Novel therapeutic targets for primary open-angle glaucoma identified through multicenter proteome-wide mendelian randomization.

Background: This study aimed to identify novel therapeutic targets for primary open-angle glaucoma (POAG). Methods: The summary-data-based Mendelian randomization (SMR) method was used to evaluate the genetic association between plasma proteins and POAG. Two sets of plasma protein quantitative trait loci (pQTLs) data considered exposures were obtained from the Icelandic Decoding Genetics Study and UK Biobank Pharma Proteomics Project. The summary-level genome-wide association studies data for POAG were extracted from the latest Round 10 release of the FinnGen consortium (8,530 cases and 391,275 controls) and the UK Biobank (4,737 cases and 458,196 controls). Colocalization analysis was used to screen out pQTLs that share the same variant with POAG as drug targets identified. The two-sample Mendelian randomization, reverse causality testing and phenotype scanning were performed to further validate the main findings. Protein-protein interaction, pathway enrichment analysis and druggability assessment were conducted to determine whether the identified plasma proteins have potential as drug targets. Results: After systematic analysis, this study identified eight circulating proteins as potential therapeutic targets for POAG. Three causal proteins with strong evidence of colocalization, ROBO1 (OR = 1.38, p = 1.48 × 10-4, PPH4 = 0.865), FOXO3 (OR = 0.35, p = 4.34 × 10-3, PPH4 = 0.796), ITIH3 (OR = 0.89, p = 2.76 × 10-4, PPH4 = 0.767), were considered tier one targets. Five proteins with medium support evidence of colocalization, NCR1 (OR = 1.25, p = 4.18 × 10-4, PPH4 = 0.682), NID1 (OR = 1.38, p = 1.54 × 10-3, PPH4 = 0.664), TIMP3 (OR = 0.91, p = 4.01 × 10-5, PPH4 = 0.659), SERPINF1 (OR = 0.81, p = 2.77 × 10-4, PPH4 = 0.59), OXT (OR = 1.17, p = 9.51 × 10-4, PPH4 = 0.526), were classified as tier two targets. Additional sensitivity analyses further validated the robustness and directionality of these findings. According to druggability assessment, Pimagedine, Resveratrol, Syringaresinol and Clozapine may potentially be important in the development of new anti-glaucoma agents. Conclusion: Our integrated study identified eight potential associated proteins for POAG. These proteins play important roles in neuroprotection, extracellular matrix regulation and oxidative stress. Therefore, they have promising potential as therapeutic targets to combat POAG.

The TGFß Induced MicroRNAome of the Trabecular Meshwork.

Primary open-angle glaucoma (POAG) is a progressive optic neuropathy with a complex, multifactorial aetiology. Raised intraocular pressure (IOP) is the most important clinically modifiable risk factor for POAG. All current pharmacological agents target aqueous humour dynamics to lower IOP. Newer therapeutic agents are required as some patients with POAG show a limited therapeutic response or develop ocular and systemic side effects to topical medication. Elevated IOP in POAG results from cellular and molecular changes in the trabecular meshwork driven by increased levels of transforming growth factor ß (TGFß) in the anterior segment of the eye. Understanding how TGFß affects both the structural and functional changes in the outflow pathway and IOP is required to develop new glaucoma therapies that target the molecular pathology in the trabecular meshwork. In this study, we evaluated the effects of TGF-ß1 and -ß2 treatment on miRNA expression in cultured human primary trabecular meshwork cells. Our findings are presented in terms of specific miRNAs (miRNA-centric), but given miRNAs work in networks to control cellular pathways and processes, a pathway-centric view of miRNA action is also reported. Evaluating TGFß-responsive miRNA expression in trabecular meshwork cells will further our understanding of the important pathways and changes involved in the pathogenesis of glaucoma and could lead to the development of miRNAs as new therapeutic modalities in glaucoma.

Elevated VEGF-A Levels in the Aqueous Humor of Patients With Primary Open Angle Glaucoma.

