Primary Open-angle Glaucoma Cases Research Articles

Determining Possible Shared Genetic Architecture Between Myopia and Primary Open-Angle Glaucoma.

PurposeTo determine genetic correlations between common myopia and primary open-angle glaucoma (POAG).MethodsWe tested the association of myopia polygenic risk scores (PRSs) with POAG and POAG endophenotypes using two studies: the Australian & New Zealand Registry of Advanced Glaucoma (ANZRAG) study comprising 798 POAG cases with 1992 controls, and the Rotterdam Study (RS), a population-based study with 11,097 participants, in which intraocular pressure (IOP) and optic disc parameter measurements were catalogued. PRSs were derived from genome-wide association study meta-analyses conducted by the Consortium for Refractive Error and Myopia (CREAM) and 23andMe. In total, 12 PRSs were constructed and tested. Further, we explored the genetic correlation between myopia, POAG, and POAG endophenotypes by using the linkage disequilibrium score regression (LDSC) method.ResultsWe did not find significant evidence for an association between PRS of myopia with POAG (P = 0.81), IOP (P = 0.07), vertical cup–disc ratio (P = 0.42), or cup area (P = 0.25). We observed a nominal association with retinal nerve fiber layer (P = 7.7 × 10−3) and a significant association between PRS for myopia and disc area (P = 1.59 × 10−9). Using the LDSC method, we found a genetic correlation only between myopia and disc area (genetic correlation [RhoG] = −0.12, P = 1.8 × 10−3), supporting the findings of the PRS approach.ConclusionsUsing two complementary approaches we found no evidence to support a genetic overlap between myopia and POAG; our results suggest that the comorbidity of these diseases is not influenced by common variants. The association between myopia and optic disc size is well known and validates this methodology.

Frequencies of 4 Distinct Patterns of Glaucomatous Disc Appearance and Their Clinical Associations in Japanese Population-based Studies

To study the frequencies and factors associated with 4 disc patterns in primary open-angle glaucoma (POAG) identified in population-based studies: focal glaucomatous (FG type), generalized enlargement of cup (GE type), myopic glaucomatous (MG type), and senile sclerotic glaucomatous (SS type) patterns. In total, 270 disc photographs of acceptable quality were extracted from the records of 270 definitive POAG cases diagnosed according to the International Society of Geographical and Epidemiological Ophthalmology Criteria in 2 Japanese population-based glaucoma surveys. One randomly chosen eye from the bilateral POAG cases was included. Using a method of κ coefficient of reproducibility of classification of 0.80 according to a preliminary study, 143 discs were classified as FG, GE, MG, or SS types with respective frequencies of 57% (95% confidence interval [CI], 48-66), 33% (95% CI, 25-42), 7% (95% CI, 3-13), and 3% (95% CI, 0-7), and 127 discs as the miscellaneous type. Multinomial logistic regression analysis showed that the MG type was associated (P=0.052, 0.025, 0.019, and 0.018) with younger age, lower body mass index (BMI), and greater disc area and ovality, and the GE type was associated (P<0.001, 0.036, and 0.056) with greater disc area, corneal radius, and hyperopic refraction than the FG type. The FG type occurs most frequently in Japanese POAG followed by the GE type. The MG and SS types occurred much less often than previously reported in Japanese. Associations with age, BMI, disc area and ovality, refraction, and corneal radius differed among the FG, GE, and MG types.

