Genotype/Phenotype Correlation in Primary Congenital Glaucoma Patients in the Lebanese Population: A Pilot Study

Background: The incidence of primary congenital glaucoma (PCG) varies among geographic regions and ethnic groups. The frequency of PCG in Lebanon and identification of disease-causing mutations have not been studied previously.

Purpose: To investigate the role of Cytochrome P1B1 (CYP1B1) gene and Myocillin (MYOC) gene mutations in PCG in the Lebanese population and study possible genotype/phenotype correlations.

Methods: Patients with unilateral or bilateral PCG diagnosed at the American University of Beirut Medical Center and their first-degree relatives (parents and siblings) were screened for CYP1B1 and MYOC mutations. Demographic and phenotypic characteristics were recorded. Phenotypic characteristics pertaining to disease severity and outcomes were compared.

Results: Eighteen Lebanese families (66 subjects) with at least one member affected with PCG were included in this study. Mutations in the CYP1B1 gene were detected in 6 families (33%). Five previously described mutations (p.R444Q; p.E229K; p.R469W; p.G61E; p.M1T) and one new single nucleotide deletion were identified (1793delC). Patients in whom CYP1B1 mutations were detected tended to have a more severe phenotype as evidenced by earlier age at diagnosis, higher rate of bilateral disease, and higher number of glaucoma surgeries than those in whom no CYP1B1 mutations were present. MYOC gene mutations were not detected in any patients.

Conclusion: The rate of CYP1B1 mutations in Lebanese patients with PCG is lower than that reported in other Arab and Middle Eastern populations and suggests other genes are responsible for PCG in the remainder.     

Lack of Association Between LOXL1 Gene Polymorphisms and Primary Open Angle Glaucoma in the Saudi Arabian Population

Purpose: To investigate whether major single nucleotide polymorphisms (SNPs) in the LOXL1 gene associated with pseudoexfoliation glaucoma are associated with primary open angle glaucoma (POAG) in the Saudi Arabian population.

Methods: The regions of the LOXL1 gene associated with pseudoexfoliation glaucoma, encompassing the three common SNPs, (rs1048661, rs3825942 and rs2165241), were sequenced in a Saudi Arabian dataset consisting of 96 POAG cases and 101 healthy controls.

Results: The allele frequency of the G exfoliation risk allele for SNP rs1048661 in POAG cases and controls was 0.75 and 0.76 (p?=?0.886), respectively and the allele frequency difference was not statistically significant (p?=?0.866). There was no statistically significant difference in the genotypes between patients and controls (p?=?0.261 and 0.156 for genotypes G/G and G/T respectively). As for SNP rs3825942, the frequency of the “G” allele in the POAG patients was comparable to that in the controls (p?=?0.477) and there was no statistically significant difference in genotype G/G and A/G frequency in the study groups. As for SNP rs2165241, the “T” allele frequency in the POAG patients (0.46) was slightly higher than the frequency in controls (0.39), but this difference was not statistically significant (p?=?0.176).

Conclusion: The Saudi Arabian POAG population, similar to all other populations studied to date, demonstrates no association with SNPs associated with pseudoexfoliation glaucoma.     

Analysis of the polymorphic variants of RAN and GEMIN3 genes and risk of Primary Open-Angle Glaucoma in the Polish population

Background: Glaucoma is considered as a neurodegenerative disorder in which the optic nerve damage leads to irreversible blindness. Many scientific findings indicate miRNA implication in the neurodegeneration process. In this study, we aimed to evaluate the polymorphic variants of miRNA processing genes, RAN (rs14035) and GEMIN3 (rs197388), and their association with a risk of primary open-angle glaucoma (POAG) in relation to selected clinical parameters.

Materials and methods: The study included 246 POAG patients and 188 controls. The selected gene polymorphisms were analyzed by TaqMan SNP Genotyping Assay using DNA extracted from blood samples.

Results: The obtained results indicated that the AA genotype of rs197388 as well as the A allele in the same gene may be associated with an elevated risk of POAG development (P = 0.021, P = 0.017 respectively). The correlation between the data and clinical parameters has shown that the A allele of rs197388 in relation to retinal nerve fiber layer(RNFL) could be responsible for an increased risk of glaucoma occurrence (P = 0.028), while the AT genotype could be associated with a decreased risk of POAG according to the mean deviation parameter (P = 0.023).

