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PubMed2025

Causal association between 91 circulating inflammatory proteins and primary open-angle glaucoma: a bidirectional Mendelian randomization study.

BACKGROUND: Glaucoma, especially primary open-angle glaucoma (POAG), is a leading cause of irreversible vision loss. While elevated intraocular pressure is a major risk factor, the pathogenesis of POAG also involves genetics, oxidative stress, abnormal hemodynamics, and inflammatory factors. The role of systemic inflammation in POAG remains a subject of debate. This study aimed to investigate the causal relationships between circulating inflammatory proteins and POAG using a bidirectional Mendelian randomization (MR) approach. METHODS: A bidirectional two-sample MR analysis was conducted using genome-wide association study summary statistics. The primary stage involved 91 circulating inflammatory proteins and POAG, followed by a replication stage to verify significant findings using independent data and meta-analysis. The random-effects inverse-variance weighted model was employed as the primary method, complemented by multiple sensitivity analyses employed to ensure robustness, including multivariable MR to adjust for potential confounders. RESULTS: In the primary stage, 9 circulating inflammatory proteins were found to have significant causal effects on POAG. Specifically, the higher levels of Delta and Notch-like epidermal growth factor-related receptor (DNER) (OR: 1.12, 95 % CI: 1.04-1.21, P = 0.004), leukemia inhibitory factor (LIF) (OR: 1.20, 95 % CI: 1.06-1.36, P = 0.003), matrix metalloproteinase-10 (MMP-10) (OR: 1.08, 95 % CI: 1.02-1.16, P = 0.013), and stem cell factor (SCF) (OR: 1.09, 95 % CI: 1.03-1.15, P = 0.005) were positively associated with the risk of POAG. Conversely, the levels of fibroblast growth factor 19 (FGF-19) (OR: 0.88, 95 % CI: 0.82-0.95, P = 0.002), interleukin-18 (IL-18) (OR: 0.92, 95 % CI: 0.86-0.99, P = 0.019), IL-18 receptor 1 (IL-18R1) (OR: 0.96, 95 % CI: 0.92-1.00, P = 0.037), tumor necrosis factor ligand superfamily member 14 (TNFSF14) (OR: 0.91, 95 % CI: 0.86-0.97, P = 0.004), and tumor necrosis factor-related activation-induced cytokine (TRANCE) (OR: 0.94, 95 % CI: 0.88-1.00, P = 0.041) exhibited inverse associations with the risk of POAG. Multivariable MR analysis adjusting for confounders supported the roles of DNER, FGF-19, IL-18, IL18R1, LIF, and SCF. The replication stage confirmed the significant associations for FGF-19 (OR: 0.89, 95 % CI: 0.84-0.95, P = 4.63 × 10-4), IL-18 (OR: 0.93, 95 % CI: 0.89-0.97, P = 0.002), IL-18R1 (OR: 0.96, 95 % CI: 0.93-0.99, P = 0.023), and LIF (OR: 1.18, 95 % CI: 1.04-1.34, P = 0.013). Sensitivity analyses further supported the robustness of these findings. CONCLUSION: This study elucidated the causal relationships between circulating inflammatory proteins and POAG, highlighting FGF-19, IL-18, IL-18R1, and LIF as potential therapeutic targets. These findings provide new insights for the prevention and management of POAG, although further studies are needed to understand the precise biological mechanisms.

Humans↗

PubMed2025

New insights into genetic comorbidity mechanisms: type 2 diabetes and primary open-angle glaucoma.