BACKGROUND/AIM: The purpose of the current study was to compare the vascular endothelial growth factor-A (VEGF-A) levels in the aqueous humor of patients with primary open angle glaucoma (POAG) and non-glaucomatous eyes and reveal any potential statistically significant correlations. PATIENTS AND METHODS: This was an observational cross-sectional study. Aqueous humor samples (50-100 µl) were collected under aseptic conditions, from the anterior chamber at the start of glaucoma or cataract surgery. The levels of VEGF-A were measured using a multiplex bead-based immunoassay. RESULTS: Aqueous humor samples were obtained from 76 participants: 39 with POAG and 36 with age-related cataracts as controls. VEGF-A levels were significantly elevated in the POAG group (166.37±110.04 pg/ml, p=0.011) compared to the control group (119.02±49.09 pg/ml). The receiver operating characteristic (ROC) analysis showed that VEGF-A had significant prognostic ability for POAG (AUC=0.67; p=0.006). An optimal cut-off for VEGF-A was found to be 148.5 pg/ml with a sensitivity of 54%, specificity of 81.1%, positive prognostic value (PPV) of 75% and negative prognostic value (NPV) of 62.5%. Logistic regression analysis showed that after adjusting for sex and age, patients with VEGF-A higher than 148.5 pg/ml had almost 10 times greater likelihood for POAG. CONCLUSION: VEGF-A is elevated in patients with POAG and can potentially have a prognostic ability for these patients.

Advancing Glaucoma Care in Bangladesh With Minimally Invasive Glaucoma Surgery.

Minimally invasive glaucoma surgery (MIGS) is a cutting-edge approach to treating glaucoma that provides a range of techniques and technology to reduce intraocular pressure (IOP). An 80-year-old man with visually significant cataracts and primary open-angle glaucoma (POAG) underwent combined cataract surgery and TrabEx+ (MicroSurgical Technology, Washington, United States) in his left eye, a unique type of MIGS, as we described in this study. Over the one-year follow-up, this patient showed improved visual function with well-controlled IOP without anti-glaucoma medications.

Anterior Segment Changes in Patients With Glaucoma Following Cataract Surgery.

This prospective observational study investigates the impact of cataract surgery on anterior segment parameters in nonglaucomatous and primary open-angle glaucoma (POAG) eyes, utilizing anterior segment optical coherence tomography (AS-OCT). The study involved 42 Caucasian patients, divided into a control group and a POAG group. Comprehensive ophthalmic examinations were performed along with AS-OCT imaging and biometry preoperatively, as well as on one day, one week, and one month following cataract surgery. The results showed significant post-operative changes in anterior chamber depth (ACD) and angle width in both groups, suggesting that cataract surgery may influence the structural parameters associated with glaucoma risk and management. Specifically, a marked increase in ACD and improvement in angle-opening distances were observed, highlighting the potential of cataract extraction to alter intraocular fluid dynamics favorably. Despite these changes, the study noted an initial spike in increased intraocular pressure (IOP) in POAG patients immediately post-operative, which stabilized during follow-up. For the control group, IOP showed gradually reducing IOP values in the follow-up visits. The findings underscore the role of advanced imaging technologies in understanding glaucoma's pathophysiology and the potential benefits of cataract surgery in glaucoma patients. The study advocates for further research with a larger, more diverse patient population and extended follow-up to explore the long-term implications of cataract surgery on glaucoma dynamics, emphasizing the importance of personalized management and treatment strategies particularly for glaucoma patients.

Advances in aqueous humor proteomics for biomarker discovery and disease mechanisms exploration: a spotlight on primary open angle glaucoma.

Altered protein levels in the aqueous humor (AH) may be a valuable source of novel biomarkers in neurodegenerative retinal disease. The proximity of this body fluid to the disease focus, and its corresponding enrichment for tissue specific proteins, renders it an excellent matrix to study underlying molecular mechanisms. Novel proteomic methods accordingly hold large potential for insight into pathologies based on the composition of the AH proteome, including primary open angle glaucoma (POAG). Recent mass spectrometry-based studies use novel approaches to tackle the challenges arising from the combination of low available sample volume and protein concentration, thereby increasing proteome coverage. But despite significant improvements in mass spectrometry (MS), a different class of proteomic technologies is poised to majorly impact the analysis of ocular biofluids. Affinity proteomic workflows, having become available commercially recently, have started to complement data obtained by MS and likely will grow into a crucial tool for ophthalmological biomarker research. This review highlights corresponding approaches in proteome analysis of aqueous humor and discusses recent findings on alterations of the AH proteome in POAG.

