Severity Of Primary Angle Closure Glaucoma Research Articles

Metabolomics identifies and validates serum androstenedione as novel biomarker for diagnosing primary angle closure glaucoma and predicting the visual field progression

Background:Primary angle closure glaucoma (PACG) is the leading cause of irreversible blindness in Asia, and no reliable, effective diagnostic, and predictive biomarkers are used in clinical routines. A growing body of evidence shows metabolic alterations in patients with glaucoma. We aimed to develop and validate potential metabolite biomarkers to diagnose and predict the visual field progression of PACG.Methods:Here, we used a five-phase (discovery phase, validation phase 1, validation phase 2, supplementary phase, and cohort phase) multicenter (EENT hospital, Shanghai Xuhui Central Hospital), cross-sectional, prospective cohort study designed to perform widely targeted metabolomics and chemiluminescence immunoassay to determine candidate biomarkers. Five machine learning (random forest, support vector machine, lasso, K-nearest neighbor, and GaussianNaive Bayes [NB]) approaches were used to identify an optimal algorithm. The discrimination ability was evaluated using the area under the receiver operating characteristic curve (AUC). Calibration was assessed by Hosmer-Lemeshow tests and calibration plots.Results:Studied serum samples were collected from 616 participants, and 1464 metabolites were identified. Machine learning algorithm determines that androstenedione exhibited excellent discrimination and acceptable calibration in discriminating PACG across the discovery phase (discovery set 1, AUCs=1.0 [95% CI, 1.00–1.00]; discovery set 2, AUCs = 0.85 [95% CI, 0.80–0.90]) and validation phases (internal validation, AUCs = 0.86 [95% CI, 0.81–0.91]; external validation, AUCs = 0.87 [95% CI, 0.80–0.95]). Androstenedione also exhibited a higher AUC (0.92–0.98) to discriminate the severity of PACG. In the supplemental phase, serum androstenedione levels were consistent with those in aqueous humor (r=0.82, p=0.038) and significantly (p=0.021) decreased after treatment. Further, cohort phase demonstrates that higher baseline androstenedione levels (hazard ratio = 2.71 [95% CI: 1.199–6.104], p=0.017) were associated with faster visual field progression.Conclusions:Our study identifies serum androstenedione as a potential biomarker for diagnosing PACG and indicating visual field progression.Funding:This work was supported by Youth Medical Talents – Clinical Laboratory Practitioner Program (2022-65), the National Natural Science Foundation of China (82302582), Shanghai Municipal Health Commission Project (20224Y0317), and Higher Education Industry-Academic-Research Innovation Fund of China (2023JQ006).

Correlation of pattern of visual field loss by perimetry and anterior chamber angle parameters by anterior segment optical coherence tomography in primary angle-closure glaucoma.

To correlate and analyze the pattern of the visual field (VF) defects by perimetry and anterior chamber angle parameters by AS-OCT in primary angle-closure glaucoma (PACG) across varied severity levels on presentation to a tertiary eye care center. This was a cross-sectional study, which included 323 eyes of clinically diagnosed cases of PACG. Glaucoma severity was categorized according to mean deviation (MD) as mild (-6.00 dB or more), moderate (-6.01 to -12.00 dB), and severe (-12.01 to -30.00 dB). AS-OCT measured the nasal (N) and temporal (T) angle opening distance at 500 μm (AOD 500) and 750 μm (AOD 750), anterior chamber angle (ACA), lens vault (LV), and anterior chamber width (ACW). The VF severity was then correlated with the AS-OCT parameters using statistical analysis. The mean age ± standard deviation (SD) of the patients included in the study was 56.03 ± 8.6 years, with a 1:1.2 gender ratio. The number of eyes with mild, moderate, and severe VFs were 140 (43.3%), 88 (27.24%), and 95 (29.41%), respectively. There was no statistically significant correlation in the mean anterior chamber angle parameters (AOD 500, AOD 750, ACA 500, ACA 750, LV, ACW, and axial length (AL)) among the groups. However, the correlation between AOD 500 and LV thickness was found to be significant (P = 0.0000) with a negative Spearman's rank correlation coefficient (r = -0.3329). The ACA parameters obtained by AS-OCT along the horizontal axis after elimination of pupillary block by laser peripheral iridotomy do not correlate and cannot be used to assess the disease severity of PACG.

HLA-DPA1 gene polymorphism in primary glaucoma.