Conclusion: Our data has shown that GEMIN3 gene (rs197388) polymorphisms might be associated with a risk of POAG development in the Polish population. This is the first report evaluating the polymorphic variants of miRNA processing genes, RAN and GEMIN3, with a changed risk of glaucoma.     

Type 2 Diabetes,Fasting Glucose,Hemoglobin A1c Levels and Risk of Primary Open-Angle Glaucoma: A Mendelian Randomization Study

PurposeTo evaluate the potential causal associations between type 2 diabetes and fasting glucose and HbA1c levels and the risk of primary open-angle glaucoma (POAG) in European and East Asian populations.MethodsWe selected genetic variants (P < 5 × 10⁻⁸) for type 2 diabetes (898,130 Europeans; 433,540 East Asians), fasting glucose, and HbA1c (196,991 Europeans; 36,584 East Asians) from three meta-analyses of genome-wide association studies (GWAS). The GWAS for POAG provided summary statistics (192,702 Europeans; 46,523 East Asians). Mendelian randomization (MR) analysis was accomplished using the inverse variance–weighted method, weighted-median method, MR Egger method, and MR-Pleiotropy RESidual Sum and Outlier test.ResultsGenetically predicted type 2 diabetes was potentially positively associated with POAG in the European ancestry (body mass index [BMI]–unadjusted: odds ratio [OR] = 1.07, 95% confidence interval [CI], 1.01–1.14, P = 0.028; BMI-adjusted: OR = 1.07, 95% CI, 1.01–1.15, P = 0.035), but not in the East Asian ancestry (BMI-unadjusted: OR = 1.01, 95% CI, 0.95–1.06, P = 0.866; BMI-adjusted: OR = 1.00, 95% CI, 0.94–1.05, P = 0.882). There was no evidence to support a causal association of fasting glucose (European: OR = 1.19, P = 0.157; East Asian: OR = 0.94, P = 0.715) and HbA1c (European: OR = 1.27, P = 0.178; East Asian: OR = 0.85, P = 0.508) levels with POAG.ConclusionsThe causal effect of type 2 diabetes on the risk of POAG is different in European and East Asian populations. The point estimates of fasting glucose and Hb1Ac with POAG are large but not statistically significant, which prompts the question of statistical power.     

A 7-Year Population Study of Primary Angle Closure Glaucoma Admissions and Climate in Taiwan

Purpose: Using data from seven years of hospital admissions in Taiwan, this study sets out to investigate meteorological factors associated with primary angle closure glaucoma (PACG). We investigated the relationship between PACG admissions and five different climate indices. Method: Hospital admissions data from the Taiwan National Health Insurance Research Database (1997 to 2003) provided monthly PACG admission rates (per 100,000 population). We categorized the 4,722 PACG cases by gender and age (including four subgroups: 40–49, 50–59, 60–69, and ≥ 70 years). After adjusting for the time-trend effect, the Auto-Regressive Integrated Moving Average regression method was performed to evaluate the effects of climatic and monthly factors on PACG admission rates. Results: The mean annual rate of PACG admissions across the entire study period was 9.48/100,000 and higher in females than males (11.28 vs. 7.80/100,000). The PACG admissions were significantly higher in March for male patients, and for the 60 to 69-year-old and > 69-year-old age groups (p < 0.05). After adjustment for seasonality, month, and time-trend, a significant association between relative humidity and monthly PACG admission rates was observed for the total data set, for males, and for the 60- to 69-year-old (p < 0.05) populations. No such relationship existed with temperature, rainfall, barometric pressure or hours of sunshine. Conclusion: This is the largest, nationwide, population-based study to investigate the dependence of PACG admission rates on meteorological conditions. PACG admission rates were significantly higher in March and with increased relative humidity. We recommend data be collected from other regions and from other ethnic groups to determine the general pattern worldwide.     

