Search

Background: Glaucoma is a leading cause of vision impairment and permanent blindness. Primary open-angle glaucoma (POAG) is a prominent type of primary glaucoma; however, its cause is difficult to determine. This study aimed to analyze the serum lipid profile of Chinese POAG patients and assess its correlation with intraocular pressure (IOP)., Methods: The study included 1,139, 1,248, and 356 Chinese individuals with POAG, primary angle closure glaucoma (PACG), and controls, respectively. Peripheral whole blood samples were collected at the time of diagnosis. Enzymatic colorimetry was used to determine serum levels of different lipids: high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides, cholesterol, and very low-density lipoproteins (VLDL). Additionally, immunoturbidimetry was used to quantify serum levels of apolipoproteins A (APOA), B (APOB), E (APOE), and lipoprotein A [Lp(a)], while intraocular pressure (IOP) was measured in all patients with POAG., Results: After adjusting for age and sex, patients with POAG exhibited elevated serum levels of VLDL, APOA, and APOE but mitigated cholesterol levels compared with the control participants. Significantly lower serum triglyceride, VLDL, and Lp(a) levels were found in patients with PACG than in control participants. Serum cholesterol (P = 0.019; β = -0.75, 95% confidence interval [CI]: -1.38 - -0.12) and HDL levels (P < 0.001; β = -2.91, 95% CI: -4.58 - -1.25) were inversely linked to IOP in patients with POAG, after adjusting for age, sex, and ocular metrics. In addition, serum Lp(a) levels were correlated with the average IOP (P = 0.023; β = -0.0039, 95% CI: -0.0073 - -0.006) and night peak (P = 0.027; β = -0.0061, 95% CI: -0.0113 - -0.0008) in patients with POAG., Conclusions: Significantly different serum lipid and lipoprotein profiles were observed in POAG and PACG patients. This study highlighted the differences in serum lipid and lipoprotein levels among Chinese POAG patients and their relationship with IOP and IOP fluctuation. Serum lipid and lipoprotein profiles should be considered while evaluating glaucoma risk., (© 2024. The Author(s).)

Objective: Our study aimed to investigate the relationship between vascular endothelial growth factor (VEGF), NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory complex, erythropoietin (EPO) levels, and ocular hemodynamics in patients diagnosed with primary open-angle glaucoma (POAG)., Methods: This is a prospective observational study. Patients diagnosed with POAG at The Sixth Hospital of Wuhan hospital between November 2022 and February 2023were enrolled.The patients were categorized into three groups based on the average visual field defect (mean deviation, MD) value: severe injury group (MD > 12 dB, 93 cases), moderate injury group (7 ≤ MD ≤ 12 dB, 89 cases), and mild injury group (MD < 7 dB, 85 cases). The levels of VEGF, NLRP3 inflammatory complex, EPO, and ocular hemodynamics were compared among the groups. Furthermore, the relationship between VEGF, NLRP3, EPO levels, and ocular hemodynamics in patients with POAG was analyzed using Pearson correlation analysis. After adjusting for confounding factors such as age and gender, multivariate Logistic regression analysis was performed with the ocular hemodynamics indexes being used as dependent variables, and VEGF, NLRP3, ASC, Caspase-1, and EPO being used as independent variables., Results: A total of267 patients with POAG were enrolled. There were no significant differences in sex, age, body mass index, systolic blood pressure, diastolic blood pressure, smoking, alcohol consumption, and blood glucose between the two groups (P > 0.05). The levels of NLRP3, ASC, Caspase-1, and EPO in the severe and moderate injury groups were higher than those in the mild injury group, whereas the VEGF levels were lower in the severe and moderate groups compared to the mild group, showing significant differences (P < 0.05). The severe group exhibited higher levels of NLRP3, ASC, Caspase-1, and EPO than the moderate group, while the VEGF levels were lower in the severe group compared to the moderate group, showing significant differences (P < 0.05). The peak systolic velocity(PSV) and resistance index (RI) were higher in the severe and moderate groups than in the mild group, whereas the EDV was significantly lower in the severe and moderate groups compared to the mild group (P < 0.05). The severe group exhibited higher PSV and RI values compared to the moderate group, while the EDV was lower in the severe group compared to the moderate group, showing significant differences (P < 0.05). Pearson correlation analysis was performed to examine the relationship between VEGF, NLRP3, EPO levels, and ocular hemodynamics in patients with POAG. VEGF, NLRP3, ASC, Caspase-1, and EPO showed positive correlations with PSV and RI, and negative correlations with EDV in patients with POAG. Regression analysis showed that VEGF, NLRP3, ASC, Caspase-1 and EPO were significantly correlated with ocular hemodynamics in POAG (all P < 0.001)., Conclusion: We demonstrated that the levels of VEGF, NLRP3 inflammatory complex, and EPO were highly associated with ocular hemodynamics in patients diagnosed with POAG., (© 2024. The Author(s).)

Background and Objectives : Several studies suggest the complex relationship between Endothelin-1 (ET-1) levels with various types of glaucoma. This systematic review and meta-analysis explore ET-1 levels in plasma and aqueous humor among different types of glaucoma. Materials and Methods : A literature search (PubMed, ScienceDirect, Cochrane Library) was made up to April 2024 (PROSPERO: CRD42023430471). The results were synthesized according to PRISMA Guidelines. Results were presented as standardized mean differences (SMD) with 95% confidence intervals (CI). Results : A total of 2597 subjects (1513 patients with glaucoma vs. 1084 healthy controls) from 23 studies were included in a meta-analysis. Notably, patients with glaucoma reported significantly higher plasma levels of ET-1 compared to controls (SMD: 1.21, 95% CI: 0.59-1.82, p < 0.001). Particularly, plasma ET-1 levels were higher in primary open-angle glaucoma (POAG) (SMD: 0.87, 95% CI: 0.09-1.65, p < 0.05), normal-tension glaucoma (SMD: 0.86, 95% CI: 0.27-1.46, p = 0.05), and angle-closure glaucoma patients (SMD: 1.03, 95% CI: 0.43-1.63, p < 0.001) compared to healthy controls. Moreover, ET-1 aqueous humor levels were significantly higher in patients with glaucoma compared to controls (SMD: 1.60, 95% CI: 1.04-2.15, p < 0.001). In particular, aqueous humor levels were higher in POAG patients (SMD: 2.03 95% CI: 1.00-3.14, p < 0.001), and pseudoexfoliative glaucoma patients (SMD: 2.03, 95% CI: 1.00-3.07, p < 0.001) compared to controls. Conclusions : This meta-analysis indicates that elevated levels of ET-1 plasma and aqueous humor are significantly associated with different types of glaucoma. The pathogenesis of ET-1-related mechanisms may vary across different glaucoma types, indicating that possible therapeutic approaches targeting ET-1 pathways should be tailored to each specific glaucoma type.

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.

Purpose: We hypothesized that the effect of blood lipid-related metabolites on primary open-angle glaucoma (POAG) would differ according to specific lipoprotein particles and lipid sub-fractions. We investigated the associations of blood levels of lipoprotein particles and lipid sub-fractions with POAG., Design: Cross-sectional study., Participants: Individuals recruited for the baseline visit of the population-based Singapore Epidemiology of Eye Disease study (n = 8503)., Methods: All participants underwent detailed standardized ocular and systemic examinations. A total of 130 blood lipid-related metabolites were quantified using a nuclear magnetic resonance metabolomics platform. The analyses were conducted in 2 stages. First, we investigated whether and which lipid-related metabolites were directly associated with POAG using regression analyses followed by Bayesian network modeling. Second, we investigated if any causal relationship exists between the identified lipid-related metabolites, if any, and POAG using 2-sample Mendelian randomization (MR) analysis. We performed genome-wide association studies (GWAS) on high-density lipoprotein (HDL) 3 cholesterol (after inverse normal transformation) and used the top variants associated with HLD3 cholesterol as instrumental variables (IVs) in the MR analysis., Main Outcome Measure: Primary open-angle glaucoma., Results: Of the participants, 175 (2.1%) had POAG. First, a logistic regression model showed that total HDL3 cholesterol (negatively) and phospholipids in very large HDL (positively) were associated with POAG. Further analyses using a Bayesian network analysis showed that only total HDL3 cholesterol was directly associated with POAG (odds ratio [OR], 0.72 per 1 standard deviation increase in HDL3 cholesterol; 95% confidence interval [CI], 0.61-0.84), independently of age, gender, intraocular pressure (IOP), body mass index (BMI), education level, systolic blood pressure, axial length, and statin medication. Using 5 IVs identified from the GWAS and with the inverse variance weighted MR method, we found that higher levels of HDL3 cholesterol were associated with a decreased odds of POAG (OR, 0.91; 95% CI, 0.84-0.99, P = 0.021). Other MR methods, including weighted median, mode-based estimator, and contamination mixture methods, derived consistent OR estimates. None of the routine lipids (blood total, HDL, or low-density lipoprotein [LDL] cholesterol) were associated with POAG., Conclusions: Overall, these results suggest that the relationship between HDL3 cholesterol and POAG might be causal and specific, and that dysregulation of cholesterol transport may play a role in the pathogenesis of POAG., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To establish if SNPs in TNF-α and IL-2 genes are associated with Primary Open-Angle Glaucoma (POAG) in African Americans (AA). We also determined whether plasma TNF-α and IL-2 levels could serve as biomarkers for POAG in African Americans using sandwich enzyme-linked immunosorbent assay., Methods: A single SNP association analysis was performed to investigate the association between potential gene variants in TNF-α and IL-2 genes and POAG in the AA population. Plasma samples from 190 African Americans (72 from normal subjects and 118 POAG cases) were obtained for TNF- α studies and 367 samples (135 from normal subjects and 232 from POAG cases) were obtained for IL-2 studies. TNF-α levels and IL-2 levels were measured by sandwich enzyme-linked immunosorbent assays (ELISA) and analyzed to see if they reached significance in cases with POAG and endophenotypes when compared to normal subjects., Results: The SNP, rs1800630, in TNF-α gene was found to be marginally associated with POAG. SNPs in IL-2 gene were not associated with POAG in the case-control analysis. No significant difference was found between TNF-α levels and IL-2 levels in normal and POAG case subjects in our study. IL-2 levels were inversely correlated with high IOP in POAG cases., Conclusions: Although we found a marginal SNP association of TNF-α, assessing the expression levels of TNF-α and IL-2 may serve as promising biomarkers for African American POAG. Further investigation is needed to determine if POAG can be subdivided into more specified cohorts of the disease, which may affect plasma cytokine levels differently.