Inflammatory model in patients with primary open angle glaucoma and diabetes

To assess the inflammatory cytokines expression in aqueous humor in diabetic primary open angle glaucoma (POAG) patients. A cross-sectional study on 87 eyes, distributed as following: 26 eyes from diabetic patients, 16 eyes with POAG and 21 eyes from diabetic POAG patients; healthy controls (24 eyes) were recruited from patients undergoing conventional cataract surgery. A volume of 100 µL of aqueous humor (AH) was collected during phacoemulsification and 21 inflammatory markers were quantified using a Luminex® cytometric bead assay: IL-1Ra, IL-1α, IL-1β, IL-5, IL-6, IL-10, IL-17, GM-CSF, IFNγ, CCL2, CCL3, CCL4, CXCL5, CXCL8, bFGF, VEGF, TNFα. Main changes in cytokine profile were analyzed and compared between groups. Data on demographics, duration of glaucoma, intraocular pressure (IOP), number of anti-glaucoma substances were recorded for correlation analysis and prediction models. Significant differences in cytokine expression between groups were detected for CXCL5 (P<0.001), CXCL8 (P=0.004), IL-1α (P<0.001), IL-2 (P<0.001), CCL4 (P=0.003), CCL5 (P<0.001) and TNFα (P=0.05). Post-hoc analysis identified IL-2 (P=0.009) and CXCL5 (P<0.001) as "separation markers" between POAG and diabetic POAG eyes. In POAG patients, the "separation markers" could highly predict the TNFα levels F(1, 16)=14.639, P<0.001, whereas in diabetic patients F(1, 24)=4.844, P=0.006 and diabetic POAG patients F(1, 19)=2.358, P=0.05 the level of prediction was inferior. Our results reveal an inflammatory model based on increased TNFα levels in POAG eyes. Simultaneous co-stimulatory molecules and additional inflammatory pathways need to be further explored in diabetic POAG cases, since the prediction model could only partially explain the increased TNFα level in this category of patients.

Association of Statin Use and High Serum Cholesterol Levels With Risk of Primary Open-Angle Glaucoma

The use of statins (hydroxymethylglutaryl coenzyme A inhibitors) has been associated with a lower risk of primary open-angle glaucoma (POAG); however, results have been conflicting, and little is known about the association between high cholesterol levels and POAG. To assess the association of elevated cholesterol levels and statin use with incident POAG. This study used data collected biennially from participants aged 40 years or older who were free of glaucoma and reported eye examinations, within 3 population-based cohorts: the Nurses' Health Study (N = 50 710; followed up from 2000 to 2014), the Nurses' Health Study 2 (N = 62 992; 1999-2015), and the Health Professionals Follow-up Study (N = 23 080; 2000-2014). Incident cases of POAG were confirmed by medical record review. The analyses were performed in January 2019. Biennially updated self-reported information on elevated cholesterol level status, serum cholesterol levels, and duration of statin use. Multivariable-adjusted relative risks (RRs) and 95% CIs were estimated using Cox proportional hazards regression models on pooled data, with stratification by cohort. Among the 136 782 participants in the 3 cohorts (113 702 women and 23 080 men), 886 incident cases of POAG were identified. Every 20-mg/dL increase in total serum cholesterol was associated with a 7% increase in risk of POAG (RR, 1.07 [95% CI, 1.02-1.11]; P = .004). Any self-reported history of elevated cholesterol was also associated with a higher risk of POAG (RR, 1.17 [95% CI, 1.00-1.37]). A history of any statin use was associated with a 15% lower risk of POAG (RR, 0.85 [95% CI, 0.73-0.99]). Use of statins for 5 or more years vs never use of statins was associated with a 21% lower risk of POAG (RR, 0.79 [95% CI, 0.65-0.97]; P = .02 for linear trend). The association between use of statins for 5 or more years vs never use of statins and risk of POAG was more inverse in those who were older (≥65 years: RR, 0.70 [95% CI, 0.56-0.87] vs <65 years: RR, 1.05 [95% CI, 0.68-1.63]; P = .01 for interaction). Among adults aged 40 years or older, higher serum cholesterol levels were associated with higher risk of POAG, while 5 or more years of statin use compared with never use of statins was associated with a lower risk of POAG.

Evaluation of dynamic thiol-disulfide homeostasis in glaucoma patients and the correlation with retinal nerve fiber layer analysis.

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. 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. 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). 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.

