.0007) and rs7865618 (OR=0.63, p=0.0006) in CDKN2B-AS1, and rs10483727 in SIX1/SIX6 (OR=0.68, p=7.9E–05) were nominally associated with the risk of POAG. The replication cohorts revealed nominal associations with rs2157719 (OR=0.72, p=0.0135), rs1063192 (OR=0.63, p=0.0007) and rs7865618 (OR=0.52, p=0.0004) in CDKN2B-AS1. A mega-analysis from the entire Korean population revealed significance with rs1063192 (OR=0.77, p=6.0E–05), rs2157719 (OR=0.63, p=0.0007) and rs7865618 (OR=0.58, p=1.9E–06) in CDKN2B-AS1 and with rs10483727 in SIX1/SIX6 (OR=0.79, p=9.4E–05), with the same direction of effect between the discovery association and the replication sample.ConclusionsVariants near CDKN2B-AS1 and SIX1/SIX6 may require further investigation to obtain more genetic information on POAG development in a Korean population.

scholarly journals Crosstalk between MicroRNA and Oxidative Stress in Primary Open-Angle Glaucoma

2021 ◽  
Vol 22 (5) ◽  
pp. 2421
Author(s):  
Saray Tabak ◽  
Sofia Schreiber-Avissar ◽  
Elie Beit-Yannai
Keyword(s):  
Oxidative Stress ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Additional Treatment ◽  
Type I ◽  
Open Angle ◽  
Outflow Resistance ◽  
Stress Injury

Reactive oxygen species (ROS) plays a key role in the pathogenesis of primary open-angle glaucoma (POAG), a chronic neurodegenerative disease that damages the trabecular meshwork (TM) cells, inducing apoptosis of the retinal ganglion cells (RGC), deteriorating the optic nerve head, and leading to blindness. Aqueous humor (AH) outflow resistance and intraocular pressure (IOP) elevation contribute to disease progression. Nevertheless, despite the existence of pharmacological and surgical treatments, there is room for the development of additional treatment approaches. The following review is aimed at investigating the role of different microRNAs (miRNAs) in the expression of genes and proteins involved in the regulation of inflammatory and degenerative processes, focusing on the delicate balance of synthesis and deposition of extracellular matrix (ECM) regulated by chronic oxidative stress in POAG related tissues. The neutralizing activity of a couple of miRNAs was described, suggesting effective downregulation of pro-inflammatory and pro-fibrotic signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), transforming growth factor-beta 2 (TGF-β2), Wnt/β-Catenin, and PI3K/AKT. In addition, with regards to the elevated IOP in many POAG patients due to increased outflow resistance, Collagen type I degradation was stimulated by some miRNAs and prevented ECM deposition in TM cells. Mitochondrial dysfunction as a consequence of oxidative stress was suppressed following exposure to different miRNAs. In contrast, increased oxidative damage by inhibiting the mTOR signaling pathway was described as part of the action of selected miRNAs. Summarizing, specific miRNAs may be promising therapeutic targets for lowering or preventing oxidative stress injury in POAG patients.

scholarly journals Genetic Risk and Phenotype Correlation of Primary Open-Angle Glaucoma Based on Rho-Kinase Gene Polymorphisms

2021 ◽  
Vol 10 (9) ◽  
pp. 1953
Author(s):  
Yong-Woo Kim ◽  
Eunoo Bak ◽  
Seoyoung Wy ◽  
Seung-Chan Lee ◽  
Yu-Jeong Kim ◽  
...  
Keyword(s):  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Corneal Thickness ◽  
Coiled Coil ◽  
Rho Kinase ◽  
Normal Tension Glaucoma ◽  
Nucleotide Polymorphisms ◽  
Open Angle ◽  
Phenotype Correlation ◽  
Kinase Gene

Rho-associated coiled-coil kinase (ROCK) signaling can affect glaucoma risk by regulating trabecular meshwork outflow. We investigated the effect of ROCK gene polymorphism on the risks of primary open-angle glaucoma (POAG) and POAG-related phenotypes including intraocular pressure (IOP) in a Korean population. A total of 24 single-nucleotide polymorphisms (SNPs) from ROCK1 and ROCK2 were selected and genotyped for 363 POAG patients and 213 healthy controls. Among the 363 POAG patients, 282 were normal-tension glaucoma (NTG, baseline IOP ≤ 21 mmHg) and 81 were high-tension glaucoma (HTG, baseline IOP > 21 mmHg). The SNPs rs288979, rs1006881, rs35996865, rs10083915, and rs11873284 in ROCK1 (tagged to each other, r2 = 1) were nominally associated with risk of HTG (OR = 0.52, p = 0.045). However, there were no SNPs that were significantly associated with the risk of NTG. In the genotype-phenotype correlation analysis, the SNPs rs2230773 and rs3771106 in ROCK2 were significantly correlated with central corneal thickness (CCT)-adjusted IOP (p = 0.024) and axial length (AXL; p = 0.024), respectively. The present data implicated the role of ROCK in POAG development, and as such, can serve as a good reference for upcoming Rho/ROCK-pathway-related studies on POAG.