AIMS: To investigate the shared genetic mechanisms between type 2 diabetes (T2D) and primary open-angle glaucoma (POAG). Using large-scale genome-wide association study (GWAS) data, we performed single nucleotide polymorphism (SNP) level analysis to detect pleiotropic variants and loci, paired eQTL mapping analysis and gene-level analysis to identify candidate pleiotropic genes. In addition, Mendelian randomisation (MR) analysis was performed to assess causal associations. MATERIALS AND METHODS: We used POAG GWAS data from Finngen (9565 cases and 430 250 controls) and T2D GWAS data from 55 555 European ancestry samples. We used Linkage Disequilibrium SCore (LDSC) regression to assess the genetic association between T2D and POAG and further used PLeiotropic Analysis under the COmposite null hypothesis (PLACO) to identify shared genetic variants between paired traits. Finally, we further used MR analysis to explore the causal association between T2D and POAG at the genetic level. RESULTS: The LDSC results and MR analysis revealed that the T2D effect was significantly higher than that of the POAG (OR=1.09, 95% CI 1.03 to 1.14, p=1.50×10-3). The PLACO property analysis determined that the T2D sum POAG shared 178 individual SNPs, separate localisation of 79 individual causes. The five most popular choices are based on the effectiveness of CCND2, SVEP1, ST6GAL1, TCF7L2 and HMGA2. expression quantitative trait loci mapping further revealed 36 genes with regulatory roles in optic nerve-related brain tissues. Functional enrichment analyses indicated that these pleiotropic genes are involved in neurodevelopmental, neuroprotective and metabolic pathways, with tissue-specific enrichment observed in neural, pancreatic, adipose and retinal tissues. It is possible to present the main comorbid mechanisms of T2D and POAG. CONCLUSIONS: Our study provides new insights into the aetiology and pathogenesis of T2D and POAG at the genetic level.

Humans↗

PubMed2025

Exploring diagnostic m6A regulators in primary open-angle glaucoma: insight from gene signature and possible mechanisms by which key genes function.

PURPOSE: The purpose of this study was to interrogate the potential role of N6-methyladenosine (m6A) regulators in the process of trabecular meshwork (TM) tissue damage in patients with primary open-angle glaucoma (POAG). METHODS: Firstly, the expression profile of m6A regulators in TM tissues of POAG patients was comprehensively analyzed by bioinformatics analysis; Plasmid transfection and siRNA gene interference were used to enhance or weaken the expression levels of YTHDC2 in human trabecular meshwork cells (HTMCs); Cell migration ability was detected by transwell chamber assay; Immunofluorescence staining assay was used to evaluate the expression of extracellular matrix (ECM) related proteins. RESULTS: Through the analysis of GSE27276 database, 5 m6A regulators with different expression in POAG were screened out. The results of random forest model showed that these 5 m6A regulators exhibited diagnostic potential and were characteristic genes of POAG. All POAG samples could be effectively divided into two groups based on the expression levels of these 5 hub m6A regulators. Immune cell infiltration analysis indicated that the levels of activated CD8+ T cells and regulatory T cells were different in the two subtypes. HTMC oxidative stress cell model and TGF-β2 stimulation cell model were further constructed to verify the expression of the aforementioned hub m6A regulators, and it was found that YTHDC2 mRNA showed the same expression trend in both models. The silencing of YTHDC2 enhanced the migration ability of HTMCs and increased the synthesis ability of ECM. However, when YTHDC2ΔYTH, which lacks the YTH domain, is overexpressed in HTMCs, there is no significant change in the ECM synthesis ability. CONCLUSIONS: The differentially expressed m6A regulators in TM tissues may serve as potential diagnostic biomarkers for POAG. And, in HTMCs, the expression level of YTHDC2 mRNA was changed under oxidative stress or TGF-β2 intervention, and then exerted its regulation on cell migration and ECM synthesis capability through m6A modification, which may be an important part of the disease process of POAG.

Humans↗

PubMed1977

Family history in primary open-angle glaucoma.

A family history of glaucoma was found in 50% of patients with primary open-angle glaucoma (POAG) and 43% of patients with ocular hypertension (OH). Positive family history was twice as prevalent in those with OH and either HLA-B7 or B12 antigens than in OH with neither antigen (P less than .01). Although POAG occurred equally in men and women, the prevalence of a positive family history of glaucoma on the maternal side of the family in POAG patients was six to seven times greater than on the paternal side (P less than .0005). However, in patients with OH, but no glaucomatous field loss, there was no difference in prevalence of maternal and paternal family history. Even in OH with HLA-B7 or B12 antigens, there was no predominance of maternal family history. The implication that offspring were more likely to develop POAG when their mother's side of the family rather than their father's side had the disease has provided an additional potentially useful risk factor in patients with OH. In addition, it has raised interesting questions as to possible maternal cytoplasmic factors in the transmission and pathogenesis of POAG.