Background: IL6 is an important candidate gene implicated in the pathogenesis of glaucoma. The present study assessed the genetic association of -174G > C and -572G > C polymorphisms in the IL6 promoter region with primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) in a north Indian Punjabi cohort., Methods: 910 subjects (313 POAG, 148 PACG cases and 449 controls) were recruited. Genotyping was done by TaqMan assays. Genetic association was tested under different genetic models using Plink. Diplotype and linkage disequilibrium (LD) analysis was done through Haploview. Association of clinical parameters with the genotypes was assessed by one-way ANOVA. Adjustment for potential confounding variables was done by binary logistic regression. IL6 levels were measured in POAG patients and controls., Results: 572G > C variant showed marginal difference in genotype frequency between pooled cases and POAG subgroup with respect to controls (p = 0.042; OR = 1.33; and p = 0.041; OR = 1.37). The GC genotype conferred 1.37-fold protection under codominant model in POAG cases (p = 0.034, OR = 1.37, 95% CI = 1.02-1.85; p corr  = 0.025, OR = 1.45, 95% CI = 1.04-2.02). The mean value for IOP was elevated among cases having 'CC' genotype at the -572G > C locus (p = 0.037). Lower levels of IL6 were detected in POAG patients in plasma samples (p = 0.0001)., Conclusion: The study reports suggestive evidence for -572G > C variant in IL6 in affecting genetic susceptibility to POAG in the targeted North Indian Punjabi cohort. A correlation of IL6 levels in aqueous humor (AH) and systemic circulation in POAG was observed, the functional and diagnostic relevance of which may be further investigated., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Purpose: Identify differentially expressed microRNAs (miRNAs) in aqueous humor (AH) and blood of primary open-angle glaucoma (POAG) patients by using small RNA sequencing. These may provide insight into POAG pathophysiology or serve as diagnostic biomarker., Methods: AH and plasma of nine POAG patients and 10 cataract control patients were small RNA sequenced on Illumina NovaSeq 6000. Identification of gene transcripts targeted by differentially expressed miRNAs was done with miRWalk and MirPath. These targets were used for pathway analysis and Gene Ontology enrichment. Diagnostic potential was evaluated by receiver operating characteristics analysis., Results: We identified 715 miRNAs in plasma and 62 miRNAs in AH. Plasma miRNA profile did not differ between POAG and control. In contrast, in AH, seven miRNAs were differentially expressed. Hsa-miR-30a-3p, hsa-miR-143-3p, hsa-miR-211-5p, and hsa-miR-221-3p were upregulated, whereas hsa-miR-92a-3p, hsa-miR-451a, and hsa-miR-486-5p were downregulated in POAG. Compared to previous studies, hsa-mir-143-3p, hsa-miR-211-5p, and hsa-miR-221-3p were reported previously, strengthening their involvement in POAG whereas hsa-miR-30a-3p, hsa-miR-92a-3p, and hsa-miR-486-5p are implicated in POAG for the first time. Identified gene transcripts were involved in several pathways, some implicated in glaucoma before (e.g., TGF-β and neurotrophin signaling), whereas others are new (e.g., prolactin and apelin signaling). In respect to diagnostics, AH concentration of hsa-mir-143-3p had an area under the curve (AUC) of 0.889. Combined with hsa-miR-221-3p, AUC improved to 0.96., Conclusions: Small RNA sequencing identified seven differentially expressed miRNAs in AH of POAG patients. The differentially expressed miRNAs may be useful as POAG biomarkers or could become targets for new therapeutic strategies.

Aim: Recently, the level of growth differentiation factor 15 (GDF-15) in blood, was proposed as biomarker to detect mitochondrial dysfunction. In the current study, we evaluate this biomarker in open-angle glaucoma (OAG), as there is increasing evidence that mitochondrial dysfunction plays a role in the pathophysiology of this disease., Methods: Plasma GDF-15 concentrations were measured with ELISA in 200 OAG patients and 61 age-matched controls (cataract without glaucoma). The OAG patient group consisted of high tension glaucoma (HTG; n = 162) and normal tension glaucoma (NTG; n = 38). Groups were compared using the Kruskal-Wallis nonparametric test with Dunn's multiple comparison post-hoc correction. GDF-15 concentration was corrected for confounders identified with forward linear regression models., Results: Before correcting for confounders, median plasma GDF-15 levels was significantly lower in the combined OAG group (p = 0.04), but not when analysing HTG and NTG patients separately. Forward linear regression analysis showed that age, gender, smoking and systemic hypertension were significant confounders affecting GDF-15 levels. After correction for these confounders, GDF-15 levels in OAG patients were no longer significantly different from controls. Subgroup analysis of the glaucoma patients did not show a correlation between disease severity and plasma GDF-15, but did reveal that for NTG patients, intake of dietary supplements, which potentially improve mitochondrial function, correlated with lower plasma GDF-15., Conclusion: The present study suggests that plasma GDF-15 is not suited as biomarker of mitochondrial dysfunction in OAG patients., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Agonistic β2-adrenergic receptor autoantibodies (β2-agAAb) have been observed in sera of patients with ocular hypertension and open-angle glaucoma (OAG). They target the β2-receptors on trabecular meshwork, ciliary body and pericytes (Junemann et al. 2018; Hohberger et al. 2019). In addition to their influence on the intraocular pressure, an association to retinal microcirculation is discussed. This study aimed to investigate foveal avascular zone (FAZ) characteristics by en face OCT angiography (OCT-A) in glaucoma suspects and its relationship to β2-agAAb status in patients with OAG., Material and Methods: Thirty-four patients (28 OAG, 6 glaucoma suspects) underwent standardized, clinical examination including sensory testing as white-on-white perimetry (Octopus G1, mean defect, MD) and structural measures as retinal nerve fibre layer (RNFL) thickness, neuroretinal rim width (BMO-MRW), retinal ganglion cell layer (RGCL) thickness, and inner nuclear layer (INL) thickness with high-resolution OCT. FAZ characteristics were measured by OCT-A scans of superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). FAZ-R was calculated (area FAZ (SVP)/area FAZ (ICP)). Using cardiomyocyte bioassays we analysed serum samples for the presence of β2-agAAb., Results: (I) Total mean FAZ area [mm2]: 0.34±0.16 (SVP), 0.24±0.12 (ICP), and 0.49±0.24 (DCP); mean FAZ-R 1.58±0.94. No correlation was seen for FAZ-R with MD, RNFL, BMO-MRW, RGCL thickness and INL thickness (p>0.05). (II) ß2-agAAb have been observed in 91% patients and showed no correlation with MD, RNFL, BMO-MRW, RGCL thickness and INL thickness (p>0.05). (III) FAZ-R correlated significantly with the β2-agAAb-induced increase of the beat rate of cardiomyocyte (p = 0.028)., Conclusion: FAZ characteristics did not correlate with any glaucoma associated functional and morphometric follow-up parameter in the present cohort. However, level of β2-agAAb showed a significantly correlation with FAZ-ratio. We conclude that β2-agAAb might be a novel biomarker in glaucoma pathogenesis showing association to FAZ-ratio with OCT-A., Competing Interests: Hohberger B, none; Hosari S, none; Wallukat G, Berlin Cures (emblyoyed), patent EP1832600A1: Peptides against autoantibodies associated with glaucoma and use of these peptides; Kunze R, patent EP1832600A1: Peptides against autoantibodies associated with glaucoma and use of these peptides; Krebs J, none; Müller M,none; Hennig T, none; Lämmer R, none; Horn F, none; Muñoz L.E., none; Herrmann M, patent EP1832600A1: Peptides against autoantibodies associated with glaucoma and use of these peptides; Mardin C, none. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: Agonistic β 2-adrenergic receptor autoantibodies ( β 2-agAAbs) were recently observed in sera of patients with ocular hypertension (OHT), primary (POAG), and secondary open-angle glaucoma (SOAG), yet not in healthy controls (HCs). It was the aim of the present study to investigate the presence of β 2-agAAb in aqueous humor (AH) samples of OAG patients and to correlate these with the corresponding β 2-agAAb serum data., Material and Methods: Thirty-nine patients (21 male, 18 female) were recruited from the Department of Ophthalmology, University of Erlangen-Nürnberg: twenty-one POAG, 18 SOAG. Aqueous humor samples were collected during minimal invasive glaucoma surgery. Serum and AH samples were analyzed for β 2-agAAb by a bioassay quantifying the beating rate of cultured cardiomyocyte (cut-off: 2 U)., Results: Thirty-six of 39 (92.3%) and 34 of 39 (87.2%) of OAG patients showed a β 2-agAAb in their sera and AH samples, respectively. All β 2-agAAb AH-positive OAG patients were also seropositive. We also observed a β 2-agAAb seropositivity in 95 and 89% of patients with POAG and SOAG, respectively. Beta2-agAAbs were seen in 86% (POAG) and 78% (SOAG) of AH samples. The β 2-agAAb adrenergic activity was increased in the AH of patients with POAG (6.5 ± 1.5 U) when compared with those with SOAG (4.1 ± 1.1 U; p = 0.004). Serum β 2-agAAb adrenergic activity did not differ between the cohorts [POAG (4.5 ± 1.5 U); SOAG (4.6 ± 2.1 U; p=0.458)]. No correlation of the beating rates were observed between serum and AH samples for group and subgroup analyses., Conclusion: The detection of β 2-agAAb in systemic and local circulations supports the hypothesis of a direct functional impact of these agAAbs on ocular G-protein coupled receptors. The high prevalence of β 2-agAAb in serum and AH samples of patients with POAG or SOAG suggests a common role of these AAbs in the etiopathogenesis of glaucoma, independent of open-angle glaucoma subtype., Competing Interests: RK, patent EP1832600A1; MH, patent EP1832600A1; and GW, Berlin Cures, patent EP1832600A1. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hohberger, Wörn, Lämmer, Mahajan, Mardin, Schötzer-Schrehardt, Kunze, Herrmann and Wallukat.)