To explore the association between human leukocyte antigen (HLA)-DPA1 gene polymorphism and primary glaucoma. Six single nucleotide polymorphisms (SNPs) were genotyped in 51 patients and 51 healthy controls through Polymerase Chain Reaction (PCR). The possible association between HLA-DPA1 gene mutation and primary glaucoma was detected using the t-test and the Chi-square test. Rs1676486 genotype had a significant genetic correlation. Rs3753841 and rs12138977 genotypes had a higher minor-allele frequency in control group. The CT + CC genotype frequency of rs12138977 showed a significant genetic correlation in both case group and control group. Moreover, the rs12138977 polymorphism and corneal thickness had little influence on the occurrence of primary angle-closure glaucoma (PACG). Also, the main risk factors for PACG were intraocular hypertension and short axial length. The HLA-DPA1 gene polymorphism may be related to the severity of PACG.

Relationship between ocular biometry and severity of primary angle-closure glaucoma: relevance for predictive, preventive, and personalized medicine.

Several ocular factors have been identified for primary angle-closure glaucoma (PACG), such as a small cornea, elevated intraocular pressure (IOP), shallow anterior chamber, and short axial length (AL). However, the relationship between the severity of PACG and various ocular parameters [IOP, anterior chamber depth, AL, central corneal thickness] is not fully understood. A 7-year cross-sectional study. A total of 2254 eyes of 1312 PACG patients (females = 856 [1479 eyes] and males = 456 [775 eyes]) were included. A detailed eye examination was performed. The participants were categorized into gender subgroups followed by subdivision into three different severity groups according to their mean deviation (MD) of the visual fields results as follows: mild (MD ≤ 6dB), moderate (MD 6-12dB), and severe (MD > 12dB) PACG. The associations of ocular biometry with severity of PACG were analyzed using paired Student's t test, multivariate linear regression, and logistic regression analysis. There was a significant positive correlation between the MD and AL in the female subgroup (B = 0.663, p = 0.001, 95%CI = 1.070 to 1.255) but not in the male subgroup. Increased AL levels (mild [OR = 1], moderate [OR = 1.047, p = 0.062, 95%CI = 0.947 to 2.462], and severe [OR = 1.274, p < 0.001, 95%CI = 1.114 to 1.457]) were only associated with the severity of PACG in females. Paired Student's t tests showed that the long AL female eyes have a higher MD value than in the short AL female eyes (mean difference = 3.09, t = 6.846, p < 0.001) in the same subjects, but not in the male subgroup (p = 0.648). The AL was positively and significantly related to the severity of PACG in female but not male subjects. This finding refers to the PACG pathogenesis and suggests the use of AL assessment in glaucoma monitoring, diagnosis, and progression. This may contribute to further development of personalized strategies in preventive medicine.

Associations between the red blood cell distribution width and primary angle-closure glaucoma: a potential for disease prediction.

The red blood cell distribution width (RDW) is a simple and inexpensive laboratory parameter that can be linked to oxidative stress, inflammation and microvascular flow resistance. For this research, we performed a large-sample case-control study to describe the relationships between the RDW and primary angle-closure glaucoma (PACG). A total of 1191 PACG patients (422 males and 769 females), who were divided into mild, moderate and severe PACG groups, and 982 healthy controls (344 males and 638 females) were recruited between January 2008 and June 2018. Detailed eye and physical examinations were performed for each subject. Based on the laboratory results, the mean RDW was significantly higher (p < 0.001) in the PACG group (13.01 ± 0.82%) than in the control group (12.65 ± 0.53%). Moreover, the mean RDW level was lower (p < 0.05) in the mild PACG group than in the moderate and severe PACG groups. The Pearson correlation analyses showed significant positive correlations between the mean deviation and the RDW (r = 0.141, p < 0.001) and the intraocular pressure and the RDW (r = 0.085, p = 0.004). After adjusting for the confounding factors, the logistic regression analyses indicated that the odds ratio for the PACG group was 2.318 (p < 0.001, 95% confidence interval 1.997, 2.690) when compared to the control group. Additionally, an increased RDW was associated with the PACG severity, and this trend was also observed in the gender and age subgroups. In summary, the results of our study showed that an elevated RDW was associated with PACG and its severity. If future studies confirm this relationship, the use of an RDW assessment may help to predict the PACG severity in each patient in order to better customise effective prevention treatments.