Black or African American↗

PubMed2026

Gene polymorphisms associated with progression of primary open-angle glaucoma: A systematic review.

Glaucoma is the leading global cause of irreversible blindness, with primary open-angle glaucoma (POAG) its most prevalent subtype. While elevated intraocular pressure is a major risk factor, glaucoma progression is multifactorial, influenced by genetic, environmental, vascular and mechanical factors. Genetic polymorphisms have been linked to both POAG susceptibility and progression, yet most studies focus on risk factors for disease onset rather than progression. We provide an overview of the current literature on gene polymorphisms associated with POAG progression. We conducted a systematic search following PRISMA guidelines in MEDLINE, EMBASE, Web of Science, Cochrane Library, Scopus and Public Health Genomics and Precision Health Knowledge Base. Eligible studies investigated associations between genetic variants and structural or functional markers of glaucoma progression in adult-onset POAG patients. Eighteen articles were included. HLA class I haplotypes (A1-B8 and A2-B40) and MYOC.mt1+ carriers showed faster progression of optic nerve head damage. The APOE ε4 allele was linked to faster macular thinning in normal tension glaucoma patients. BDNF rs6265 Val/Val homozygotes exhibited accelerated retinal nerve fiber layer loss, particularly in females. TGFBR3-CDC7 (rs1192415: G) and MYOC.mt1+ carriers experienced accelerated visual field deterioration. Carriers of GAS7 (rs9913911: AA), IL1B (rs1143627: CT and rs16944: CT) and OPTN (rs2234968) had a higher likelihood of requiring surgery. Variants in ABCA1, CDKN2B-AS, eNOS and Piezo1 showed inconclusive results. These findings support a role for genetic polymorphisms in POAG progression and highlight the potential of genetic screening to identify patients at increased risk for rapid disease progression.

Disease progression↗

PubMed1977

HLA in primary open-angle glaucoma.

Histocompatibility antigen typing was carried out in 50 Caucasian patients with primary open-angle glaucoma (POAG) and 50 Caucasian ocular-normotensive subjects. HLA-A 3 was present in 46%, B7 in 52%, B12 in 50%, and either B7 or B12 in 88% of p,tients with POAG. These prevalences in POAG patients were significantly greater than in ocular-normotensive subjects (p less than 0.01, p less than 0.0005, p less than 0.001, and p less than less than 0.0005, respectively). The prevalences of A 3-B 7, A 3-B 12 and either combination were also significantly greater in POAG patients than in the ocular normotensives (p less than 0.005, p less than 0.005, and p less than 0.0005, respectively). HLA-BW 35 was noted to be in deficit in Caucasian POAG patients (8%) as compared to Caucasian ocular normotensives (32%; p less than 0.01).

Glaucoma↗

PubMed2026

Decoding Primary Open-Angle Glaucoma: A Multi-Omics Approach to Identify Druggable Effector Genes.

PURPOSE: Genomewide association studies (GWAS) have identified numerous primary open angle glaucoma (POAG) risk loci, yet most reside in non-coding regions with unclear function. Mapping these loci to effector genes can elucidate disease mechanisms, identify functionally conserved variants, improve cross-ancestry risk prediction by reducing population-specific noise, and uncover shared therapeutic targets. METHODS: Here, we integrate European POAG GWAS with six types of multi-omics molecular Quantitative Trait Locis (xQTLs) using multi-trait colocalization to identify candidate effector variants and evaluate their cross-population relevance using genetic risk score (GRS) analysis, and their therapeutic potential through drug target prioritization. RESULTS: We identified 25 POAG effector variants colocalized with at least one xQTLs. In non-European populations, effector variants showed stronger effect size correlations with Europeans than non-colocalized variants (Pearson r2 = African 0.85 vs. 0.71; East Asian 0.81 vs. 0.69; and Latin American 0.91 vs. 0.75). Effector variants also had smaller allele frequency variations across populations (average interquartile range [IQR] = 0.15 vs. 0.20). The genetic risk score based on effector variants performed comparably to the genome-wide significant single-nucleotide polymorphism (SNP)-based GRS in non-European populations. Drug prioritization identified zinc, copper, sunitinib, probucol, and astemizole as potential common therapeutic agents for POAG and its subtypes. CONCLUSIONS: Our findings offer deeper insight into the molecular mechanisms underlying glaucoma and effector variants for developing more robust GRS models and broadly effective therapeutic strategies for POAG.