scholarly journals Astragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma

2021 ◽  
Vol 22 (22) ◽  
pp. 12508
Author(s):  
Ramesh B. Kasetti ◽  
Prabhavathi Maddineni ◽  
Bindu Kodati ◽  
Bhavani Nagarajan ◽  
Sam Yacoub
Keyword(s):  
Er Stress ◽  
Ocular Hypertension ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Matrix Metalloproteases ◽  
Eye Drops ◽  
Open Angle ◽  
Astragaloside Iv

Elevated intraocular pressure (IOP) is a major risk factor in developing primary open angle glaucoma (POAG), which is the most common form of glaucoma. Transforming growth factor-beta 2 (TGFβ2) is a pro-fibrotic cytokine that plays an important role in POAG pathogenesis. TGFβ2 induced extracellular matrix (ECM) production, deposition and endoplasmic reticulum (ER) stress in the trabecular meshwork (TM) contribute to increased aqueous humor (AH) outflow resistance and IOP elevation. Drugs which alter the glaucomatous fibrotic changes and ER stress in the TM may be effective in reducing ocular hypertension. Astragaloside IV (AS.IV), a novel saponin isolated from the roots of Astragalus membranaceus, has demonstrated antifibrotic and ER stress lowering effects in various tissues during disease conditions. However, the effect of AS.IV on glaucomatous TM fibrosis, ER stress and ocular hypertension has not been studied. Primary human TM cells treated with AS.IV decreased TGFβ2 induced ECM (FN, Col-I) deposition and ER stress (KDEL, ATF4 and CHOP). Moreover, AS.IV treatment reduced TGFβ2 induced NF-κB activation and αSMA expression in TM cells. We found that AS.IV treatment significantly increased levels of matrix metalloproteases (MMP9 and MMP2) and MMP2 enzymatic activity, indicating that the antifibrotic effects of AS.IV are mediated via inhibition of NF-κB and activation of MMPs. AS.IV treatment also reduced ER stress in TM3 cells stably expressing mutant myocilin. Interestingly, the topical ocular AS.IV eye drops (1 mM) significantly decreased TGFβ2 induced ocular hypertension in mice, and this was associated with a decrease in FN, Col-1 (ECM), KDEL (ER stress) and αSMA in mouse TM tissues. Taken together, the results suggest that AS.IV prevents TGFβ2 induced ocular hypertension by modulating ECM deposition and ER stress in the TM.

An update: mechanisms of microRNA in primary open-angle glaucoma

2020 ◽  
Author(s):  
Yuanping Wang ◽  
Lingzhi Niu ◽  
Jing Zhao ◽  
Mingxuan Wang ◽  
Ke Li ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Nucleotide Polymorphisms ◽  
Open Angle ◽  
Single Nucleotide ◽  
Optic Nerve Damage ◽  
The World ◽  
And Function ◽  
Main Factor

Abstract Glaucoma is a disease with characteristic optic neuropathy and loss of vision, leading to blindness, and primary open-angle glaucoma (POAG) is the most common glaucoma type throughout the world. Genetic susceptibility is the main factor in POAG, and most susceptibility genes cause changes in microRNA expression and function, thereby leading to POAG occurrence and development. Increasing evidence indicates that many microRNAs are involved in the regulation of intraocular pressure (IOP) and play an important role in the increase in IOP in POAG. Additionally, microRNA is closely related to optic nerve damage factors (mechanical stress, hypoxia and inflammation). This review discusses the effect of single-nucleotide polymorphisms in POAG-related genes on microRNA and the value of microRNA in the diagnosis and treatment of POAG.

scholarly journals Comparison of cytokine/chemokine levels in aqueous humor of primary open-angle glaucoma patients with positive or negative outcome following trabeculectomy

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Beata Gajda-Deryło ◽  
Thomas Stahnke ◽  
Stephan Struckmann ◽  
Gregor Warsow ◽  
Kerstin Birke ◽  
...  
Keyword(s):  
Growth Factor ◽  
Aqueous Humor ◽  
Transforming Growth Factor ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Transforming Growth Factor Β ◽  
Positive Outcome ◽  
Open Angle ◽  
Antifibrotic Therapy ◽  
Cytokines And Chemokines