The effect of topical latanoprost on corneal clarity; 1-year prospective study†

Purpose: Quantitatively investigate the effects of topical latanoprost on the corneal optical density parameters by using Scheimpflug system.Materials and methods: New cases of primary open-angle glaucoma treated with topical latanoprost as first-line treatment were enrolled in this prospective study. Corneal densitometry measurements obtained with the Scheimpflug system (Pentacam; Oculus, HR) at baseline and 1st, 3rd, 12th months after topical latanoprost treatment. For densitometry analysis, the 12-mm diameter area of the cornea was subdivided into 4 concentric radial zones and also into anterior, central, and posterior layers based on corneal depth. Pre and post-treatment values were compared statistically by a paired sample t-test.Results: The mean age of 18 female (66.7%) and 9 male (33.3%), totally 27 cases were 59.48 ± 10.1 years. There was no statistically significant difference between pretreatment and 1st-month post-treatment corneal densitometry values in all regions (p > 0.05 for all). Corneal densitometry values began to decline at 3rd month after treatment. The decrease continued until the 12th month of the beginning of the treatment and was significant in all zones except 2–6 mm of the anterior and central zones (p = 0.23, p = 0.08, respectively).Conclusion: Long-term administration of topical latanoprost may cause decrease in corneal densitometry measurements. Further prospective studies with a longer follow-up period are required to clarify the relationship between prostaglandin analogues and their effects on the cornea transparency.

Comprehensive sequencing of the myocilin gene in a selected cohort of severe primary open-angle glaucoma patients

Primary open-angle glaucoma (POAG) is the most common form of glaucoma, prevalent in approximately 1–2% of Caucasians in the UK over the age of 40. It is characterised by an open anterior chamber angle, raised intraocular pressure (IOP) and optic nerve damage leading to loss of sight. The myocilin gene (MYOC) is the most common glaucoma-causing gene, accounting for ~2% of British POAG cases. 358 patients were selected for next generation sequencing (NGS) with the following selection criteria: Caucasian ethnicity, intraocular pressure (IOP) 21–40 mm Hg, cup:disc ratio ≥0.6 and visual field mean deviation ≤−3. The entire MYOC gene (17,321 bp) was captured including the promoter, introns, UTRs and coding exons. We identify 12 exonic variants (one stop-gain, five missense and six synonymous variants), two promoter variants, 133 intronic variants, two 3′ UTR variants and 23 intergenic variants. Four known or predicted pathogenic exonic variants (p.R126W, p.K216K, p.Q368* and p.T419A) were identified across 11 patients, which accounts for 3.07% of this POAG cohort. This is the first time that the entire region of MYOC has been sequenced and variants reported for a cohort of POAG patients.

Resting nailfold capillary blood flow in primary open-angle glaucoma

Background/AimsAn altered haemodynamic profile for various ocular posterior segment capillary beds has been documented in primary open-angle glaucoma (POAG). POAG may also involve abnormal non-ocular blood flow, and the nailfold...

Microvascular endothelial function and primary open angle glaucoma.

Purpose:To determine the role of microvascular endothelial dysfunction as risk factor for primary open angle glaucoma.Methods:A cross-sectional study was conducted involving 114 Malay patients with POAG seen at the eye clinic of Hospital Universiti Sains Malaysia. Patients aged between 40 and 80 years who were diagnosed with other types of glaucoma, previous glaucoma filtering surgery or other surgeries except uncomplicated cataract surgery and pterygium surgery were excluded. A total of 101 patients who were followed up for dry eyes, age-related cataracts or post cataracts extraction surgery were recruited as control subjects. Those with family history of glaucoma or glaucoma suspect were excluded. Microvascular endothelial function was assessed using laser Doppler fluximetry and the process of iontophoresis. Iontophoresis with acetylcholine (ACh) and sodium nitroprusside (SNP) was used to measure microvascular endothelium-dependent and endothelium-independent vasodilatations, respectively.Results:In general, POAG patients demonstrated lower ACh% and AChmax values compared with controls. There was significant difference in microvascular endothelial function [ACh%: mean, 95% confidence interval = 503.1 (378.0, 628.3), and AChmax: mean, 95% confidence interval = 36.8 (30.2, 43.5)] between primary open angle glaucoma cases (p < 0.001) and controls [ACh%: mean, 95% confidence interval = 1378.4 (1245.4, 1511.3), and AChmax: mean, 95% confidence interval = 79.2 (72.1, 86.2)]; this difference remained significant even after controlling for potential confounders. Similar difference was also found in SNP% and SNPmax between POAG and controls (p < 0.001). Age and diastolic blood pressure were inversely correlated with microvascular endothelial function.Conclusion:There was an impairment of microvascular endothelial function and endothelial-independent vasodilatation in POAG patients. Microvascular endothelial function is a potential risk factor for POAG.