A meta-analysis of the association between high-sensitivity c-reactive protein level and glaucoma.

OBJECTIVE: Glaucoma is the second-leading cause of blindness in the US for people over the age of 40; the most common form is primary open-angle glaucoma (POAG). It has been suggested that inflammatory markers have a role in the development and the progression of glaucoma (GL). High-sensitivity C reactive protein (HsCRP) is an inflammatory marker that has been linked to cardiovascular disease and a possible link to GL. Although a number of studies have found a link between CRP and GL; POAG, normal tension glaucoma (NTG), exfoliation glaucoma (XFG), Exfoliation syndrome (XFS), other research has shown the opposite. PURPOSE: This systematic review is to determine the association between HsCRP and GL. METHODOLOGY: A literature search was conducted using the MEDLINE database. We identified thirty-six peer-reviewed studies. RESULTS: Five retrospective studies were included and summed up to 164305 study participants, 161759 POAG patients, and 2546 controls. The pooled result of all studies revealed that HsCRP (SMD: 0.44 mg/dl; [95% confidence interval -0.10 to 0.99]; P = 0.11, I2 89%) concentration was not significantly higher in POAG patients compared to the healthy controls. The SMD for NTG, XFG and XFS; 0.64 mg/dl; 0.03 mg/dl, 0.03 mg/dl respectively. The pooled result revealed that HsCRP concentration was not significantly higher in POAG, NTG, XFG, and XFS. No publication bias was found using the funnel plot. CONCLUSION: The meta-analysis concluded that there is no correlation between the elevated plasma levels of HsCRP and GL. Future studies should be conducted.

Aqueous humour protein dysregulation in Asian eyes with primary open angle glaucoma.

The pathophysiology of Primary Open Angle Glaucoma (POAG) remains poorly understood. Through proteomic analysis of aqueous humour (AH) from POAG patients, we aim to identify changes in protein composition of these samples compared to control samples. High resolution mass spectrometry-based TMT6plex quantitative proteomics analysis is performed on AH samples collected from POAG patients, and compared against a control group of patients with cataracts. Data are available via ProteomeXchange with identifier PXD033153. 1589 proteins were quantified from the aqueous samples using Proteome Discoverer version 2.2 software. Among these proteins, 210 were identified as unique master proteins. The proteins which were up or down-regulated by ±3 fold-change were considered significant. Human neuroblastoma full-length cDNA clone CS0DD006YL02 was significantly upregulated in patients with severe POAG on >2 medications, while actin, cytoplasmic 1, V2-7 protein (fragment), immunoglobulin-like polypeptide 1 and phosphatidylethanolamine-binding protein 4 were only present in these patients with severe POAG on >2 medications. Beta-crystallin B1 and B2, Gamma-crystallin C, D and S were significantly downregulated in the severe POAG ≤2 glaucoma medications group. Beta-crystallin B2, Gamma-crystallin D and GCT-A9 light chain variable region (fragment) were significantly downregulated in the non-severe POAG group. Actin, cytoplasmic 1 was significantly upregulated in subjects with severe POAG who required more than 2 glaucoma medications. Crystallins (Beta-crystallin B1 and B2, Gamma-crystallin C, D and S) were significantly downregulated in subjects with severe POAG who required less than 2 glaucoma medications.

Profile of Lipoprotein Subclasses in Chinese Primary Open-Angle Glaucoma Patients.