Humans↗

PubMed1977

Increased ocular and systemic responsiveness to epinephrine in primary open-angle glaucoma.

Sixteen patients with primary open-angle gaucoma (POAG) were matched as to age, sex, and race with an equal number of patients with secondary glaucoma. Although initial intraocular pressures were comparable, treatment with topical epinephrine hydrochloride, decreased intraocular pressure more than 5 mm Hg in 14 (88%) of the 16 patients with POAG but in only five (31%) of the 16 patients with secondary glaucoma (p less than .005). Eleven (69%) of the 16 patients with POAG demonstrated premature ventricular contractions during tonography as opposed to three (19%) of the 16 patients with secondary glaucoma (p less than .025). These findings suggested greater ocular as well as cardiac responsiveness to epinephrine in patients with POAG.

Age Factors↗

PubMed1978

Histocompatibility antigens and primary open-angle glaucoma. A reassessment.

Histocompatibility (HLA) antigen typing was performed on 306 patients who had been studied and classified carefully. Black individuals with primary open-angle glaucoma (POAG) had no significant differences in HLA antigen prevalences from black control subjects. In one white population with POAG, a significant decrease in HLA-A1, a significant increase in HLA-Aw31, and a significant increase in the antigen combination HLA-B7 and HLA-Bw22 were noted. However, these differences were not confirmed in a second white population with POAG. We concluded that associations between the A and B loci of the HLA antigen system and POAG were not as impressive as has been previously reported.

Black People↗

PubMed2026

Incidence patterns and genetic validation of primary glaucoma subtypes among 1 million adults in China and the UK.

BACKGROUND/AIMS: Primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) are distinct diseases, yet many glaucoma cases in population-based datasets lack subtype specification. We assessed incidence patterns of glaucoma subtypes in China and the UK and used genetic evidence to infer the likely subtype composition of cases recorded as unspecified glaucoma. METHODS: Incident primary glaucoma was identified from linked inpatient records in the prospective China Kadoorie Biobank (CKB; n=512 504) and UK Biobank (UKB; n=492 329) studies. Cohort-specific phenotyping algorithms defined POAG, PACG and unspecified glaucoma. Adjusted incidence rates were estimated by direct standardisation. To support subtype inference, polygenic risk scores (PRSs) were constructed using ancestry-specific genome-wide association studies, including a new East Asian PACG meta-analysis, and tested for association with glaucoma phenotypes using multivariable logistic regression. RESULTS: Over 12 years of follow-up, 1658 primary glaucoma cases were identified in CKB and 7643 in UKB. Most (>68%) cases lacked subtype specification. Incidence increased with age and was twofold higher among women for PACG in both cohorts and for unspecified glaucoma in CKB. In UKB, POAG incidence was fivefold higher among Black than White participants, with a similar but attenuated pattern for unspecified glaucoma. PRS analyses indicated that unspecified glaucoma closely aligned with PACG in CKB but was more heterogeneous in UKB. CONCLUSION: Healthcare-recorded incidence patterns for POAG and PACG were consistent with established demographic risk factors, whereas unspecified glaucoma showed differences in subtype composition between populations. Integrating epidemiological and genetic evidence improves interpretation of glaucoma phenotypes when detailed clinical information is unavailable.

Epidemiology↗

PubMed1977

[Preferential screening to prevent glaucoma blindness (author's transl)].