Screening of CYP1B1 Arg368His as predominant mutation in North Indian primary open angle glaucoma and juvenile onset glaucoma patients.

In India, mutations in Cytochrome P450 (CYP1B1) are a predominant cause of not only primary congenital glaucoma (PCG) but also involved in primary open angle glaucoma (POAG) and juvenile onset glaucoma (JOAG). After ethical clearance, 100 POAG patients, 30 primary angle closure glaucoma (PACG) patients and 130 ethnically matched controls were recruited in this study. Genomic DNA was isolated from the blood and screened for p.Arg368His mutation in CYP1B1 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). On PCR-RFLP, 10/100 cases (10%) were found positive for Arg368His mutation. In North Indian POAG cases studied, p.Arg368His mutation was found only in heterozygous state. The frequency of p.Arg368His CYP1B1 mutation in heterozygote state (10.0%) observed in our study in North Indian POAG patients is the highest in comparison to frequency observed in other ethnic groups from Southern and Eastern India.

Lack of Association between Variant rs7916697 in ATOH7 and Primary Open Angle Glaucoma in a Saudi Cohort.

A case-control genetic association study was performed to investigate whether variant rs7916697 in atonal bHLH transcription factor 7 (ATOH7), which has been previously reported to be associated with optic disc parameters and primary open angle glaucoma (POAG) in different ethnic groups, is a risk factor for POAG or any of its clinical phenotypes in a Saudi cohort. Genotyping of rs7916697 (G>A) variant was performed in 186 unrelated POAG cases and 171 unrelated nonglaucomatous controls of Saudi origin using real-time Taq-Man® assay. Genotypic and allelic association with POAG and its related clinical indices were evaluated. Demographic and systemic disease status did not differ significantly between POAG cases and controls. Association analysis between POAG cases and controls showed no significant genotype effect under additive (p=0.707), dominant (p=0.458), and recessive (p=0.554) models. Besides, the minor ‘A' allele frequency was 0.39 in POAG cases and 0.36 in controls with no significant distribution (p=0.406). In addition, there was no significant difference between genotypes and clinical phenotypes such as intraocular pressure and cup/disc ratio within the POAG group, or any age and sex adjusted genotype effect on the disease outcome in regression analysis. Variant rs7916697 in ATOH7 is not associated with POAG or its clinical indices such as IOP and cup/disc ratio in a Saudi cohort.

Sex hormone levels and risk of primary open-angle glaucoma in postmenopausal women.