To investigate the plasma lipoprotein subclasses in patients with primary open-angle glaucoma (POAG), a total of 20 Chinese POAG patients on intraocular pressure (IOP)-lowering treatment and 20 age-matched control subjects were recruited. Based on the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), the study subjects were divided into elevated- and normal-level subgroups. The plasma lipoprotein, lipoprotein subclasses, and oxidized LDL (oxLDL) levels were quantitatively measured. The discrimination potential of the lipoproteins was evaluated using the area under the receiver operating characteristic curve (AUC), and their correlation with clinical parameters was also evaluated. Compared to the control subjects with elevated TC and/or LDL-C levels, the levels of TC, LDL-C, non-high-density lipoprotein cholesterol (non-HDL), LDL subclass LDL3 and small dense LDL (sdLDL), and oxLDL were significantly higher in POAG patients with elevated TC and/or LDL-C levels. No differences in any lipoproteins or the subclasses were found between the POAG patients and control subjects with normal TC and LDL-C levels. Moderate-to-good performance of TC, LDL-C, non-HDL, LDL3, sdLDL, and oxLDL was found in discriminating between the POAG patients and control subjects with elevated TC and/or LDL-C levels (AUC: 0.710-0.950). Significant negative correlations between LDL3 and sdLDL with retinal nerve fiber layer (RNFL) thickness in the superior quadrant and between LDL3 and average RNFL thickness were observed in POAG patients with elevated TC and/or LDL-C levels. This study revealed a significant elevation of plasma lipoproteins, especially the LDL subclasses, in POAG patients with elevated TC and/or LDL-C levels, providing insights on monitoring specific lipoproteins in POAG patients with elevated TC and/or LDL-C.

Polygenic Risk Scores Driving Clinical Change in Glaucoma.

Glaucoma is a clinically heterogeneous disease and the world's leading cause of irreversible blindness. Therapeutic intervention can prevent blindness but relies on early diagnosis, and current clinical risk factors are limited in their ability to predict who will develop sight-threatening glaucoma. The high heritability of glaucoma makes it an ideal substrate for genetic risk prediction, with the bulk of risk being polygenic in nature. Here, we summarize the foundations of glaucoma genetic risk, the development of polygenic risk prediction instruments, and emerging opportunities for genetic risk stratification. Although challenges remain, genetic risk stratification will significantly improve glaucoma screening and management.

Glaucoma, Pseudoexfoliation and Hearing Loss: A Systematic Literature Review.

Purpose: To investigate the relationship between glaucoma, pseudoexfoliation and hearing loss (HL). Methods: A systematic literature search following PRISMA guidelines was conducted using the PubMed, Embase, Scopus and Cochrane databases from 1995 up to 28 August 2023. Results: Thirty studies out of the 520 records screened met the inclusion criteria and were included. Most articles (n = 20) analysed the association between pseudoexfoliation syndrome (XFS) and HL, showing XFS patients to have higher prevalence of sensorineural hearing loss (SNHL) at both speech frequencies (0.25, 0.5, 1 and 2 kHz), and higher frequencies (4 and 8 kHz) compared to controls in most cases. No significant differences in prevalence or level of HL between XFS and pseudoexfoliative glaucoma (XFG) were detected in most studies. Eight articles analysed the relationship between primary open-angle glaucoma (POAG) and HL. Overall, a positive association between the two conditions was highlighted across all studies except for two cases. Similarly, articles focusing on NTG and HL (n = 4) showed a positive association in most cases. The role of autoimmunity and, in particular, the presence of antiphosphatidylserine antibodies (APSA) in patients with NTG and HL suggested an underlying autoimmune or vascular mechanism contributing to their pathogenesis. Only one study analysed the relationship between angle-closure glaucoma (ACG) and HL, showing higher incidence of ACG in patients with SNHL compared to normal hearing controls. Conclusions: Most studies detected an association between XFS and HL as well as POAG/NTG/ACG and HL, suggesting the presence of a similar pathophysiology of neurodegeneration. However, given the strength of the association of XFS with HL, it remains unclear whether the presence of XFG is further associated with SNHL. Further research specifically targeted to assess the correlation between glaucoma, XFS and HL is warranted to provide a more comprehensive understanding of this association.

The association between perceived cause of glaucoma and illness perceptions.