COL11A1 Polymorphisms Are Associated with Primary Angle-Closure Glaucoma Severity.

Purpose PLEKHA7 and COL11A1 were genotyped for single-nucleotide polymorphisms (SNPs) to investigate the possible association of these two genes with primary angle-closure glaucoma (PACG) and disease severity. Method A total of 51 PACG cases and 51 normal controls were recruited. Twelve SNPs in the PLEKHA7 (rs216489, rs1027617, rs366590, rs11024060, rs6486330, rs11024097, and rs11024102) and COL11A1 (rs1676484, rs3753841, rs12138977, rs2126642, and rs2622848) genes were genotyped by direct Sanger sequencing. Distributions of allele frequencies and genotype frequencies in cases and controls, as well as in mild, moderate, and severe subgroups, were compared based on mean defect (MD ≤ 6.00 dB, 6 dB < MD ≤ 12 dB, and MD > 12 dB were considered mild, moderate, and severe, respectively). Independent Student's t-tests and chi-square tests were used to compare characteristics of PACG cases and controls. Chi-square tests were used to compare the distribution of allele frequencies in cases and controls and in MD-based subgroups with various degrees of glaucoma severity. Binary logistic regression was used to compare the distribution of genotype frequencies and calculate odds ratios (OR) with confidence intervals (CI). Result Three of the 12 SNPs in COL11A1, rs1676486 (P=0.026, OR = 2.089, 95% CI = 1.092–3.996), rs3753841 (P=0.036, OR = 1.886, 95% CI = 1.038–3.426), and rs12138977 (P=0.024, OR = 2.133, 95% CI = 1.104–4.123) were found to have a significant association with PACG. Furthermore, in the subgroup analysis, rs1676486 (P=0.018, OR = 2.416, 95% CI = 1.284–4.544; P=0.011, OR = 2.119, 95% CI = 1.204–3.729), rs12138977 (P=0.009, OR = 2.158, 95% CI = 1.287–3.618; P=0.006, OR = 1.962, 95% CI = 1.239–3.106), and rs3753841 (P=0.007, OR = 2.550, 95% CI = 1.344–4.839) showed statistically significant differences between moderate/severe groups and controls. Conclusion Our data suggested that COL11A1 rs1676484, rs3753841, and rs12138977 polymorphisms may be of value for further study as potential gene-dependent risk factors for developing PACG. Moreover, COL11A1 rs1676484 and rs12138977 polymorphisms might be associated with PACG disease severity.

Cigarette Smoking on Severity of Primary Angle Closure Glaucoma in Malay Patients.

The purpose of this study was to determine the association between cigarette smoking and the severity of primary angle closure glaucoma (PACG) in Malay patients residing in Malaysia. A cross-sectional study was conducted involving 150 Malay PACG patients between April 2014 and August 2016. Ocular examination was performed including Humphrey visual field (HVF) 24-2 analysis assessment. On the basis of the 2 consecutive reliable HVFs, the severity of glaucoma was scored according to modified Advanced Glaucoma Intervention Study (AGIS) by 2 masked investigators and classified as mild, moderate, and severe. Those with retinal diseases, neurological diseases, memory problem, and myopia ≥4 diopters were excluded. Their smoking status and details were obtained by validated questionnaire from Singapore Malay Eye Study (SiMES). The duration of smoking, number of cigarettes per day, and pack/year was also documented. Multiple linear regression analysis was conducted. There was a significant association between education level and severity of PACG (P=0.001). However, there was no significant association between cigarette smoking and severity of glaucoma (P=0.080). On the basis of multivariate analysis, a linear association was identified between cigarette smoked per day (adjusted b=0.73; 95% CI: 0.54, 1.45; P<0.001) and body mass index (adjusted b=0.32; 95% CI: 0.07, 1.35; P=0.032) with AGIS score. There was no significant association between cigarette smoking and severity of PACG. Cigarette smoked per day among the smokers was associated with severity of PACG. However, because of the detrimental effect of smoking, cessation of smoking should be advocated to PACG patients.

Association of Plasma Complement C3 Levels With Primary Angle-Closure Glaucoma in Older Women.