We evaluated the relation of prediagnostic sex hormone levels in postmenopausal women with primary open-angle glaucoma (POAG) and intraocular pressure (IOP). Among postmenopausal participants of the Nurses' Health Study, POAG cases (n = 189; diagnosed 1990-2008) and controls (n = 189) were matched on age, fasting status, and postmenopausal hormone use at blood draw (1989-1990). Plasma concentrations of estrone sulfate, estradiol, testosterone, sex hormone binding globulin, and dehydroepiandrosterone sulfate were assessed. The primary outcome was POAG; in secondary analyses, among cases only, we evaluated maximum untreated IOP at diagnosis. Multivariable-adjusted logistic/multiple linear regression models were used to evaluate tertiles (Ts) of biomarker levels and the two outcomes, adjusting for various potential confounders. We observed no significant associations of estrone, estradiol, sex hormone binding globulin, or dehydroepiandrosterone sulfate with POAG risk or with maximum IOP at glaucoma diagnosis among cases. Suggestive significant associations were observed with highest testosterone and POAG risk (T3 vs T1 multivariable-adjusted odds ratio 1.84; 95% confidence interval 1.02, 3.33; P trend 0.10). Similarly, for maximum IOP at diagnosis among cases only (mean 8 years after blood draw), higher testosterone was significantly associated with higher IOP (multivariable-adjusted difference in IOP T3 vs T1 2.17 mm Hg; 95% confidence interval 0.34, 3.99; P trend 0.02). Overall, plasma sex hormone levels in postmenopausal women were not associated with POAG risk; however, a trend of higher testosterone levels being associated with higher POAG risk and higher IOP at diagnosis was observed and needs confirmation.

Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26–1.93; P = 4.79 × 10−5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10−8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.

Association between IL1A and IL1B polymorphisms and primary open angle glaucoma in a Brazilian population.

The aim of this study was to investigate the association of five polymorphisms in the IL1A and IL1B genes in Brazilian patients with primary open angle glaucoma (POAG). A case–control study, including 214 unrelated POAG patients and 187 healthy individuals, was conducted to evaluate the frequency of polymorphisms in the IL1A and IL1B genes. Ophthalmic evaluation was performed and genomic DNA was obtained from all participants. Five single nucleotide polymorphisms (SNPs): IL1A (–889C/T: rs1800587:C > T, +4845G/T:rs17561G>T) and IL1B (–31C/T:rs1143627:T > C, –511C/T:rs16944C>T and +3954C/T:rs1143634:C > T) were genotyped through direct sequencing. The association of individual SNPs was tested using logistic regression. There was an association between the –31C/T and –511 C/T polymorphisms in the IL1B gene with POAG (p = 0.002 and p = 0.009, respectively). High linkage disequilibrium was observed between the –31C/T and –511C/T polymorphisms. The statistical analysis showed that the T/C haplotype (–31/–511) in the IL1B gene is more frequent in controls (p = 0.011) and the C/T haplotype (–31/–511) is more common in POAG patients (p = 0.018). Among POAG cases, the genotypic distribution of the –31C/T and –511 C/T SNPs was significantly different in patients who underwent anti-glaucomatous surgery compared to patients without surgery (p = 0.016 and 0.023, respectively). There was no statistically significant difference for the remaining SNPs between POAG patients and controls. In conclusion, the C allele of the –31C/T and the T allele of the –511C/T polymorphisms in the IL1B gene may represent a “risk haplotype” for the development of POAG in Brazilian individuals. Further studies with larger cohorts of patients are necessary to substantiate these findings.

Local genetic ancestry in CDKN2B-AS1 is associated with primary open-angle glaucoma in an African American cohort extracted from de-identified electronic health records

BackgroundGlaucoma is a leading cause of blindness in developed countries. Primary open-angle glaucoma (POAG), the most prevalent clinical subtype of glaucoma in the United States, affects African Americans at a higher rate compared with European Americans. Risk factors identified for POAG include increased age and family history, which coupled with heritability estimates, suggest this complex condition is associated with genetic and environmental factors. To date, several genome-wide studies have identified loci significantly associated with POAG risk, but most of these studies were performed in populations of European-descent.MethodsTo identify population-specific and trans-population genetic associations for POAG, we genotyped 11,521 African Americans using the Illumina Metabochip as part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study accessing BioVU, the Vanderbilt University Medical Center’s biorepository linked to de-identified electronic health records. Among this study population, we identified 138 cases of POAG and 1376 controls and performed Metabochip-wide tests of association. We also estimated local genetic ancestry at CDKN2B-AS1, a POAG-associated locus established in European-descent populations.ResultsOverall, we did not identify significant single SNP-POAG associations after adjusting for multiple testing. We did, however, detect a significant association between POAG risk and local African genetic ancestry at CDKN2B-AS1, where on average cases were of 90% African descent compared with controls at 58% (p = 2 × 10− 6).ConclusionsThese data suggest that CDKN2B-AS1 is an important locus for POAG risk among African Americans, warranting further investigation to identify the variants underlying this association.