The C677T Variant in the Methylenetetrahydrofolate Reductase Gene Is Not Associated with Disease in Cohorts of Pseudoexfoliation Glaucoma and Primary Open-Angle Glaucoma Patients from Iowa

The rds-peripherin gene encodes a photoreceptor-specific protein that is localized in the outer segment disc membranes of both rods and cones. We screened a Spanish family with central areolar choroidal dystrophy for mutations in candidate genes. A base substitution was identified in the RDS-peripherin gene of one patient and dna sequencing revealed a C-to-T transition in codon 172, arginine being substituted by tryptophan. The mutation was also detected in two asymptomatic family members who showed irregular pigmentation in the retinal pigment epithelium (rpe). The pheno-type is similar to other macular dystrophies caused by mutation in the rds-peripherin gene.     

Genes of tumor necrosis factors and their receptors and the primary open angle glaucoma in the population of Central Russia

AIM: To examine the association of genetic polymorphisms (-308)G/A TNFα, (+250)A/G Ltα, (+36)A/G TNFR1, (+1663)A/G TNFR2 with the development of primary open angle glaucoma (POAG) among people in Central Russia. METHODS: The study sample included 443 individuals, of which 252 patients with POAG and 191 individuals in the control group. Genotyping of (-308)G/A TNFα, (+250)A/G Ltα, (+36)A/G TNFR1, (+1663)A/G TNFR2 was performed using polymerase chain reaction. The distribution of alleles and genotypes of the studied DNA markers in the groups was examined by 2×2 contingency tables and χ2 with the Yates’s correction for continuity and odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Allele (-308)G TNFα (Р=0.01, OR=1.78, 95%CI 1.12-2.85) was identified as a risk factor for POAG. Homozygotes (-308) AA TNFα are at a lowest risk for development of the disease (Р=0.01, OR=0.0005). The following combination of genetic variants of cytokines were associated with a reduced risk of POAG: (+1663)A TNFR2 and (+250)G Ltα (OR=0.34) CONCLUSION: Genetic polymorphisms (-308)G/A TNFα, (+250)A/G Ltα, (+1663)A/G TNFR2 associated with the development of POAG in the population of Central Russia.     

[In Press] Genes of tumor necrosis factors and their receptors and the primary open-angle glaucoma in the population of Central Russia

AIM: To examine the association of genetic polymorphisms (-308)G/A TNFα, (+250)A/G Ltα, (+36)A/G TNFR1, (+1663)G/A TNFR2 with the development of primary open-angle glaucoma (POAG) among people in Central Russia. METHODS: The study sample included 443 individuals, of which 252 patients with POAG and 191 individuals in the control group. Genotyping of (-308)G/A TNFα, (+250)A/G Ltα, (+36)A/G TNFR1, (+1663)G/A TNFR2 was performed using polymerase chain reaction. The distribution of alleles and genotypes of the studied DNA markers in the groups was examined by 2×2 contingency tables and ?2 with the Yates’s correction for continuity and odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Allele (-308)G TNFα (Р=0.01, OR=1.78, 95%CI 1.12-2.85) was identified as a risk factor for POAG. Homozygotes (-308) AA TNFα are at a lowest risk for development of the disease (Р=0.01, OR=0.0005). The following combination of genetic variants of cytokines were associated with a reduced risk of POAG: (+1663)A TNFR2 and (+250)G Ltα (OR=0.34) CONCLUSION: Genetic polymorphisms (-308)G/A TNFα, (+250)A/G Ltα, (+1663)G/A TNFR2 associated with the development of POAG in the population of Central Russia.     

The Groningen Longitudinal Glaucoma Study. II. A prospective comparison of frequency doubling perimetry,the GDx nerve fibre analyser and standard automated perimetry in glaucoma suspect patients