Introduction: We recently performed a combined analysis of publicly available proteomic studies of aqueous humor (AH) of patients with primary open angle glaucoma (POAG). This analysis revealed changes in complement protein concentrations in the AH of progressive POAG patients, which suggested that the complement system may play a role in POAG progression. As the proteomic studies could not provide information on the activity of the complement system, we addressed this question in the current study., Methods: Blood serum and AH were obtained from 30 patients: 10 progressive POAG, 10 stable POAG and, as controls, 10 cataract patients. Glaucoma patients with a visual field Mean Deviation (MD) change of at least 1.0 dB/year were considered progressive; a MD change of less than 0.5 dB/year was considered stable. The ratio between the levels of complement factors C3a and C3 was used as indicator for activation of the complement cascade. The factors were measured with commercially available ELISA kits., Results: AH levels of complement factors C3 and C3a did not significantly differ between groups. In serum, complement factor C3 did not differ between groups whereas C3a was significantly elevated in progressive POAG patients compared to controls (p < 0.05). The resulting complement C3a/C3 ratio was significantly higher in progressive POAG patients in both AH (p < 0.05) and serum (p < 0.01), and this ratio significantly correlated between the two body fluids (p < 0.001). Furthermore, there was a strong correlation between disease progression and C3a/C3 activation ratio both in AH (p < 0.01) and in serum (p < 0.001). The higher the complement C3a/C3 ratio, the faster the disease progression., Conclusion: Significant increases in AH and serum complement C3a/C3 ratios were observed in progressive POAG patients but not in stable POAG patients. Furthermore, the complement C3a/C3 ratio correlated strongly with the rate of disease progression in both AH and serum. These findings suggest that activation of the complement system plays a role in glaucoma progression and that progressive glaucoma patients may have systemic changes in complement activation., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Evidence for immunologic contribution to glaucoma pathophysiology is steadily increasing in ophthalmic research. Particularly, an altered abundance of circulating autoantibodies to ocular antigens is frequently observed. Here, we report an analysis of autoantibody abundancies to selected antigens in sera of open-angle glaucoma patients, subdivided into normal-tension glaucoma ( N = 31), primary open-angle glaucoma ( N = 43) and pseudoexfoliation glaucoma ( N = 45), vs. a non-glaucomatous control group ( N = 46). Serum samples were analyzed by protein microarray, including 38 antigens. Differences in antibody levels were assessed by ANOVA. Five serological antibodies showed significantly altered levels among the four groups ( P < 0.05), which can be used to cluster the subjects in groups consisting mainly of PEXG or POAG/NTG samples. Among the altered autoantibodies, anti-Clathrin antibodies were identified as most important subgroup predictors, enhancing prospective glaucoma subtype prediction. As a second aim, we wanted to gain further insights into the characteristics of previously identified glaucoma-related antigens and their role in glaucoma pathogenesis. To this end, we used the bioinformatics toolset of Metascape to construct protein-protein interaction networks and GO enrichment analysis. Glaucoma-related antigens were significantly enriched in 13 biological processes, including mRNA metabolism, protein folding, blood coagulation and apoptosis, proposing a link of glaucoma-associated pathways to changes in the autoantibody repertoire. In conclusion, our study provides new aspects of the involvement of natural autoimmunity in glaucoma pathomechanisms and promotes advanced opportunities toward new diagnostic approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Beutgen, Pfeiffer and Grus.)

Purpose: The aim of this study was to measure serum levels of brain-derived neurotrophic factor (BDNF) in Japanese patients with primary open angle glaucoma (POAG) and normal tension glaucoma (NTG)., Methods: This was a prospective observational study of serum BDNF levels in 78 patients who underwent cataract surgery or trabeculectomy (27 glaucoma patients and 51 non-glaucoma cataract patients as controls). Patient age was 68.8 ± 11.1 years (mean ± standard deviation; range 35-86 years). The numbers of patients with POAG and NTG were 16 and 11, respectively. POAG was diagnosed by intraocular pressure measurement, gonioscopy, optic nerve head change, and presence of a visual field defect., Results: Serum BDNF concentration was significantly lower in the glaucoma group (including both POAG and NTG) than in the control group (7.2 ± 3.6 ng/mL vs. 12.2 ± 9.3 ng/mL, p=0.004). Serum BDNF concentration was lower in early glaucoma than in moderate glaucoma. There was no correlation between serum BDNF concentration and age. When patients with NTG and POAG were compared, serum BDNF concentration was lower in the former. Serum BDNF concentration was not significantly correlated with glaucoma parameters, including optical coherence tomography and visual field defects., Conclusion: This is the first study to investigate serum BDNF concentration in glaucoma patients in Japan. Future studies should evaluate the role of BDNF as a potential biomarker of glaucoma.

Precis: Serum netrin-1 levels are significantly lower in patients with pseudoexfoliation syndrome (PES) and pseudoexfoliative glaucoma (PEG) compared with the control group., Purpose: To investigate serum netrin-1 levels in PES and PEG patients and to determine the relevance of this molecule in the etiopathogenesis of PES-related and PEG-related diseases., Materials and Methods: This prospective study included 29 PES and 17 PEG patients in the study groups and age-sex matched 47 cataract patients without pseudoexfoliative accumulation as a control group. Serum netrin-1 levels were measured by enzyme-linked immunosorbent assay., Results: Serum netrin-1 level was significantly lower in the PES and PEG groups compared with the control group (P=0.007). Multinominal logistic regression analysis was performed in terms of netrin-1 levels ≤712.9 pg/mL, >712.9 pg/mL and sex which may affect PES and PEG. It were found that netrin-1 was a significant negative predictor for PES (odds ratio, 3.45; 95% confidence interval, 1.230-9.716; P=0.019) and PEG (odds ratio, 3.57; 95% confidence interval, 1.008-12.669; P=0.049), respectively., Conclusions: Decreased serum netrin-1 levels were detected in PES and PEG patients, similar to atherosclerosis and Alzheimer disease. Inflammation lays behind in the common pathogenesis of these diseases. Therefore, netrin-1 promises a potential anti-inflammatory role.

Purpose: To compare the plasma levels of hydrogen sulfide (H 2 S), homocysteine (Hcy), and L-cysteine (Cys) among primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), ocular hypertension (OHT), and normal individuals. To explore associated factors and evaluate their diagnostic abilities in glaucoma. Methods: POAG, NTG, OHT, and normal subjects were recruited from Ruijin Hospital between December 2016 and December 2018. All subjects underwent thorough ophthalmological examinations, and fasting venous blood was taken to determine the concentrations of H 2 S, Hcy, and Cys. Results: Forty-two POAG, 20 NTG, 52 OHT, and 78 controls were enrolled. The H 2 S levels in POAG group were significantly lower than those in OHT group ( P  = 0.036) and normal group ( P  < 0.001), while the Hcy and Cys levels in POAG and NTG groups were significantly higher ( P  = 0.007-0.043). The concentrations of H 2 S, Hcy, and Cys in glaucoma patients with different stages were not significantly different (all P  > 0.05). POAG patients with longer duration of diagnosis had lower concentrations ( P  = 0.026, P  = 0.001, P  < 0.001), but no significant differences in NTG patients (all P  > 0.05). The Hcy and Cys levels in NTG patients showed negative but weak correlations with mean deviation ( r  = -0.450, P  = 0.047; r  = -0.478, P  = 0.033). All these concentrations showed significant but poor diagnostic values in POAG-Normal group [area under curve (AUC) = 0.642-0.721, P  < 0.05]. The H 2 S level showed poor diagnostic power in POAG-OHT group (AUC = 0.657, P  < 0.01). Conclusion: Decreased levels of H 2 S and increased levels of Hcy and Cys may be associated with glaucoma, especially in POAG. However, the H 2 S/Hcy metabolic pathway is not sufficiently sensitive to be used as a reliable biomarker in glaucoma.