Bone Lead Levels and Risk of Incident Primary Open-Angle Glaucoma: The VA Normative Aging Study.

Background:Oxidative stress may play an important role in the etiology of primary open-angle glaucoma (POAG). The association between risk of POAG and lead exposure, which is an environmental source of oxidative stress, has not been fully investigated yet.Objective:Our objective was to determine the association between bone lead—a biomarker of cumulative lead dose (tibia lead) or an endogenous source of stored lead (patella lead)—and incident POAG.Methods:We examined a prospective cohort of 634 POAG-free men [mean baseline y of age ()] from the Normative Aging Study (NAS) who had tibia and patella K X-ray fluorescence lead measurements between 1 January 1991 and 31 December 1999. They also had standard ocular evaluations by NAS optometrists until 31 December 2014. POAG cases were identified by consistent reports of enlarged or asymmetric cup-to-disc ratio together with visual field defect or existence of disc hemorrhage. We used Cox proportional hazards regressions to estimate hazard ratios (HRs) of incident POAG and adjusted survival curves to examine changes in the risk of POAG during follow-up according to bone lead quartiles.Results:We identified 44 incident cases of POAG by the end of follow-up (incidence per 10,000 person-years; median y). In fully adjusted models, 10-fold increases in patella lead and tibia lead were associated with HRs of 5.06 (95% CI: 1.61, 15.88, ) and 3.07 (95% CI: 0.94, 10.0, ), respectively. The HRs comparing participants in the third and fourth quartiles with the lowest quartile were 3.41 (95% CI: 1.34, 8.66) and 3.24 (95% CI: 1.22, 8.62) for patella lead (), and 3.84 (95% CI: 1.54, 9.55) and 2.61 (95% CI: 0.95, 7.21) for tibia lead ().Conclusions:Our study provides longitudinal evidence that bone lead may be an important risk factor for POAG in the U.S. population. https://doi.org/10.1289/EHP3442

Analysis of CYP1B1 sequence alterations in patients with primary open-angle glaucoma of Saudi origin.

Cytochrome P450 Family 1 Subfamily B Member 1 (CYP1B1; OMIM# 601771) gene encodes one of the cytochrome P450 family of enzymes. CYP1B1 mutations have been associated primarily with primary congenital glaucoma (PCG). Similar studies were reported in juvenile open-angle glaucoma, Rieger’s and Peters anomalies. Reports of likely pathogenic sequence alterations in families affected with adult-onset primary open-angle glaucoma (POAG) triggered this investigation. We screened unrelated POAG cases and healthy controls for mutations in CYP1B1 using automated Sanger sequencing to identify five known polymorphisms and one CYP1B1 mutation (p.G61E) in a heterozygous status. The p.G61E mutation is known to cause PCG in a homozygous or compound heterozygous form, and thus, its presence here in a heterozygous form indicates carrier status. These findings suggest that CYP1B1 may have no major role in the pathogenesis of POAG, at least, in the Saudi population. However, further investigations are needed to validate these findings in a larger cohort.

The MT-CO1 V83I Polymorphism is a Risk Factor for Primary Open-Angle Glaucoma in African American Men.