Purpose: The perceived cause of disease is an important factor that has been linked with treatment outcomes but has not been fully assessed in primary open-angle glaucoma (POAG). This study assessed the accuracy of patients' perceived cause of POAG and identified associations between accuracy, illness perceptions, medication adherence, and quality of life (QoL). Methods: The Brief Illness Perception Questionnaire (BIPQ) was used to assess illness perceptions and asked patients to rank the three most important causes of their disease in order of importance. POAG risk factors recognized by the American Academy of Ophthalmology were used to code responses as accurate or inaccurate based on the following three methods: (1) coding any reported cause, regardless of rank, (2) coding only the first-ranked cause, and (3) coding and weighting all reported causes. Medication adherence was measured electronically. QoL was measured using the Glaucoma Quality of Life questionnaire. Mann-Whitney U test was used to detect differences in illness perceptions, medication adherence, and QoL between accuracy groups. Results: A total of 97 patients identified a cause of their POAG and were included in this analysis. A higher proportion of patients reported an accurate cause (86.6% using method 1, 78.4% using method 2, and 79.4% using method 3; all p < 0.001). Mean medication adherence was 86.0% ± 17.8 and was similar across accuracy groups (all p > 0.05). Using method 2 (p = 0.045) and method 3 (p = 0.028), patients who reported an accurate cause of their POAG believed that their illness would last for a longer time compared to patients who reported an inaccurate cause. Method 3 also revealed that patients who reported an accurate cause of their POAG had lower perceived understanding of their illness (p = 0.048) compared to patients who reported an inaccurate cause. There were no differences in QoL between accuracy groups (all p > 0.05). Conclusion: This study highlights the association between perceived cause of POAG and illness perceptions related to knowledge level and POAG duration. Future studies should assess associations between perceived cause of disease and other critical dimensions of illness perception.

Peripheral Blood B-Cell Subsets Frequency and Distribution and the BSF-2(IL-6) to CSIF:TGIF(IL-10) Ratio as Severity-Associated Signatures in Primary Open-Angle Glaucoma: A Case-Controlled Study.

Although primary open-angle glaucoma (POAG) is a major cause of blindness worldwide, patients' immune response and its relation to the disease course have not been fully unraveled in terms of analyses of circulating B-cell subsets, as well as the association of these subsets with the severity of POAG clinical features. SUBJECTS AND METHODS: Flow cytometry was used to determine B-cell subset frequencies from 30 POAG patients grouped by hierarchical cluster analysis or the mean deviation (MD) of the visual field (VF) and correlated with the patients' clinical and pathological data, as well as with BSF-2(IL-6) and CSIF:TGIF(IL-10), which were quantified in peripheral blood samples of patients and controls by ELISA. RESULTS: The total B-cell frequency was increased in the POAG group in comparison to the control group (n = 30). Frequencies of specific B-cell subsets, such as double-negative (DN) and naïve B-cell subsets, were increased in relation to the severity of the POAG disease. However, the unswitched memory B compartment subset decreased in the POAG group. Other non-typical B-cell subsets such as DN B cells also showed significant changes according to the POAG disease severity course. These differences allow us to identify POAG severity-associated inflammatory clusters in patients with specifically altered B-cell subsets. Finally, ocular parameters, biomarkers of inflammation, and other glaucoma-related or non-clinical scores exhibited correlations with some of these B-cell subpopulations. CONCLUSION: The severity of the POAG disease course is accompanied by changes in the B-cell subpopulation, namely, DN B cells. Furthermore, the existing relationship of the B-cell subset frequencies with the clinical and the inflammatory parameters BSF-2(IL-6), CSIF:TGIF(IL-10), and the BSF-2(IL-6) to CSIF:TGIF(IL-10) ratio suggests that these B lymphocyte cells could serve as potential molecular bio-markers for assessing POAG disease severity and/or progression.

Distal Nasal Part of the Visual Field and RNFL in Primary Open-Angle Glaucoma.