Purpose: We aimed to determine prospectively the incidence of abnormal test results on frequency doubling perimetry (FDT), the nerve fibre analyser (GDx) and standard automated perimetry (SAP) in a cohort of glaucoma suspect patients with normal findings for all these tests at baseline. Methods: Seventy glaucoma suspect patients were followed prospectively for 4 years with SAP (Humphrey field analyser 30‐2 SITA Fast), FDT (C‐20 full‐threshold) and GDx (Version 2.010) in a clinical setting. All patients had normal baseline test results on SAP, FDT and GDx. After the follow‐up period, the number of patients who converted (whose test results changed from normal at baseline to reproducibly abnormal during follow‐up) were counted for each technique and then compared. The cut‐off point for FDT was > 1 depressed test‐point p < 0.01 in the total deviation probability plot; the cut‐off point for GDx was the Number > 29. Results: Of the 70 glaucoma suspect patients, three converted on FDT, 14 on GDx and six on SAP. These proportions are significantly different for GDx versus SAP (p = 0.033) and GDx versus FDT (p = 0.002), but not for FDT versus SAP (p = 0.256). Conclusions: The most frequent finding after a 4‐year follow‐up was conversion on GDx.     

The Study of Relationships between the Damage of Visual Function and Hemorrheology, Ocular Rheography, as well as Other Related Factors in Patients with Primary Open Angle Glaucoma (POAG)

Researches of glaucoma visual function damage, hemorrheololgy, ocular rheography and other related multiplex factors, with computed multifactorial stepwise regresion analysis, indicate that the elevation of intraocular pressure (IOP) is not the only factor to induce visual impairment. POAG patients are shown to have markedly reduced diastolic purfussion pressure in ophthalmic artery, besides prolonged filling time of the retinal artery and vein, diminished erythrocyte deformability and increased platelet adhesion rate. The characterility of ocular rheographic changes in POAG patients of controlled IOP suggest that the abnormal changes of hemorrheololgy be responsible for the damage of visual function. The abnormal changes of plasma viscosity, blood apparent viscosity, blood viscoelasticity, hematocrit, mean red cell volume etc could be found in addition to the reduction of PO2, SQ2% and trace elements (Cr, Zn, Mg, Fe) in patients with POAG. Computed multiply stepwise regression analysts and Bayes discrimination were made among the deteriorate rate of quantitative visual field and 28 factors from the combined investigation. Only the hemorrheological index could be introduced into the multiply regression equations. The more the damage of visual function in POAG patients, the more accurate the discriminatory effect. Based upon the results, and the reports of articles published as well as the search of 1982-1989 Compact Combridge MEDLINE Medical data base, the new clinical concept could be presented that POAG might belong to the scope of blood hyperviscosity syndromes. When IOP elevation and the decrease of ocular artery pressure existed, the damage of visual function in POAG patients should be deteriorated.     

Predictive value of the vitamin K epoxide reductase complex subunit 1 G-1639A and C1173T single nucleotide polymorphisms in retinal vein occlusion

Background: To determine if vitamin K epoxide reductase complex subunit 1 gene polymorphisms have an effect on the risk of having a retinal vein occlusion. Design: Case‐control study. Participants: The study population consisted of 68 patients who were newly diagnosed with retinal vein occlusion and 66 sex‐matched controls. Methods: Genomic DNA was extracted from peripheral leukocytes from ethylenediamine tetra‐acetic acid‐anticoagulated blood. Genotyping of the vitamin K epoxide reductase complex subunit 1 G‐1639A (rs 9923231) and C1173T (rs 9934438) single nucleotide polymorphisms was performed using real‐time polymerase chain reaction and commercially available kits. Main Outcome Measures: A full ophthalmological evaluation was performed in each subject, and all subjects were screened for hypertension, hypercholesterolaemia and diabetes. The genotypes of the vitamin K epoxide reductase complex subunit 1 single nucleotide polymorphisms were determined. Results: The vitamin K epoxide reductase complex subunit 1 GG and CC genotypes were more frequent (41% vs. 21%; P = 0.021), and the combined GA/AA and CT/CC genotypes were less frequent in patients with retinal vein occlusion than in control subjects. After adjusting for hypertension, age, plasma fibrinogen levels and prevalence of diabetes and hypercholesterolaemia, the GG and CC genotypes were found to be an independent predictor of retinal vein occlusion (B = 2.28; odds ratio = 9.79; P = 0.003; 95% confidence interval: 2.22–43.24). Conclusion: It was found that subjects with the vitamin K epoxide reductase complex subunit 1 GG and CC genotypes had a higher risk of retinal vein occlusion.     