PurposeWe investigate the function of the V83I polymorphism (m.6150G>A, rs879053914) in the mitochondrial cytochrome c oxidase subunit 1 (MT-CO1) gene and its role in African American (AA) primary open-angle glaucoma (POAG).MethodsThis study used Sanger sequencing (1339 cases, 850 controls), phenotypic characterization of Primary Open-Angle African American Glaucoma Genetics study (POAAGG) cases, a masked chart review of CO1 missense cases (V83I plus M117T, n = 29) versus wild type cases (n = 29), a yeast 2-hybrid (Y2H) cDNA library screen, and quantification of protein–protein interactions by Y2H and ELISA.ResultsThe association of V83I with POAG in AA was highly significant for men (odds ratio [OR] 6.5; 95% confidence interval [CI] 2.0–21.3, P = 0.0001), but not for women (OR 1.1; 95% CI, 0.62–2.00, P = 0.78). POAG cases having CO1 double missense mutation (V83I + M117T, L1c2 haplogroup) had a higher cup-to-disc ratio (0.77 vs. 0.71, P = 0.04) and significantly worse visual function (average pattern standard deviation, 6.5 vs. 4.3, P = 0.009; average mean deviation −10.4 vs. −4.5, P = 0.006) when compared to matched wild type cases (L1b haplogroup). Interaction of the V83I region of CO1 with amyloid beta peptide (Aβ) was confirmed by ELISA assay, and this interaction was abrogated by V83I. A Y2H screen of an adult human brain cDNA library with the V83 region of CO1 as bait retrieved the UBQLN1 gene.ConclusionsThe V83I polymorphism was associated strongly with POAG in AA men and disrupts Aβ-binding to CO1. This region also interacts with a neuroprotective protein, UBQLN1.

Association of increased levels of plasma tumor necrosis factor alpha with primary open-angle glaucoma.

PurposeRetinal ganglion cell (RGC) death is a key feature of glaucoma. Elevated levels of tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine, can induce RGC apoptosis and play a critical role in glaucomatous neurodegeneration. Based on the possible role of inflammation and oxidative stress in the pathogenesis of primary open-angle glaucoma (POAG), we investigated the association between plasma levels of TNF-α and POAG or its clinical indices in comparison to non-glaucomatous controls.Patients and methodsIn a case–control retrospective cohort of 51 POAG cases and 88 controls, plasma TNF-α levels were measured using an enzyme-linked immunosorbent assay (ELISA). The assay was performed in duplicates on an automated ELISA analyzer.ResultsMean TNF-α level was significantly elevated in POAG cases (1.88 ± 2.17 pg/mL) than the controls (0.93 ± 1.49 pg/mL; p = 0.003). The overall dose–response trend was significant (χ2 = 6.12, df = 2; p = 0.047). No statistical difference was seen in age, gender and systemic disease distribution. A modest negative and significant correlation was seen between TNF-α level and number of antiglaucoma medications, an important clinical index of POAG severity. Moreover, logistic regression analysis showed that the risk of POAG was most significantly affected by TNF-α level and not by age and sex.ConclusionHigh systemic level of an inflammatory cytokine, TNF-α, is associated with POAG; however, its possible use as a biomarker for early glaucoma diagnosis and/or disease severity needs further investigation.

Family History in the Primary Open-Angle African American Glaucoma Genetics Study Cohort

To determine the relationship between positive family history (FH) and primary open-angle glaucoma (POAG) diagnosis and clinical presentation in the Primary Open-Angle African American Glaucoma Genetics (POAAGG) cohort. FH of POAG in first-degree relatives was assessed in 2365 subjects in the POAAGG cohort. A standardized interview was used to assess FH of glaucoma, demographic characteristics, lifestyle choices, and medical and ocular comorbidities. Positive FH was associated with increased risk of POAG (age-adjusted odds ratio and 95% confidence interval 3.4 [2.8, 4.1]). In age-adjusted analysis among POAG cases, positive FH was associated with younger age (P < .001), female sex (P < .001), hypertension (P= .006), use of hypertension medication (P=.03), and prior glaucoma surgery (P= .02). Cases with positive FH also had thicker retinal nerve fiber layers (P= .03). The risk conferred by positive FH suggests strong genetic underpinnings for some patients with this disease, which will be investigated by genome-wide association studies and whole exome sequencing. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.