Purpose: The aim of this study was to compare changes in the conventionally undiagnosed distal nasal visual field with RNFL in patients with early primary open-angle glaucoma (POAG). Material and Methods: 59 eyes of 32 patients (18 women, 14 men) with early stage POAG were included. All eyes were found to have a normal visual field (fast threshold program of 50 degrees nasally and 22 degrees temporally) with the Medmont M700. Visual acuity was 1.0 (with a possible correction ±3 D), and they had no other ocular pathology except glaucoma. The visual field was subsequently examined with the same instrument by moving the fixation point 40 degrees temporally (spatially adaptive program) and simultaneously turning the head 10 degrees nasally. A total of 89 examination points were included using flicker stimuli in a range of 0-120 degrees nasally. Nerve fiber layer (RNFL) and vessel density (VD) was measured using the in-built software of the Avanti RTVue XR instrument. Using Pearson's correlation coefficient, the results of visual field examination with RNFL without and after correction (by subtracting VD from total RNFL value) in the superior-nasal (SN-5) and inferior-nasal (IN-8) segments were compared. Results: In all eyes, changes were found in the distal periphery of the nasal part of the visual field. No correlation was noted by comparison with RNFL. After adjusting RNFL for VD, we observed no correlation in the SN segment (5) (r=-0.03) and a very weak correlation in the IN segment (8) (r=-0.16). Conclusion: With a normal visual field tested by the rapid threshold glaucoma program, changes in the distal part of the nasal periphery of the visual field were found in the entire cohort and did not correlate with the RNFL and RNFL results after correction from VD.

Common Variants rs429358 and rs7412 in APOE Gene Are Not Associated with POAG in a Saudi Cohort.

Adult-onset glaucoma, an age-related neurodegenerative disease, is very prevalent among the elderly Arabs of Saudi origin. This study investigated the association between apolipoprotein E (APOE) gene variants (rs429358 and rs7412) and primary open-angle glaucoma (POAG) in Arabs of Saudi origin. A case-control genetic association study involving 179 POAG patients and 251 controls utilized Sanger sequencing to genotype APOE gene variants. The allele frequencies and genotype distributions for rs429358 and rs7412 did not show significant associations with POAG. The haplotype analysis revealed apoε3 (87.6% and 87.4%) as the most prevalent, followed by ε4 (2.8% and 3.6%) and ε2 (9.6% and 8.9%) in the controls and POAG patients, respectively. Although the ε2/ε3 genotype and ε2-carriers displayed a more than two-fold increased risk, statistical significance was not reached. Notably, these polymorphisms did not affect clinical markers, such as intraocular pressure and cup/disc ratio. The logistic regression analysis demonstrated no significant influence of age, sex, rs429358, or rs7412 polymorphisms on POAG. In conclusion, within the Saudi cohort, APOE variants (rs429358 and rs7412) do not appear to be associated with POAG and are not substantial risk factors for its development. However, additional population-based studies are required to validate these findings.

Early Outcomes of Combined Phacoemulsification and Ab Interno Tanito Microhook Trabeculotomy in Open-Angle Glaucoma.