Aims: This study aimed to compare the serum thiol-disulfide homeostasis, total antioxidant status (TAS), and total oxidant status (TOS) in patients with pseudoexfoliation glaucoma (PEG) patients, primary open-angle glaucoma (POAG) patients, and healthy individuals (control)., Methods: Ninety subjects were included in this study. Three groups were separated as PEG, POAG, and control. All groups were chosen to be similar in terms of age and gender. Blood samples were obtained following an overnight fasting state and were collected on the ice at 4°C. The serum samples were separated from the cells by centrifugation at 3000 rpm for 15 min and were stored at -80°C. Serum samples analyzed for TAS and TOS, native thiol, total thiol, disulfide, and native thiol/disulfide ratio., Results: TAS and TOS levels of PEG patients were 1.2892 ± 0.0905 mmol/L; 5.0191 ± 2.7722 μmol/L, respectively. TAS and TOS levels of POAG patients were 1.2741 ± 0.1252 mmol/L; 4.1674 ± 1.7723 μmol/L, respectively. TAS and TOS levels of the control group were 2.3414 ± 0.1409 mmol/L; 4.0931 ± 0.1107 μmol/L, respectively. The TAS level was significantly lower in PEG and POAG groups compared to control. TOS level showed no significant differ ¬ ence between PEG, POAG, and control groups (P > 0.05). The mean serum total thiol and native thiol levels were significantly lower in patients with PEG compared to POAG and control group; there was no significant difference between the POAG and control group (P > 0.05). The mean serum disulfide level was significantly lower in patients with PEG compared to POAG (P = 0.018)., Conclusion: Low levels of TAS were observed in patients with glaucoma, which was likely a response to the increased oxidative stress observed in these patients. While total thiol and native thiol levels were higher in the PEG group, the disulfide level was higher in the POAG group. TAS and TOS levels showed no significant difference between POAG and PEG groups., Competing Interests: None

Background: The level of fasting plasma glucose (FPG) is positively associated with intraocular pressure. Diabetes causes early structural changes of retina, especially on ganglion cell layer. In this regard, the FPG level itself may also show an independent association with open angle glaucoma (OAG) development in general population. Herein, we investigate the association of the FPG level with the incidence of OAG., Methods: Using nationally representative data from the Korean National Health Insurance System, 374,376 subjects ≥40 years of age without OAG who underwent health examinations from 2009 to 2013 were enrolled and followed to the end of 2014. Incident cases of OAG using the International Classification of Diseases 10 codes and medication information were analyzed based on the levels of FPG., Results: Subjects with the highest FPG level (≥160 mg/dL), compared with the lowest level (<80 mg/dL), showed a higher hazard ratio (HR) [2.189; 95% confidence interval (CI): 1.779-2.695; P for trend < 0.001] for OAG after adjustments for age and sex. This result persisted after further adjustments for the presence of type 2 diabetes, current smoking, drinking, and exercise habits, diastolic blood pressure, body mass index (BMI), and total cholesterol level (HR: 1.588; 95% CI: 1.268-1.989; P for trend < 0.001). The positive association between the FPG level and the incidence of OAG was distinct in subjects 40-64 years of age, those with a BMI <25 kg/m2, and those without hypertension (HR 2.022; 95% CI: 1.494-2.736; P for trend <0.001: HR 1.817; 95% CI: 1.372-2.407; P for trend < 0.001: HR 1.706; 95% CI: 1.180-2.467; P for trend <0.001, respectively)., Conclusions: This nationwide population-based cohort study showed that the fasting glucose was associated with an increased risk of OAG. These findings suggest that subjects with high FPG levels require special attention when screening for glaucoma., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The aim of this study was to evaluate thiol/disulfide homeostasis and ischemia-modified albumin levels with primary open-angle glaucoma, ocular hypertension, and control group; also to interpret the correlation between these biochemical parameters and retinal nerve fiber layer analysis., Material and Methods: In a prospective cross-sectional study, 30 primary open-angle glaucoma cases, 30 ocular hypertension cases, and 30 control subjects were included in the study. Native thiol, total thiol, and disulfide measurements and disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios were evaluated as thiol-disulfide homeostasis. Albumin and ischemia-modified albumin parameters were also evaluated. All cases underwent detailed ophthalmologic examination including visual acuity, retinal nerve fiber layer via optical coherence tomography, intraocular pressure, and central corneal thickness measurements and visual field analysis by 24-2 Swedish Interactive Threshold Algorithm (SITA) Standard visual field test., Results: Primary open-angle glaucoma group had significantly higher ischemia-modified albumin values than ocular hypertension and control group (p < 0.001). Native thiol and total thiol values of control group were statistically higher than those of primary open-angle glaucoma and ocular hypertension groups. The correlation between the temporal retinal nerve fiber layer value and ischemia-modified albumin, disulfide/native thiol, and disulfide/total thiol values of the primary open-angle glaucoma patients included in the study was moderate correlation in negative direction (r = -0.46, r = -0.39, r = -0.39, respectively), whereas there was a statistically significant moderate correlation in positive direction between the native thiol/total thiol values (r = 0.39) (p < 0.05)., Conclusion: These findings have reinforced the role of oxidative stress in the etiopathogenesis of primary open-angle glaucoma, suggesting that the thinning retinal nerve fiber layer may be associated with oxidative stress in favor of prooxidant shift.

PRéCIS:: Apelin and asymmetric dimethylarginine (ADMA) concentrations, affecting the nitric oxide pathway, were different in the patient group compared with the control subjects. These 2 molecules may have potential effects in vascular pathologies and their possible role in predisposition to vascular comorbidities in exfoliation syndrome (XFS) or exfoliative glaucoma (XFG)., Purpose: To evaluate apelin and ADMA levels in serum samples from patients with XFS or XFG compared with healthy control subjects., Methods: Serum ADMA and apelin concentrations were evaluated from 36 and 32 XFS patients; 27 and 24 XFG patients; and 34 and 30 healthy controls, respectively. Subjects without systemic disease (including diabetes mellitus, hypertension, coronary artery disease, obesity) were included in the study and body mass index was calculated in all participants. An enzyme-linked immunosorbent assay and high-performance liquid chromatography were used to determine serum apelin and ADMA concentrations. Independent sample t test, χ test, analysis of variance test, and Pearson test were used for statistical analysis., Results: Mean serum apelin levels of XFG, XFS, and control group were 1063.3±373.4, 1196.7±433.7, and 1343.3±405.1 ng/mL, respectively. Patients with XFG demonstrated significantly lower level of apelin versus controls (P=0.034). Mean serum ADMA concentration was significantly greater in XFS subjects (2.05±0.98 µmol/L) compared with normal controls (1.57±0.58 µmol/L) (P=0.042). No association was detected between ADMA and apelin concentrations and age, sex, and body mass index for both XFS and XFG groups., Conclusions: Significant alterations in serum levels of apelin and ADMA may suggest potential effects in vascular pathologies and a possible role in predisposition to vascular comorbidities in XFS/XFG.

To investigate the association between systemic nitrotyrosine (NT) levels and primary angle-closure glaucoma (PACG) and primary open-angle glaucoma (POAG) and the mechanism involved. A case control study was conducted in the Department of Ophthalmology & Visual Science, Eye & ENT Hospital, Fudan University from April 2017 to December 2017. A total of 400 participants were consecutively recruited into this study (100 PACG, 100 POAG and 200 controls). Multivariable logistic regression analysis was performed to identify the association between serum NT level and PACG or POAG. Clinical results were validated in cell and animal models. Among 200 glaucoma patients, 101 (50.5%) were women; the age was 57.07 ± 14.51 years. 106 (53%) control participants were women and age was 58.34 ± 14.04 years. Serum levels of NT in PACG and POAG patients are significantly higher than controls (1808.53 ± 417.76 nmol/L vs. 1270.62 ± 454.60 nmol/L, p < 0.001; 1718.63 ± 437.29 nmol/L vs. 1258.38 ± 460.72 nmol/L, p < 0.001). Further, elevated serum NT level increases the risk of developing PACG (OR = 1.003, 95% CI: 1.002 to 1.004, p < 0.001) and POAG (OR = 1.002, 95% CI: 1.002 to 1.003, p < 0.001). Consistent with the clinical data, serum and aqueous humour NT levels are significantly higher in caveolin 1 knockout (Cav1 KO) mice, an animal model of glaucoma. More importantly, peroxynitrite (PN) scavenger MnTMPyP and its transduction molecule PARP inhibitor significantly reduce intraocular pressure in Cav1 KO mice. Our data show for the first time that NT is a systemic risk factor and local treatment target of glaucoma., Competing Interests: Declaration of competing interest No conflicting relationship exists for any author., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Glaucoma is the irreversible vision loss and contributes second leading cause of blindness worldwide. Matrix metalloproteinase-9 (MMP-9) is involved with remodeling and destruction of extracellular matrix. Elevated MMP-9 levels and various functional variants of MMP-9 have been associated with glaucoma in different population. In the current investigation, we tested association of MMP-9 common variants with different clinical categories of glaucoma in Chinese population., Materials and Methods: We enrolled total of 396 glaucoma patients those reported to hospital comprising of 212 primary angle closure glaucoma (PACG) cases and 184 primary open-angle glaucoma POAG patients. In addition, 329 normal individuals from similar geographical areas were enrolled as healthy controls. Five common single nucleotide polymorphisms (rs3918242, rs3918254, rs2250889, rs3918249, and rs17576) were genotyped by PCR-RFLP. Plasma levels of MMP-9 were quantified by ELISA., Results: Heterozygotes (GC) and allele "G" for rs2250889 polymorphism were more frequent in PACG cases compared with healthy controls (GC: P < .0001, OR = 2.26; G: P < .0001, OR = 1.19). Similarly, heterozygous mutant and minor allele for rs3918242 polymorphism were more prevalent in POAG in comparison with healthy controls. Interestingly, distribution of rs17576 variant was statistically higher in both PACG and POAG cases than healthy controls. Furthermore, analysis of plasma MMP-9 with MMP-9 polymorphisms revealed significant association of rs2250889, rs3918242, and rs17576 with plasma levels of the protein., Conclusions: MMP-9 mutants are associated with elevated plasma MMP-9 and predisposed to development of glaucoma., (© 2019 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals, Inc.)