The plasma complement component (C)3 concentration and clinical characteristics of primary angle-closure glaucoma (PACG) subjects were analyzed to evaluate whether C3 levels were correlated with PACG severity. Peripheral blood samples from subjects with PACG (n = 237) and normal controls (n = 158) were collected. The plasma levels of C3 were measured by immunoturbidimetry. The assessments of intraocular pressure; vertical cup/disc ratio (VCDR); central corneal thickness; axial length; anterior chamber depth; visual field-derived mean deviation; and mean sensitivity were performed by glaucoma specialists. Based on their sex and age, the PACG subjects were categorized into female (0-49 years, 50-59 years, 60-70 years, and 70+ years) and male (0-49 years, 50-59 years, 60-70 years, and 70+ years) subgroups. The mean plasma levels of C3 (101.71 ± 21.17 mg/dL) were significantly lower (P < 0.001) in PACG subjects compared with controls (110.68 ± 17.63 mg/dL). Plasma C3 concentrations were significantly lower (P < 0.001) in female subjects with PACG (100.74 ± 19.83 mg/dL) compared with controls (113.58 ± 18.80 mg/dL). A similar result was observed when plasma levels of C3 were compared between the PACG and control groups with respect to age (≥50 years). The mean plasma levels of C3 were lowest in the severe PACG group followed by moderate PACG and mild PACG, and the differences were significant (P = 0.003). Multivariable regression analyses showed that there was a significant correlation between C3 levels and VCDR (B = -0.310, P = 0.047). Older women with PACG have lower plasma C3 levels, which were further demonstrated to be negatively associated with PACG severity. These findings suggest the involvement of C3 in the pathomechanisms of PACG in older women.

The association between serum uric acid and glaucoma severity in primary angle closure glaucoma: a retrospective case-control study.

Uric acid (UA) is a major antioxidant molecule and has been hypothesized to have a protective effect on the central nervous system against oxidative damage. We prospectively investigated the serum concentration of UA in primary angle closure glaucoma (PACG), and explored the association between serum concentration of UA and the severity of PACG. Using a retrospective case-control study design, 886 PACG subjects and 994 control subjects who attended the Eye & ENT Hospital of Fudan University, were eligible for this study. Glaucoma severity was classified as mild (MD ≤ 6.00 dB), moderate (12 dB ≥ MD > 6 dB) and severe (MD > 12 dB) based on the MD (mean deviation). The levels of UA were significantly lower (p = 0.025) in PACG (0.286 ± 0.082 mmol/l) compared with control (0.295 ± 0.085 mmol/l). The mean serum UA levels were lowest in the severe group (0.281 ± 0.074 mmol/l) followed by moderate (0.282 ± 0.080 mmol/l) and mild (0.297 ± 0.090 mmol/l) with significant differences among the three groups (p = 0.032). In multivariate regression analysis, there was a significant negative correlation between UA level and vertical cup-disc ratio (B = −0.165, p = 0.035). Significantly lower serum UA concentration in PACG and its negative association with disease severity presented it as an important candidate in reaction to oxidative stress in glaucoma pathogenesis.

A catalase promoter variant rs1001179 is associated with visual acuity but not with primary angle closure glaucoma in Saudi patients

BackgroundTo Investigate whether the g.4760C>T polymorphism in the promoter region of the catalase gene (CAT) is a risk factor for primary angle closure glaucoma (PACG) in the Saudi population.Methods138 unrelated PACG patients and 403 unrelated control subjects from Saudi Arabia were genotyped for a single nucleotide polymorphism (SNP; rs1001179; g.4760C>T) utilizing Taq-Man® assay. The association between different genotypes and various clinical indices important for PACG was also investigated.ResultsThe distribution of different genotypes was comparable between both study groups. The genotype “C/C” was predominant among cafses; 94 (68.1%) and controls; 289 (71.7%). Heterozygous genotype “C/T”, was present in 41 (29.7%) of cases and 103 (25.6%) of controls, where the homozygous variant genotype was present in only 3 (2.2%) of cases and 11 (2.7%) of the controls. The distribution of variant allele was similar in both study groups (p= 0.568). Interestingly, there was a trend of association between the type of the variant (homozygous variant, heterozygous and wildtype genotype) and one important parameter for PACG, which is visual acuity. The visual acuity increase was; 0.62 (±0.74), 0.88 (±0.88) and 1.27 (±0.95) in patients carrying the “C/C”, “C/T” and “T/T” genotypes respectively, which was statistically significant in both ANOVA and pairwise individual T tests (p = 0.022, 0.031 and 0.039) when compared to controls.ConclusionsThis variant is possibly associated with visual acuity in PACG patients and thus had the potential to be used as a parameter for assessing PACG severity.