Abstract We aimed to identify differences in cytokine/chemokine levels in the aqueous humor (AH) of primary open-angle glaucoma (POAG) patients who suffered from scarring, compared with POAG patients with no scarring after trabeculectomy surgery. Identification of differently expressed cytokines and chemokines may help to understand scarring and fibrotic processes following trabeculectomy, and to make predictions for the outcome of fistulating surgery in the future. Furthermore, the identification of cell signaling pathways involved in fibrosis offers the opportunity for a more specific antifibrotic therapy with reduced side effects, and an improvement in long-term surgical outcome. Eight samples of AH were collected during trabeculectomy surgery and commercially available cytokine/chemokine arrays were used. Specific, differently expressed proteins (cytokines/chemokines) in AH samples from patients with positive and negative surgery outcomes were detected. These proteins were classified based on their known profibrotic, inflammatory, adhesive, and apoptotic properties. Transforming growth factor β (TGF-β) and vascular endothelial growth factor (VEGF) were among the most important profibrotic cytokines that we detected. Differences in the fold change of protein expression were highly significant between patients after successful and failed trabeculectomy surgery, and these were processed and visualized using ExprEssence software. This pilot study revealed differences in concentrations of cytokines/chemokines in AH between the two examined groups of patients. Our findings suggest that a positive outcome from trabeculectomy is strongly related to an inhibition of the fibrosis process.

Association of single-nucleotide polymorphisms in non-coding regions of the TLR4 gene with primary open angle glaucoma in a Mexican population

2016 ◽  
Vol 38 (4) ◽  
pp. 325-329 ◽  
Author(s):  
Jose Navarro-Partida ◽  
Beatriz Alvarado Castillo ◽  
Abril Bernardette Martinez-Rizo ◽  
Ramses Rosales-Diaz ◽  
Jesus Bernardino Velazquez-Fernandez ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Mexican Population ◽  
Nucleotide Polymorphisms ◽  
Open Angle ◽  
Single Nucleotide ◽  
Coding Regions ◽  
Tlr4 Gene

scholarly journals Сontent of cytokines and growth factors in the intraocular fluid of patients with primary open-angle glaucoma

2019 ◽  
Vol 18 (1) ◽  
pp. 257-265
Author(s):  
V. V. Chernykh ◽  
V. I. Konenkov ◽  
O. V. Ermakova ◽  
N. B. Orlov ◽  
O. O. Obukhova ◽  
...  
Keyword(s):  
Growth Factors ◽  
Transforming Growth Factor ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
Control Group ◽  
Open Angle ◽  
Beam Laser ◽  
Inflammatory Protein ◽  
Double Beam ◽  
Intraocular Fluid

Purpose. To study the content of cytokines and growth factors in the intraocular fluid of patients with developed stage of primary open-angle glaucoma (POAG).Materials and methods. 56 patients with a verified diagnosis developed stage of primary open-angle glaucomawere examined. The control group consisted of 30 patients with a diagnosis of uncomplicated cataract. A concentration of 17 cytokinesand 3 isoforms of the transforming growth factor (TGF) β was determined using a Bio-Plex Pro™ Human Cytokine 17-plex Assay and Bio-Plex Pro™ and TGFβ 3-plex Assay kit by flow-through fluorometry on a Bio-Plex 200, Bio-Rad double beam laser analyzer, USA.Results. Astatistically significant increase was shown in the concentrations of cytokines and growth factors (interleukins (IL) 4, 6, 7, 8, 12, 17, TGFβ 1, 2, 3, macrophage inflammatory protein 1 β) in the intraocular fluid of patients with developed stage of the primary open-angle glaucoma in respect to data obtained from the study of the intraocular fluid of the persons with uncomplicated cataract, as well as a statistically significant decrease in the concentrations IL-2, IL-10, granulocyte-macrophage colony-stimulating factor.Conclusion. In the pathogenesis of primary open-angle glaucoma, the activity of the local chronic inflammatory process is determined. This is confirmed by statistically significant changes in the studied cytokines and growth factors. Increase in the concentrations of the studied representatives of the superfamily of transforming growth factors-beta, which have anti-inflammatory activity, the ability to stimulate proliferation, cell growth, synthesis of extracellular matrix proteins, etc., attests to their importance in the mechanisms of primary open-angle glaucoma development. Increase concentrations of IL-7 in the intraocular fluid of patients with primary open-angle glaucoma allows us to assume participation in the pathogenesis of the primary open-angle glaucoma of this autocrine mediator of activation of the growth of lymphatic structures.

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