The - 429 T/C and - 374 T/A gene polymorphisms of the receptor of advanced glycation end products gene are not risk factors for diabetic retinopathy in Caucasians with type 2 diabetes

OBJECTIVE: The aim of this study was to look for a relationship between the - 429 T/C and the - 374 T/A gene polymorphisms of the receptor of advanced glycation end products (RAGE) gene and the development of diabetic retinopathy in Caucasians with type 2 diabetes. MATERIALS AND METHODS: One hundred and sixteen subjects with type 2 diabetes and diabetic retinopathy were compared to 70 diabetic subjects without diabetic retinopathy. Additionally, 76 subjects with proliferative diabetic retinopathy (a subgroup of diabetic retinopathy) were compared to 70 diabetic subjects without diabetic retinopathy. RESULTS: The - 429 T/C and the - 374 T/A RAGE gene distributions in patients with diabetic retinopathy (- 429 T/C: CC 0.9%, TC 25.9%, TT 73.2%; - 374 T/A: AA 9.5%, TA 47.4%, TT 43.1%) were not significantly different from those of diabetic subjects without retinopathy (- 429 T/C: CC 0%, TC 25.7%, TT 74.3%; - 374 T/A: AA 15.7%, TA 42.9%, TT 41.4%). Moreover, the - 429 T/C and the - 374 T/A RAGE gene distributions in patients with proliferative diabetic retinopathy were not statistically significantly different from those in diabetic subjects without retinopathy. CONCLUSION: Our study failed to demonstrate an association between either - 429 T/C or - 374 T/A gene polymorphism of the RAGE gene and diabetic retinopathy in Caucasians with type 2 diabetes. Additionally, we failed to demonstrate an association between either - 429 T/C or - 374 T/A gene polymorphism of the RAGE gene and proliferative diabetic retinopathy in Caucasians with type 2 diabetes.     

疏肝通窍法对青光眼视神经损害大鼠视网膜神经节细胞凋亡及视网膜、视神经超微结构的影响

目的：通过观察视网膜神经节细胞（RGCs）计数和视网膜、视神经超微结构及形态学变化,研究疏肝通窍法保护高眼压损害的视神经的作用机制,为开发保护青光眼视神经的有效中药方剂提供参考。方法：实验研究。以SD大鼠为实验动物,右眼前房注射复方卡波姆溶液建立慢性高眼压模型（90只）。将不同时间窗（1周、2周、3周）的慢性高眼压大鼠模型分别分为模型组（5只）、阴性对照组（5只）、阳性对照组（5只）、低剂量通窍明目4号治疗组（低剂量治疗组） （10 gkg-1d-1,5只）、中剂量治疗组（20 gkg-1d-1,5 只）和高剂量治疗组（40 gkg-1d-1,5 只）,以具有疏肝通窍作用的通窍明目4 号灌胃为干预手段,运用CMIAS系列数码医学图像分析系统观察RGCs计数,电镜观察视网膜、视神经超微结构,采用one-way ANOVA法和LSD法进行数据分析。结果：①RGCs计数：随着高眼压持续的时间延长,RGCs计数逐渐减少（F=87.67、29.69、33.38、38.03、33.67、23.36,P<0.001）,经药物治疗后,高眼压持续1周、2周和3周各组的高中剂量治疗组RGCs的存活量明显增加,与阴性对照组和阳性对照组比较差异均有统计学意义（P<0.001）。②模型组和阴性对照组视网膜结构排列紊乱,厚度变薄,空泡变性,细胞萎缩坏死,各治疗组视网膜的结构紊乱减轻,各层厚度略增加,空泡变性减少,细胞萎缩程度减轻。③模型组和阴性对照组视神经轴突排列紊乱,密度降低,微丝溶解,空泡样变,细胞器肿胀破坏,髓鞘变性,各治疗组视神经髓鞘的水肿程度减轻,髓索的变性有所修复,线粒体的水肿程度也减轻。结论：通窍明目4 号可以改善高眼压大鼠模型RGCs生存的微环境,保护未受损的细胞,修复轻度受损的RGCs,延缓或阻止部分受损细胞的下行性改变,减少高眼压大鼠模型RGCs的凋亡。疏肝通窍法对青光眼视神经损害具有保护作用。