The gut microbiota (GM) and its influence on host metabolism are considered to be an environmental factor that contributes to the progression of many immune and neurodegenerative diseases. However, the features of the GM and serum metabolites in Primary open-angle glaucoma (POAG) patients have not been clearly elucidated. The purpose of this research is to explore the gut microbial composition and serum metabolic phenotype in POAG patients. 16S rRNA V4 genes of bacteria from the fecal samples of 30 POAG patients and 30 healthy subjects were sequenced by the Illumina MiSeq platform and then analyzed by QIIME. Their serum samples were analyzed by gas chromatography/mass spectrometry (GC-MS)-based metabolomics. The association between gut microbial species and host circulating metabolites and clinical phenotypes was also analyzed. Compared with controls, f Prevotellaceae, g unidentified Enterobacteriaceae, and s Escherichia coli increased the most in POAG patients, whereas g Megamonas and s Bacteroides plebeius significantly decreased in POAG patients. The alteration of the endogenous metabolomic profile in POAG patients included five amino acids or dipeptides, two hormone derivates, one purine derivative, one bile acid derivative and one organic acid. It also showed that citric acid was positively correlated with Megamonas, whereas L-γ-Glutamyl-L-alanine, MHPG, cholic acid glucuronide and hypoxanthine were negatively correlated with Megamonas. Mean visual acuity was negatively correlated with Blautia, mean VF-MD was negatively correlated with Faecalibacterium, and average RNFL thickness was positively correlated with Streptococcus. Our results revealed that there was a distinct difference in GM composition and serum metabolic phenotype between POAG patients and healthy individuals. This finding suggests the potential correlations between the GM and serum metabolites in the pathogenesis of glaucoma and thus provides new insight into the GM-targeted interventions of this disease., Competing Interests: Declaration of competing interest All authors claimed there were no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Glaucoma is an optic neuropathy induced by many factors. Vascular dysfunction is involved in the mechanism underlying glaucoma., Aim: To determine the involvement of nitric oxide (NO), which is implicated in the regulation of ocular blood flow, in primary open angle glaucoma (POAG). Furthermore, lactate and uric acid (UA) levels were investigated., Methods: Concentrations of NO, UA and lactate in plasma and aqueous humor (AH) were measured in 214 Tunisian patients (100 patients with POAG and 114 subjects with cataract as control group). NO metabolites, nitrate and nitrite (NOx) production were determined using the Griess reaction. UA and lactate concentrations were measured using enzymatic- colorimetric methods., Results: NOx concentrations in patients with POAG were significantly lower compared to cataract group in plasma (5.23±1.55 µmol/L vs 18.35±6.87 µmol/L, p=0.01) and AH (20.54±7.41 µmol/L vs 45.25±10.92 µmol/L, p=0.02). Plasma and AH levels of lactate and UA were significantly higher in glaucoma patients than in control subjects., Conclusions: In the present study, decreased NO and increased UA and lactate levels were found in the AH and plasma of POAG patients compared to control subjects. These data suggest a possible involvement of these factors in glaucoma.

Purpose: To evaluate the association between monocyte count/high-density lipoprotein (HDL) ratio (MHR) and lymphocyte count/monocyte count ratio (LMR) with pseudoexfoliation syndrome (PEXS) and pseudoexfoliation glaucoma (PEXG). Materials and Methods: A total of 63 participants included in the study. Participants were divided into three groups. Twenty-one patients with PEXS regarded as group 1, 21 patients with PEXG regarded as group 2 and 21 participants without PEXS or PEXG regarded as the control group. Blood parameters were accessed from file records and database retrospectively. Results: The mean MHRs were significantly higher in group 1 and group 2 ( p = 0.003, p = 0.036) than the control group, whereas there was no difference between group 1 and group 2 ( p = 0.686). The mean LMRs were lower in group 1 and group 2 than the control group but the difference was insignificant ( p = 0.232). Conclusion: We found that there is an association between higher MHR and lower LMR with PEXS.

Around 1,3 billion people live worldwide with visual analyzer disorders such as glaucoma and cataract. These diseases are particularly common among the elderly. From glaucoma every year 10 million people completely lose vision, one of the factors of which is untimely diagnosis. Donosological diagnosis and laboratory screening can play a key role in detecting this pathology and significantly improving the quality of life of the older generation. The article presents the results of comparative analysis of the general blood analysis of glaucoma patients with a control group. The hematological indices are also compared by sex and age. Changes in some indicators consistent with existing theories of glaucoma pathogenesis have been identified. Promising directions of application of general blood analysis as a routine method of additional diagnostics of glaucoma in the future are planned.

Purpose: We aimed to evaluate whether the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune inflammation index (SII) were associated with primary open-angle glaucoma (POAG)., Materials and Methods: This retrospective case-control study included 240 patients with POAG and 300 age- and sex-matched control subjects. Complete ophthalmological examination and blood count measurements were performed for all subjects., Results: The values of NLR, PLR, and SII in the POAG group were significantly increased compared with the control group (p < 0.001; p = 0.012; p < 0.001). However, the LMR value was lower in the POAG patients than in the control group (p < 0.001). When we divided the subjects into different age and gender subgroups, the NLR and SII values in the POAG patients were always higher than those in the control group. In the comparison of laboratory parameters in POAG subjects stratified according to severity, we also found that NLR and SII increased with the severity. The receiver operating characteristic (ROC) analysis revealed that the areas under the ROC curve of NLR, PLR, LMR, and SII to predict patients with POAG were found to be 0.627, 0.569, 0.382, and 0.986, respectively. The best cutoff point of NLR was 1.998 with a sensitivity of 59.8% and a specificity of 63.0%, and the SII was 947.365 with a sensitivity of 95.4% and a specificity of 95.7%. Multivariable logistic regression analysis showed that NLR was positively associated with mean deviation; moreover, NLR and SII were independent indicators correlated with POAG (OR 1.502; 95% CI 1.227-1.839; p < 0.001; OR 1.02; 95% CI 1.009-1.021; p < 0.001)., Conclusion: We speculated that elevated NLR and SII might serve as readily available inflammatory predictors in POAG patients., (© 2020 S. Karger AG, Basel.)

Purpose: To examine levels of serum thyroid stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), vitamin D, vitamin B12 (B12), folic acid (FA), c-reactive protein (CRP), and hemoglobin in pseudoexfoliation glaucoma (XFG) and primary open angle glaucoma (POAG) patients., Materials and Methods: A hospital-based, prospective, cross-sectional study was conducted from October 2016 through June 2017 and October 2017 through January 2018. The number of patients was 33 in the control group, 29 in the XFG group and 77 in the POAG group., Results: The mean±SD levels of TSH, fT4, fT3, vitamin D, B12, FA, CRP, and hemoglobin were 2.52±2.07 mU/l, 1.15±0.24ng/dl, 3.16±3.37pg/ml, 20.83±14.06ng/ml, 318.29±115.48pg/ml, 7.7±4.01ng/ml, 3.78±3.83mg/l, 13.36±2.08g/dl in control group respectively. The levels for the XFG patients were as follows: TSH 2.02±1.16 mU/l, fT3 3.10±0.46pg/ml, fT4 1.18±0.19ng/dl, vitamin D 20.02±19.30ng/dl, B12 302.13±142.44pg/ml, FA 9.55±3.67ng/ml, CRP 3.69±3.22mg/l, and hemoglobin 13.58±1.38g/dl. In the POAG group, serum levels of TSH, fT4, fT3, vitamin D, B12, FA, CRP, and hemoglobin were 1.88±1.13 mU/l, 1.23±0.14ng/dl, 3.16±0.43pg/ml, 15.7±12.0ng/ml, 297.71±150.66pg/ml, 9.1±4.1ng/ml, 4.16±5.12mg/l, and 14.09±1.45 respectively. Only mean vitamin D levels show a significant difference between the control group and POAG (p=0.015)., Conclusion: POAG patients show decreased Vitamin D levels. Our study shows no significant differences in other biochemical markers between XFG, POAG and control subjects., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Purpose: To study the relationship between primary open-angle glaucoma (POAG) in a cohort of patients of African descent (AD) and serum vitamin D levels., Methods: A subset of the AD and glaucoma evaluation study III (ADAGES III) cohort, consisting of 357 patients with a diagnosis of POAG and 178 normal controls of self-reported AD, were included in this analysis. Demographic information, family history, and blood samples were collected from all the participants. All the subjects underwent clinical evaluation, including visual field (VF) mean deviation (MD), central cornea thickness (CCT), intraocular pressure (IOP), and height and weight measurements. POAG patients were classified into early and advanced phenotypes based on the severity of their visual field damage, and they were matched for age, gender, and history of hypertension and diabetes. Serum 25-Hydroxy (25-OH) vitamin D levels were measured by enzyme-linked immunosorbent assay (ELISA). The association of serum vitamin D levels with the development and severity of POAG was tested by analysis of variance (ANOVA) and the paired t -test., Results: The 178 early POAG subjects had a visual field MD of better than -4.0 dB, and the 179 advanced glaucoma subjects had a visual field MD of worse than -10 dB. The mean (95% confidence interval [CI]) levels of vitamin D of the subjects in the control (8.02 ± 6.19 pg/ml) and early phenotype (7.56 ± 5.74 pg/ml) groups were significantly or marginally significantly different from the levels observed in subjects with the advanced phenotype (6.35 ± 4.76 pg/ml; p = 0.0117 and 0.0543, respectively). In contrast, the mean serum vitamin D level in controls was not significantly different from that of the subjects with the early glaucoma phenotype (p = 0.8508)., Conclusions: In this AD cohort, patients with advanced glaucoma had lower serum levels of vitamin D compared with early glaucoma and normal subjects.