The chief barrier to formulating an effective program of preventing glaucoma blindness is the difficulty of identifying those individuals in the population who have glaucoma but do not know it and those who are likely to develop the disease. Primary open-angle glaucoma (POAG), the most common tupe of glaucomatous disease, is an inherited disease. Fifty percent of all patients who have POAG also have a family history of glaucoma. Further, it is estimated that six to seven percent of the first degree relatives of POAG patients will develop POAG. This information suggests that for ophthalmologists who are likely to have limited time available for glaucoma screening, the most practical glaucoma screening program is that which is directed at those individuals who are first degree relatives of patients known to have glaucoma. For these people, the minimal screening tests should include tonometry, perimetry, and a meticulous examination of the optic discs. If tonometric testing reveals an intraocular pressure of 21-23 mmHg, tonometry should be repeated at different hours of the day. If results of these tests are negative, the patient then should be tested for increased sensitivity to corticosteroids and epinephrine. If all tests are negative, the patient still should be tested periodically. A relationship between HLA antigens and primary open-angle glaucoma has not been confirmed.

Glaucoma↗

PubMed1977

Increased cellular responsiveness to epinephrine in primary open-angle glaucoma.

The concentration of I-epinephrine hydrochloride necessary to inhibit lymphocyte transformation by 50% (I50 value) was determined in vitro for nine patients with primary open-angle glaucoma (POAG) and in seven controls. The lymphocytes of the patients with POAG were significantly (P less than .05) more responsive. This result is consistent with the hypothesis that patients with POAG have an increased responsiveness to agents that elevate intracellular cyclic adenosine monophosphate levels.

Adult↗

PubMed1979

Absence of association between HLA antigens and primary open angle glaucoma in Israel.

HLA antigens of the A and B loci were determined in 57 Israeli patients with primary open angle glaucoma (POAG) presenting visual field loss and in 715 normal control subjects. The glaucoma patients and control subjects were non-related and randomly selected from the Jewish Israeli population. Frequencies of HLA antigens among the POAG patients showed no differences from those observed in the control subjects. Similar results were observed for all patients as well as within subgroups of the patient population as defined by origin. Thus, the association reported between B7 and/or B12 and POAG in white and black Americans could not be confirmed in an Israeli population.

Adult↗

PubMed1977

Primary open-angle glaucoma and sensitivity to corticosteroids in vitro.

Corticosteroid inhibition of mitogen induced lymphocyte transformation was studied in patients with definite or suspected primary open-angle plaucoma (POAG). Patients without glaucoma served as normal controls. From a dose response curve with prednisolone-21-PO4 or prednisolone the value of 50% inhibition (I50) was determined for each patient. In Series I it was necessary to disqualify 70% of the data whereas in Series II less than 5% were excluded. In Series I the median I50 (M X 10(-8) prednisolone-21-PO4) was 12 for 11 controls and 8 for 18 total POAG'S (p less than .01). In Series II the opposite result was obtained. The median I50 was 8 for 49 controls and 12 for 79 total POAG'S (p less than .01). In series II similar results were obtained with prednisolone. There was no difference between definite and suspected glaucoma patients. The cause of the discrepancy between the present two series and among the other published studies is not clear. The source of normal controls, from either an eye clinic or volunteer groups, may be a factor.

Adrenal Cortex Hormones↗

PubMed1977

Glucocorticoid responsiveness associated with HLA-B12.

Primary open-angle galucoma (POAG) patients are more responsive to glucocorticoids, and have increased prevalences of the histocompatibility antigens HLA-B7 and HLA-B12. We report herein a comparison of in vitro cellular responsiveness to glucocorticoids and HLA classification for 25 POAG patients, and 25 individuals who respond to topical dexamethasone with intraocular pressure is greater than 31 mm. HG. (GG responders). Within both the POAG and GG groups, significantly greater responsiveness to prednisolone occurs in patients with HLA-B12 antigen. No such association occurs for patients with HLA-B7.

Aged↗

PubMed1978

HLA antigens-risk factors for primary open-angle glaucoma?

The comparison of the HLA A, B, and C phenotypes of 70 patients with primary open-angle glaucoma (POAG) with the phenotypes of 450 healthy control individuals and the rather discordant data published by other investigators show that there is no genetical influence of HLA A, HLA B, or HLA C genes on POAG and on the clinical complications associated with this disease.

Adult↗