PURPOSE: To study the early postoperative efficacy and safety of an Ab Interno microhook trabeculotomy (microLOT) combined with cataract surgery in patients with open-angle glaucoma. METHODS: This prospective, randomized, interventional study was conducted on consecutive patients with visually significant cataract and mild-moderate open-angle glaucoma. One hundred fourteen patients were included for analysis. The patients were randomized to undergo microhook trabeculotomy with phacoemulsification (group 1) or phacoemulsification alone (group 2). All patients were evaluated on postoperative day 1, 15, and 30, as well as 3, 6, and 12 months postoperatively. A P value < 0.05 was considered statistically significant. Baseline and follow-up visits were compared to determine significant differences in the number of antiglaucoma medications (AGMs), intraocular pressure (IOP), and best-corrected visual acuity. RESULTS: There were 57 patients in each group. The baseline characteristics were similar between the 2 groups, except the number of AGMs, which was greater in group 2. The mean preoperative IOP for group 1 (phaco-microLOT) was 26.5 mmHg ± 5.2 and group 2 (phaco-alone group) was 25.3 mmHg ± 3.1 which decreased to 12.5 mmHg ±3.6 (P < 0.001) and 20.0 mmHg ± 2.7(P < 0.001) at 12 months, respectively. Logarithm of the minimum angle of resolution visual acuity improved from 0.48 (interquartile range [IQR], 0.30-0.60) preoperatively to 0.00 (0.00-0.18) postoperatively (P < 0001) in group 1 and improved from 0.30 (IQR, 0.30-0.48) to 0.00 (0.00-0.00) in group 2 (P < 0.001). In group 1, the mean (standard deviation [SD]) AGM used preoperatively was 0.6 (0.9) which was significantly reduced to 0.2 (0.5) at 12 months postoperatively, whereas in group 2, at 12 months, the mean (SD) AGM used was reduced from 1.4 (0.6) to 1.1 (0.9). In group 1, 90.3% of eyes achieved complete success at the end of 1 year. The most common complication was hyphema, noted in 4 patients with 1 eye requiring an anterior chamber washout. CONCLUSION: Ab interno microhook trabeculotomy (microLOT) combined with phacoemulsification in patients with open-angle glaucoma is an efficacious procedure with relatively minimal complications. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Mendelian randomization study on the causal relationship between gut microbiota and primary open angle glaucoma / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To investigate the potential causal relationship between gut microbiota(GM)and primary open-angle glaucoma(POAG)based on a two-sample Mendelian randomization(MR)analysis.METHODS: The exposure data was derived from the Genome-Wide Association Studies(GWAS)of GM at the University of Bristol, while the outcome data for POAG was sourced from the MRC Integrative Epidemiology Unit(IEU)Open GWAS database. In this study, inverse variance weighted(IVW), MR Egger, weighted median(WM), Simple Mode, and Weighted Mode were analyzed to investigate the potential causal relationships between GM and POAG. IVW was used as the primary method for this study, and sensitivity analysis was conducted to assess the reliability of the MR analysis.RESULTS: The IVW analysis revealed that Butyrivibrio(OR=1.170, 95%CI: 1.057-1.295, P=0.002), Howardella(OR=1.188, 95%CI: 1.043-1.355, P=0.010), and LachnospiraceaeUCG001(OR=1.229, 95%CI: 1.016-1.485, P=0.033)were correlated with the risk of POAG. Conversely, Candidatus Soleaferrea(OR=0.810, 95%CI: 0.670-0.981, P=0.031), Ruminococcustorquesgroup(OR=0.656, 95%CI: 0.453-0.950, P=0.026), and RuminococcaceaeUCG013(OR=0.770, 95%CI: 0.598-0.990, P=0.041)were protective factors for POAG. Sensitivity analysis showed that there were no heterogeneity and pleiotropy among the instrumental variables.CONCLUSION: The MR study indicated a causal relationship between GM and POAG. Given the sight-threatening characteristic of POAG, early identification and intervention in the relative factors was significant for the prognosis of POAG.

Effect of genotype on individual response to the pharmacological treatment of glaucoma: a systematic review and meta-analysis.

The social impact of glaucoma is worth of note: primary open-angle glaucoma (POAG) is one of the leading causes of irreversible blindness worldwide, affecting some 68.56 million people with overall prevalence of 2.4%. Since one of the main risk factors for the development of POAG is the increase of intraocular pressure (IOP) causing retinal ganglion cells death, the medical treatment of POAG consists in the use of drugs endowed with neuroprotective effect and able to reduce IOP. These drugs include beta-blockers, prostaglandin analogues, carbonic anhydrase inhibitors, alpha or cholinergic agonists and rho kinase inhibitors. However, not all the patients respond to the same extent to the therapy in terms of efficacy and safety. Genetics and genome wide association studies have highlighted the occurrence of mutations and polymorphisms influencing the predisposition to develop POAG and its phenotype, as well as affecting the response to pharmacological treatment. The present systematic review and meta-analysis aims at identifying genetic variants and at verifying whether these can influence the responsiveness of patients to therapy for efficacy and safety. It follows the most updated Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 recommendations. The literature search was conducted consulting the most relevant scientific databases, i.e. PubMed/MEDLINE, Scopus, Web of Science and Public Health Genomics and Precision Health Knowledge Base up to June 14th, 2023. The search retrieved 1026 total records, among which eight met the eligibility criteria for inclusion in the analysis. The results demonstrated that the most investigated pharmacogenetic associations concern latanoprost and timolol, and that efficacy was studied more in depth than safety. Moreover, the heterogeneity of design and paucity of studies prompt further investigation in randomized clinical trials. In fact, adequately powered and designed pharmacogenetic association studies are needed to provide body of evidence with good certainty for a more appropriate use of medical therapy in POAG.PROSPERO registration: CRD42023434867.