Aim : Glaucoma is an optic neuropathy causing progressive impairment of visual functions. We aimed to assess the alterations in thiol-disulfide homeostasis and serum ischemia modified albumin (IMA) levels, which are the determinants of antioxidant status, in patients with primary open-angle glaucoma (POAG). Material and Method : A total of 140 eyes from 70 patients with POAG and 174 eyes of 87 healthy, control cases were included in the study. All study participants underwent a complete ophthalmic evaluation. Alterations in serum thiol-disulfide homeostasis and IMA levels were measured in all participants. Results : IMA levels were significantly higher in glaucoma group (p:0.001). Native thiol, Total thiol and Native/Total thiol ratio were significantly decreased while Disulfide, Disulfide/Native thiol, and Disulfide/Total thiol ratios were significantly higher in glaucoma group (p:0.001). There was no significant difference regarding central corneal thickness (CCT), iridocorneal angle, albumin, IMA and adjusted IMA levels in patients with different stages of glaucoma. In correlation analysis, there was a negative correlation between Native thiol, Total thiol and Native/Total thiol ratio and disease period, number of daily drops required and stage of the disease in glaucoma patients. There was also a positive correlation between Disulfide, Disulfide/Native thiol and Disulfide/Total thiol levels and the disease activity. Conclusion : In patients with POAG, thiol-disulfide homeostasis is disturbed in the favor of pro-oxidant molecules and IMA levels are increased, indicating the presence of augmented oxidative stress. In that aspect, systemic and local anti-oxidant treatments may be new targets in glaucoma treatment. Larger, prospective studies about the role of anti-oxidants in prevention and treatment of POAG are warranted.

Purpose: Blood-based examination tools for glaucoma diagnosis in clinical practice, which can be useful for screening patients when traditional ophthalmic examinations cannot be utilized, are not available thus far. This study aimed to identify circulating microRNAs (miRNAs) associated with primary open-angle glaucoma (POAG) and explore their utility as diagnostic markers., Methods: A total of 136 POAG patients and controls were enrolled. Next-generation RNA sequencing was used to explore the expression profile of circulating miRNAs in the sequencing set, and potential miRNAs from independent samples in both the screening and validation sets were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was used to evaluate the ability of certain miRNAs to distinguish POAG patients from control subjects., Results: Using sequencing and qRT-PCR, hsa-miR-210-3p was found to be elevated in POAG patients in all sets. ROC analysis of the screening and validation sets revealed that hsa-miR-210-3p differentiated between POAG patients and matched controls with an area under the curve (AUC) of 0.846 (sensitivity: 84.6%; specificity: 80.8%) and 0.813 (sensitivity: 84.8%; specificity: 69.7%), respectively. In case of all nonsequencing participants, analysis revealed that hsa-miR-210-3p differentiated between severe POAG patients and controls with an AUC of 0.880 (sensitivity: 85.4%; specificity: 85.7%). In addition, the expression of hsa-miR-210-3p was associated with visual field defects of |mean deviation| (β = 0.237; P = 0.022) and average retinal nerve fiber layer thickness (β = -5.792; P = 0.014)., Conclusions: Circulating hsa-miR-210-3p may serve as a potential diagnostic marker for POAG (especially for severe POAG patients).

Purpose: To investigate the plasma concentration of nicotinamide in primary open-angle glaucoma (POAG)., Methods: Plasma of 34 POAG individuals was compared to that of 30 age- and sex-matched controls using a semiquantitative method based on liquid chromatography coupled to high-resolution mass spectrometry. Subsequently, an independent quantitative method, based on liquid chromatography coupled to mass spectrometry, was used to assess nicotinamide concentration in the plasma from the same initial cohort and from a replicative cohort of 20 POAG individuals and 15 controls., Results: Using the semiquantitative method, the plasma nicotinamide concentration was significantly lower in the initial cohort of POAG individuals compared to controls and further confirmed in the same cohort, using the targeted quantitative method, with mean concentrations of 0.14 μM (median: 0.12 μM; range, 0.06-0.28 μM) in the POAG group (-30%; P = 0.022) and 0.19 μM (median: 0.18 μM; range, 0.08-0.47 μM) in the control group. The quantitative dosage also disclosed a significantly lower plasma nicotinamide concentration (-33%; P = 0.011) in the replicative cohort with mean concentrations of 0.14 μM (median: 0.14 μM; range, 0.09-0.25 μM) in the POAG group, and 0.19 μM (median: 0.21 μM; range, 0.09-0.26 μM) in the control group., Conclusions: Glaucoma is associated with lower plasmatic nicotinamide levels, compared to controls, suggesting that nicotinamide supplementation might become a future therapeutic strategy. Further studies are needed, in larger cohorts, to confirm these preliminary findings.

Purpose: Glaucoma disease is known as multifactorial. Trace elements seemed to be linked via oxidative stress mediated changes to the complex glaucoma pathophysiology. Thus, it was the aim of this study to investigate serum levels of trace elements in primary open-angle glaucoma patients (POAG)., Patients and Methods: Peripheral venous blood samples were taken from a total of 40 subjects: 22 primary open-angle glaucoma patients (mean age 58.1 ± 13.9, female 8, male 14) and 18 controls (mean age 38.9 ± 11.6, 6 female 6, male 12). Serum samples of cadmium, cobalt, copper, iron, lead, manganese and zinc were analyzed by Inductively-Coupled-Plasma-Optical Emission Spectrometry (Cu, Fe, Zn) and Inductively-Coupled-Plasma-sectorfield-Mass-Spectrometry (Cd, Co, Mn, Pb, Se). Data were analyzed using ANCOVA and presented as log transformed LS-mean., Results: Patients with POAG had significantly increased serum levels of iron (2.98 ± 0.03 μg/L vs 2.98 ± 0.03 μg/L) when compared to controls, and of cadmium (1.57 ± 0.05 ng/L vs. 1.40 ± 0.06 ng/L) considering the interaction between age and the class variable (control versus POAG). A gender effect was seen for cadmium, cobalt, copper, and iron in controls and POAG patients. Iron concentration was reduced in dependency of age for both genders in normals, however lesser in POAG patients. No difference was seen in serum levels of lead, manganese, and zinc between patients with POAG and controls., Conclusion: A significant elevation of serum cadmium and iron levels in POAG patients as well as an additional gender effect of cadmium, cobalt, copper, and iron in normals and POAG patients, may argue for a potential role of these trace elements in the pathogenesis of primary open-angle glaucoma., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Purpose: It has been hypothesised that uric acid (UA) has a protective effect against oxidative damage in the central nervous system. Therefore, we investigated serum UA concentrations in patients with primary open-angle glaucoma (POAG) and explored the relationship between serum UA concentration and glaucoma severity., Methods: This prospective, cross-sectional, case-control study was conducted in 163 POAG patients and 103 normal controls. Clinical and demographic information was obtained from the medical data platform of the Eye & ENT Hospital of Fudan University, Shanghai, China. The POAG patients were categorised into mild [median deviation (MD) ≤ 6.00 dB], moderate (MD > 6 Db-≥12 dB) and severe (MD > 12 dB) subgroups, based on their visual field MD results., Results: The level of serum UA in the POAG group (0.321 ± 0.084 mmol/l) was approximately 12.77% lower (p < 0.001) than that of the control group (0.362 ± 0.053 mmol/l). The UA/creatinine (Cr) ratio was approximately 14.99% lower (p < 0.001) in patients with POAG (4.47 ± 1.15), compared with the control group (5.14 ± 1.05). The mean level of UA was lowest in the severe POAG group, followed by the moderate POAG group, and the mild POAG group (p < 0.001). A similar trend was observed when UA levels were compared between the POAG and control groups in males. Multivariate regression analyses showed a significant negative correlation between UA and vertical cup-disc ratio (B = -0.320, p = 0.034), and UA and MD (B = -0.441, p = 0.031) in males., Conclusion: Primary open-angle glaucoma patients have lower UA levels; however, a negative association between UA levels and disease severity was evident in male patients., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Glaucoma is an optic neurological disorder and the leading cause of irreversible blindness worldwide, with primary open angle glaucoma (POAG) as its most prevalent form. An early diagnosis of the disease is crucial to prevent loss of vision. Mechanisms behind glaucoma pathogenesis are not completely understood, but disease related alterations in the serological autoantibody profile indicate an immunologic component. These changes in immunoreactivity may serve as potential biomarkers for glaucoma diagnostics. We aimed to identify novel disease related autoantibodies targeting antigens in the trabecular meshwork as biomarkers to support early detection of POAG. We used serological proteome analysis (SERPA) for initial autoantibody profiling in a discovery sample set. The identified autoantibodies were validated by protein microarray analysis in a larger cohort with 60 POAG patients and 45 control subjects. In this study, we discovered CALD1, PGAM1, and VDAC2 as new biomarker candidates. With the use of artificial neural networks, the panel of these candidates and the already known markers HSPD1 and VIM was able to classify subjects into POAG patients and non-glaucomatous controls with a sensitivity of 81% and a specificity of 93%. These results suggest the benefit of these potential autoantibody biomarkers for utilization in glaucoma diagnostics.

We previously reported that lower systemic antioxidant capacity is involved in primary open-angle glaucoma (POAG) and exfoliation syndrome pathogeneses as measured by ferric-reducing activity. In the present study, we measured hydroxylinoleate (HODE) and hydroxyarachidonate (HETE) isomer serum levels after sample reduction and saponification to investigate POAG pathogenesis. POAG patients (n = 198) were recruited and divided into normal- and high-tension glaucoma groups (n = 84 and 114, respectively) depending on intraocular pressure. Total HODE (/linoleic acid) and HETE (/arachidonic acid) serum levels were significantly higher in the POAG group (211.9 ± 143.0 and 181.0 ± 164.1 µmol/mol, respectively) than in controls (167.1 ± 105.2 and 132.5 ± 139.7 µmol/mol, p = 0.0025 and 0.0101, respectively). The associations between HODEs/HETEs and glaucoma were further confirmed by multivariate analyses after adjusting for differences in demographic parameters. Among the HODE isomers, the levels of 9- and 13-(Z,E)-HODEs (p = 0.0014) and singlet oxygen-specific products (i.e., 10- and 12-(Z,E)-HODEs, p = 0.0345) were higher in the POAG group than in controls, while free radical-mediated oxidation-specific products (i.e., 9- and 13-(E,E)-HODEs, p = 0.0557) demonstrated a marginal difference. Enzymatic and singlet oxygen-mediated fatty acid oxidation may be major pathways of oxidation process in glaucoma subjects.

Objective: Elucidate the relation between neuroglobin and the primitive open-angle glaucoma., Patients and Methods: This cross-sectional case-control study involved 64 patients with primitive open-angle glaucoma on 2 eyes and 64 control subjects. Glaucoma was classified as early, moderate or severe according to ophthalmological examination. Then we determined neuroglobin concentration and compared his ROC curve with characteristics of glaucoma. Chi-square test was used to compare proportions and spearman test for correlations between quantitative variables., Results: Neuroglobin concentrations were higher among patients with glaucoma compared to control's (4.7±4.6 ng/mL versus 0.9±1.1 ng/mL, p=0.0000). Neuroglobin concentration was related to visual acuity, to the cup/disc ratio (eye right: r=0.340, p=0.006 and left eye: r=0.413, p=0.001). In addition, neuroglobin concentration was correlated with duration (r=0.565; p=0.000) and glaucoma severity (r=0.506, p=0.000). The area under the curve of neuroglobin concentration was 0.82 compared to that of intra ocular pressure (0.70)., Conclusion: This study suggests that neuroglobin could be used as biomarker for glaucoma diagnosis.

Purpose: Glaucoma, a leading cause of blindness worldwide, often remains undetected until irreversible vision loss has occurred. Treatments focus on lowering intraocular pressure (IOP), the only modifiable and readily measurable risk factor. However, IOP can vary and does not always predict disease progression. MicroRNAs (miRNAs) are promising biomarkers. They are abundant and stable in biological fluids, including plasma and aqueous humor (AqH). We aimed to identify differentially expressed miRNAs in AqH and plasma from glaucoma, exfoliation syndrome (XFS), and control subjects., Methods: Plasma and AqH from two ethnic cohorts were harvested from glaucoma or XFS (often associated with glaucoma, n = 33) and control (n = 31) patients undergoing elective surgery. A custom miRNA array measured 372 miRNAs. Molecular target prediction and pathway analysis were performed with Ingenuity Pathway Analysis (IPA) and DIANA bioinformatical tools., Results: Levels of miRNAs in plasma, a readily accessible biomarker source, correlated with miRNA levels in AqH. Twenty circulating miRNAs were at least 1.5-fold higher in glaucoma or XFS patients than in controls across two ethnic cohorts: miR-4667-5p (P = 4.1 × 10-5), miR-99b-3p (P = 4.8 × 10-5), miR-637 (P = 5.1 × 10-5), miR-4490 (P = 5.7 × 10-5), miR-1253 (P = 6.0 × 10-5), miR-3190-3p (P = 3.1 × 10-4), miR-3173-3p (P = 0.001), miR-608 (P = 0.001), miR-4725-3p (P = 0.002), miR-4448 (P = 0.002), and miR-323b-5p (P = 0.002), miR-4538 (P = 0.003), miR-3913-3p (P = 0.003), miR-3159 (P = 0.003), miR-4663 (P = 0.003), miR-4767 (P = 0.003), miR-4724-5p (P = 0.003), miR-1306-5p (P = 0.003), miR-181b-3p (P = 0.004), and miR-433-3p (P = 0.004). miR-637, miR-1306-5p, and miR-3159, in combination, allowed discrimination between glaucoma patients and control subjects (AUC = 0.91 ± 0.008, sensitivity 85.0%, specificity 87.5%)., Conclusions: These results identify specific miRNAs as potential biomarkers and provide insight into the molecular processes underlying glaucoma.

Purpose: To determine the plasma metabolomic signature of primary open-angle glaucoma (POAG)., Methods: We compared the metabolomic profiles of plasma from individuals with POAG (n = 36) with age- and sex-matched controls with cataract (n = 27). A targeted metabolomics study was performed using the standardized p180 Biocrates Absolute IDQ p180 kit with a QTRAP 5500 mass spectrometer. Multivariate analyses were performed using principal component analysis (PCA) and the least absolute shrinkage and selection operator (LASSO) method., Results: Among the 151 metabolites accurately measured, combined univariate and multivariate analyses revealed 18 discriminant metabolites belonging to the carbohydrate, acyl-carnitine, phosphatidylcholine, amino acids, and polyamine families. The metabolomic signature of POAG points to three closely interdependent pathophysiologic conditions; that is, defective mitochondrial oxidation of energetic substrates, altered metabolism resembling that observed in senescence, and a deficiency in spermidine and spermine, both polyamines being involved in the protection of retinal ganglion cells., Conclusions: Our results highlight a systemic and age-related mitochondrial defect in the pathogenesis of POAG.

Purpose: To evaluate the serum complement component (C)3 concentration in patients with primary open-angle glaucoma (POAG) and to investigate the association between C3 levels and POAG severity., Materials and Methods: This study enrolled 190 consecutive POAG patients and 204 normal control subjects. A detailed eye and systematic examination, including intraocular pressure, gonioscopy, fundus photography, A-scan ultrasound, visual field testing, electrocardiograms, x-rays, liver function, renal function, infectious disease, etc., and measurement of serum C3 concentration by immunoturbidimetry, was performed. The subgroups were classified according to age (17 to 29, 30 to 49, 50 to 69, 70+ y), sex, and visual field: mild (MD≤6 dB), moderate (6 dB12 dB) glaucoma., Results: The serum C3 level of the POAG (95.63±17.71 mg/dL) was ∼20.93% lower than that of the control group (115.65±22.19 mg/dL) (P<0.001). A similar result was observed when serum levels of C3 were compared between the POAG and control groups with respect to age and sex. The mean serum C3 level was lowest in the severe POAG group (85.18±19.62 mg/dL), followed by the moderate POAG group (96.62±12.63 mg/dL) and the mild POAG group (110.44±14.89 mg/dL) (P<0.001). Multiple logistic regression analyses revealed a significant correlation between the C3 levels and the vertical cup-disc ratio (B=-0.373, P=0.026), C3 levels and MD (B=-0.546, P=0.001). Logistic regression analyses revealed that serum C3 levels were associated (odds ratio=0.939, 95% CI=0.901-0.979, P=0.003) with severity of POAG., Conclusions: The POAG patients had decreased C3 levels, which were further negatively associated with POAG severity, suggesting the involvement of C3 in the pathomechanisms of POAG.

Purpose: To measure the serum bile acids (SBA) in patients with primary open-angle glaucoma (POAG) and to compare with nonglaucomatous controls., Patients and Methods: A hospital-based case control study of 90 patients above the age of 40 years was conducted. Patients with POAG formed the study group and individuals without glaucoma in the same age group formed the control group. SBA estimation was done using ELISA kit enzymatic assay technique and the median value was compared between the 2 groups., Results: The median of SBA level was found to be more in POAG patients when compared with the control group. The difference was statistically significant (P<0.001). Median SBA level was not affected by the age or sex of the participants in the study., Conclusions: "Bile acids" may have a role in the oxidative stress and apoptosis involved in the pathophysiology of POAG.

BACKGROUND HSP60-related immunological activities are found in normal-pressure glaucoma (NPG) patients, in whom an elevated intraocular pressure (IOP) found in primary open-angle glaucoma (POAG) is not observed. HSP60 was found in POAG and NPG patients, while anti-HSP60 level was mainly found to be higher in NPG patients. The purpose of this study was to compare the percentages of Th cells and levels of related cytokines, attempting to provide evidence to explain this discrepancy. MATERIAL AND METHODS Blood samples from POAG, NPG, and normal control (NC) groups were collected and peripheral blood monocytes were isolated and cultured with or without the stimulation of HSP60. Flow cytometry and enzyme-linked immunosorbent assay were used to assess the percentages of Th1, Th2, Th17, and Treg cells, as well as HSP60 antibody levels and related cytokine levels, before and after culture. RESULTS Significantly higher titers of anti-HSP60 were observed only in NPG patients. Comparable Th1 and Th2 cell frequencies, IL-4 level, and IFN-γ level were found in POAG and NPG patients, while higher Treg cell frequency was only found in POAG patients. After culturing with HSP60, increased Th2 frequencies and decreased Th1 frequencies were observed in the POAG, NPG, and NC groups, while increased Treg frequency was only identified in the POAG and NC groups. CONCLUSIONS Different Th cell patterns were observed among POAG, NPG, and NC groups. Lack of induction of Treg cells and imbalance of the pro-inflammatory and anti-inflammatory response patterns of Th cells exist in some NPG patients.