Genetic Risk Assessment of Degenerative Eye Disease (GRADE): study protocol of a prospective assessment of polygenic risk scores to predict diagnosis of glaucoma and age-related macular degeneration.

BACKGROUND: Glaucoma and age-related macular degeneration (AMD) account for a substantial portion of global blindness. Both conditions are highly heritable, with recognised monogenic and polygenic inheritance patterns. Current screening guidelines lack decisive recommendations. Polygenic risk scores (PRS) allow for cost-effective broad population risk stratification for these conditions. The predictive potential of PRS could facilitate earlier diagnosis and treatment, and prevent unnecessary vision loss. METHODS: The Genetic Risk Assessment of Degenerative Eye disease (GRADE) study is a prospective study designed to generate high-quality evidence about the feasibility of PRS to stratify individuals from the general population, enabling identification of those at highest risk of developing glaucoma or AMD. The targeted recruitment is 1000 individuals aged over 50 years, from which blood or saliva samples will be used for genotyping and an individual PRS for glaucoma and AMD will be derived. Individuals with PRS values in the bottom decile (n = 100), top decile (n = 100) and middle 80% (n = 100) for both glaucoma and AMD will undergo a detailed eye examination for glaucoma and/or AMD. DISCUSSION: The primary objective will be to compare the prevalence of glaucoma and AMD cases between low, intermediate, and high PRS risk groups. We expect to find a higher prevalence of both diseases in the high PRS risk group, as compared to the middle and low risk groups. This prospective study will assess the clinical validity of a PRS for glaucoma and AMD in the general Australian population. Positive findings will support the implementation of PRS into clinical practice.

Comparative study of surgical outcomes of twin-site phacotrabeculectomy with mitomycin C in primary open-angle glaucoma versus primary angle-closure glaucoma.

Purpose: To compare the surgical outcomes of twin-site phacotrabeculectomy with Mitomycin C (MMC) in primary open-angle glaucoma (POAG) versus primary angle-closure glaucoma (PACG). Methods: Prospective, comparative, observational study. Patients with visually significant cataract and primary glaucoma were divided into two groups: POAG and PACG. They underwent twin-site phacotrabeculectomy with MMC and followed up on days 1, 15, 1 month, 6 months, and 12 months. Baseline and follow-up visits were compared to find the differences in intraocular pressure (IOP), antiglaucoma medications (AGM), success rates, anterior chamber depth (ACD), and axial length (AXL). Results: There were 50 eyes each in POAG and PACG groups. Mean IOP reduction from baseline to 12 months (21.22 ± 6.0 to 11.40 ± 2.8-POAG group vs 24.16 ± 7.6 to 12.42 ± 3.2-PACG group) was statistically significant in both groups (P < 0.001), but no significant difference between groups (P = 0.095). There was a statistically significant decline in the number of AGM in POAG [1.66 (0.7) to 0.38 (0.7), P < 0.001] and PACG [2.10 (0.7) to 0.70 (0.8), P < 0.001]; the decline was more in POAG (P = 0.012) at last visit. Probability of overall (complete and qualified) success at 12 months postop was 72.0% [95% confidence interval (CI): 57.4-82.4] in PACG and 84.0% (95% CI: 70.5-91.7) in POAG group. There was a significant increase in ACD and a decrease in AXL in both groups (P < 0.001). More interventions were required in the PACG group (38, P = 0.012). Conclusion: Phacotrabeculectomy with MMC causes a significant reduction in IOP and improvement in biometric parameters in both POAG and PACG. Patients with PACG required more postoperative interventions, while a lesser number of antiglaucoma medications were needed in POAG patients.