Purpose: To determine the plasma metabolomic signature of the exfoliative syndrome (XFS), the most common cause worldwide of secondary open-angle glaucoma., Methods: We performed a targeted metabolomic study, using the standardized p180 Biocrates Absolute IDQ p180 kit with a QTRAP 5500 mass spectrometer, to compare the metabolomic profiles of plasma from individuals with XFS (n = 16), and an age- and sex-matched control group with cataract (n = 18)., Results: A total of 151 metabolites were detected correctly, 16 of which allowed for construction of an OPLS-DA model with a good predictive capability (Q2cum = 0.51) associated with a low risk of over-fitting (permQ2 = -0.48, CV-ANOVA P-value <0.001). The metabolites contributing the most to the signature were octanoyl-carnitine (C8) and decanoyl-carnitine (C10), the branched-chain amino acids (i.e., isoleucine, leucine, and valine), and tyrosine, all of which were at higher concentrations in the XFS group, whereas spermine and spermidine, together with their precursor acetyl-ornithine, were at lower concentrations than in the control group., Conclusions: We identified a significant metabolomic signature in the plasma of individuals with XFS. Paradoxically, this signature, characterized by lower concentrations of the neuroprotective spermine and spermidine polyamines than in controls, partially overlaps the plasma metabolomic profile associated with insulin resistance, despite the absence of evidence of insulin resistance in XFS.

Autoantibody profiling has gained increasing interest in the research field of glaucoma promising the detection of highly specific and sensitive marker candidates for future diagnostic purposes. Recent studies demonstrated that immune responses are characterized by the expression of congruent or similar complementarity determining regions (CDR) in different individuals and could be used as molecular targets in biomarker discovery. Main objective of this study was to characterize glaucoma-specific peptides from the variable region of sera-derived immunoglobulins using liquid chromatography--mass spectrometry (LC-MS)-based quantitative proteomics. IgG was purified from sera of 13 primary open-angle glaucoma patients (POAG) and 15 controls (CTRL) and subsequently digested into Fab and Fc by papain. Fab was further purified, tryptic digested and measured by LC-MS/MS. Discovery proteomics revealed in total 75 peptides of the variable IgG domain showing significant glaucoma-related level changes (P < 0.05; log2 fold change ≥ 0.5): 6 peptides were high abundant in POAG sera, whereas 69 peptides were low abundant in comparison to CTRL group. Via accurate inclusion mass screening strategy 28 IgG V domain peptides were further validated showing significantly decreased expression levels in POAG sera. Amongst others 5 CDR1, 2 CDR2 and 1 CDR3 sequences. In addition, we observed significant shifts in the variable heavy chain family distribution and disturbed κ/λ ratios in POAG patients in contrast to CTRL. These findings strongly indicate that glaucoma is accompanied by systemic effects on antibody production and B cell maturation possibly offering new prospects for future diagnostic or therapy purposes., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. The genetics of POAG are complex, and population-specific effects have been reported. Although many polymorphisms associated with POAG risk have been reported, few studies have analyzed their additive effects. We investigated, in a southern European Mediterranean population, the association between relevant POAG polymorphisms, identified by initial genome-wide association studies (GWASs) and POAG risk, both separately and as an aggregated multi-locus genetic risk score (GRS). Also, bearing in mind that oxidative stress is a factor increasingly recognized in the pathogenesis of POAG, we analyzed the potential association of the GRS with plasma concentrations of antioxidant vitamins (C and E). We carried out a case-control study including 391 POAG cases and 383 healthy controls, and analyzed four genetic polymorphisms (rs4656461- TMCO1 , rs4236601- CAV1 / CAV2 , rs2157719- CDKN2B-AS1 and rs3088440- CDKN2A ). An unweighted GRS including the four non-linked polymorphisms was constructed. A strong association between the GRS and POAG risk was found. When three categories of the GRS were considered, subjects in the top category of the GRS were 2.92 (95% confidence interval (CI): 1.79-4.77) times more likely to have POAG compared with participants in the bottom category ( p < 0.001). Moreover, the GRS was inversely correlated with plasma vitamin C ( p = 0.002) and vitamin E ( p = 0.001) concentrations, even after additional adjustment for POAG status. In conclusion, we have found a strong association between the GRS and POAG risk in this Mediterranean population. While the additional correlation found between GRS and low levels of vitamins C and E does not indicated a causal relationship, it does suggest the need for new and deeper research into the effects of oxidative stress as a potential mechanism for those associations., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Background: Controversy exists regarding the role of oxidative DNA damage and DNA repair in primary open angle glaucoma (POAG). We performed a case control study to test the hypothesis that oxidative DNA damage and base excision repair (BER) genes PARP1 and OGG1 are involved in POAG pathogenesis., Materials and Methods: The study included 116 POAG patients and 116 cataract patients as controls. The 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were measured by ELISA. RNA was extracted from blood by Trizol and converted to cDNA. The relative quantification of PARP1 and OGG1 genes normalized to β-actin was calculated by the 2 -ΔCt method. Comparisons between groups were done by student's t-test and correlation between parameters was seen by Pearson correlation coefficient. All p values less than 0.05 were considered significant., Results: Mean levels of 8-OHdG were (patients v/s controls) 19.53 ± 1.40 vs. 15.0 ± 2.6 ng/ml in plasma and 8.55 ± 1.94 vs. 5.15 ± 1.09 ng/ml in aqueous humor (p < 0.0001). Expression levels of PARP1 (0.44 ± 0.05 vs. 0.88 ± 0.04) and OGG1 (0.46 ± 0.05 vs. 0.8 ± 0.01) were significantly (p < 0.0001) less in the patients than controls. There was a significant negative correlation between the expression levels of PARP1 and OGG1 with plasma and aqueous 8-OHdG. There was a strong positive correlation between plasma and aqueous 8-OHdG levels., Conclusion: These results support our hypothesis that oxidative stress-induced DNA damage is associated with POAG. Increased oxidative DNA damage in POAG may be attributed to decreased expression of DNA repair enzymes of the BER pathway.

Systemic oxidative stress is thought to be an important factor in the pathogenesis of glaucoma. In particular, low systemic antioxidative capacity, which normally counters oxidative stress, may contribute to glaucoma. Thus, we investigated the association between biological antioxidant potential (BAP), a biomarker of systemic antioxidative capacity, and glaucoma severity in patients with open-angle glaucoma (OAG). This study included 480 eyes of 240 patients with OAG and 66 healthy control eyes. We measured the BAP serum level with a free radical analyzer and compared it with a weighted estimate of the number of retinal ganglion cells (wrgc), derived from circumpapillary retinal nerve fiber layer thickness and visual field mean deviation. We found that wrgc was uncorrelated with BAP in the overall, male, and female OAG patients, but was correlated in young (aged ≤ 65 years) male OAG patients (better eye: r = 0.33, P = 0.02; worse eye: r = 0.27, P = 0.047). Furthermore, a mixed-effects regression analysis revealed that BAP was an independent contributing factor to wrgc in young male OAG patients (P = 0.02). Thus, systemic antioxidant capacity was associated with glaucomatous damage in relatively young male patients, suggesting that anti-oxidant therapy might be more effective in these patients.

Purpose: Glaucoma-related molecular biomarkers can improve clinical testing to diagnose the disease early, predict its prognosis, and monitor treatment responses. Based on the evidence of increased oxidative stress in glaucomatous tissues, this study analyzed oxidative stress-related biomarker candidates in blood and aqueous humor samples with or without glaucoma., Methods: The blood and aqueous humor samples collected from carefully selected groups of 96 patients with glaucoma and 64 healthy subjects without glaucoma were included in the study. The samples were analyzed for protein carbonyls and advanced glycation end products (AGEs) through ELISA-based quantification assays. To allow proper comparisons, the Goldmann-Witmer coefficient that reflects the ratio of aqueous humor to blood values corrected to total protein concentration in individual samples was calculated., Results: Blood and aqueous humor levels of protein carbonyls and AGEs were found significantly higher in glaucomatous samples compared with age-matched nonglaucomatous controls (P < 0.001). The glaucoma-related increase in protein carbonyls and AGEs was more prominent in aqueous humor samples than blood samples (2.6-fold versus 1.9-fold for protein carbonyls, and 3.1-fold versus 1.9-fold for AGEs; P < 0.001). Comparison of the Goldmann-Witmer coefficients indicated greater values for protein carbonyls (1.37 ± 0.3 vs. 3.07 ± 0.8) and AGEs (1.2 ± 0.3 vs. 3.2 ± 1.1) in the glaucoma group (P < 0.001)., Conclusions: Findings of this study encourage further validation studies of oxidative stress-related biomarkers in glaucoma. Analysis of protein carbonyls and AGEs in longitudinal studies of larger and heterogeneous patient cohorts should better assess the value of these promising candidates as molecular biomarkers of glaucoma for clinical predictions.

Although vitamins play a major role in health, and their deficiency may be linked to symptoms of optic-nerve dysfunction, the association between serum vitamin levels and glaucoma in humans remains controversial. In this study, articles in the PubMed, Web of Science, and EMBASE databases were searched up to 25March 2017. Nine studies on primary open-angle glaucoma (POAG), four studies on normal tension glaucoma (NTG), and six studies on exfoliative glaucoma (EXG) were retrieved. The combined results showed no differences in the levels of serum vitamin B₆ between POAG ( p = 0.406) and EXG ( p = 0.139) patients and controls. The weighted mean differences (WMDs) with 95% confidence intervals (CIs) were 2.792 ng/mL (-3.793 to 9.377) and 1.342 ng/mL (-3.120 to 0.436), respectively. There was no difference between POAG ( p = 0.952), NTG ( p = 0.757), or EXG ( p = 0.064) patients and controls in terms of serum vitamin B 12 . The WMDs with 95% CIs were 0.933 pg/mL (-31.116 to 29.249), 6.652 pg/mL (-35.473 to 48.777), and 49.946 pg/mL (-102.892 to 3.001), respectively. The serum vitamin D levels exhibited no differences ( p = 0.064) between POAG patients and controls; the WMD with 95% CI was 2.488 ng/mL (-5.120 to 0.145). In conclusion, there was no association found between serum vitamin B₆, vitamin B 12 , or vitamin D levels and the different types of glaucoma., Competing Interests: The authors declare no conflict of interest.