Association of polymorphisms in 17 loci with primary open-angle glaucoma in Chinese and Japanese.

Glaucoma Risk Alleles at CDKN2B-AS1 Are Associated with Lower Intraocular Pressure, Normal-Tension Glaucoma, and Advanced Glaucoma

To detect the single nucleotide polymorphisms (SNPs) of the myocilin (MYOC) and optineurin (OPTN) genes, and to investigate their associations with high tension glaucoma (HTG) and normal tension glaucoma (NTG). SNPs were detected using polymerase chain reaction (PCR), followed by conformation sensitive gel electrophoresis (CSGE) and fluorescent labeling automated DNA sequencing among 94 unrelated patients with HTG, 48 unrelated patients with NTG, and 77 unrelated control subjects. Fourteen MYOC sequence alterations were identified, five of them: V53A, I304I, T347T, 1-126T > C, and IVS2 + 172C > A, were novel. Among them, V53A was for the first time found in primary open angle glaucoma (POAG) patient. R76K usually occurred with the promoter polymorphism 1-83G > A. No sequence alterations in the MYOC gene showed significant differences among the HTG, NTG and control subjects (all P > 0.05). A total of 12 sequence alterations were identified in the OPTN gene, and three of them: V161M, I407T and L211L, were novel. Among them, I407T and L211L were found only in the HTG patients. The allele and genotype frequencies of T34T in the NTG patients were significantly higher than those of the controls (P = 0.001 and 0.004 respectively). In HTG, only the allele frequency of T34T was 24% (23/96), significantly higher than those of the NTG group (16.5%, 31/188) and the control group (9.1%, 14/154) (both P < 0.05). In addition, IVS8 + 20G > A was found only in the HTG (3.1%, 3/96) and NTG patients (3.7%, 7/188), and had significantly higher frequencies in the HTG and NTG patients when compared with the controls (P = 0.016 and 0.014, and P = 0.027 and 0.026). Polymorphisms in the MYOC and OPTN genes are associated with POAG in Chinese people. Moreover, sequence alterations not causing amino acid changes may play a role in the pathogenesis of POAG.

To observe the diurnal variations of intraocular pressure (IOP) measured with dynamic contour tonometer (DCT) in primary open angle glaucoma (POAG) patients, normal tension glaucoma (NTG) patients, and healthy controls, and to compare the differences of diurnal variation curves between the two eyes of each subject and define the distribution of the peak of IOP; to analyze the diurnal variation range of ocular pulse amplitude (OPA) and compare the differences among the POAG and NTG patients and healthy controls. DCT was used to measure the diurnal variations of IOP and OPA in the two eyes of 18 POAG patients, 17 NTG patients and 30 normal controls at 5:00, 7:00, 10:00, 14:00, 18:00, and 22:00 and the distribution of the peak IOP was observed. The range of the diurnal variation of OPA was identified. The diurnal variation curves of IOP were different among the POAG patients, NTG patients, and normal people, and also between the two eyes of each subject. Four right eyes (13.3%) and 6 left eyes (20.0%) of the healthy controls, 4 right eyes (23.5%) and 5 left eyes (29.4%) of the NTG patients, and 5 right eyes (27.8%) and 4 left eyes (22.2%) of the POAG patients reached the peak IOP values in out-office period. Diurnal variation of OPA was detected in both the patients and controls, and the variation curves were different within different groups sampled and between the two eyes of each subject. The diurnal OPA range of the right and left eyes of the POAG group were (2.1 +/- 1.3) mm Hg, and (2.4 +/- 1.9) mm Hg respectively, significantly larger than those of the normal controls [(1.1 +/- 0.5) mm Hg and 1.2 +/- 0.5) mm Hg respectively], and those of the NTG group [(1.1 +/- 0.8) mm Hg and (1.0 +/- 0.5) mm Hg) respectively] (all P < 0.01). OPA has diurnal variation. The diurnal variation of the POAG patients is the largest. NTG patients and normal controls have asymmetric IOP and OPA diurnal variations. The two eyes of the same individual cannot always be treated as the same. The value of IOP measured in the office-time cannot completely represents the 1 d IOP.

Glaucoma patients had a reduction in the inner annulus peripapillary choroidal microvascular density (PCMD) that became worse as the glaucoma severity progressed, which might provide new evidence supporting the vascular theory. To compare PCMD among normal tension glaucoma (NTG), primary open angle glaucoma (POAG), and healthy controls using optical coherence tomography (OCT) angiography (OCTA). The study included 40 POAG, 25 NTG, and 33 healthy controls. All subjects underwent OCT and OCTA testing. The inner annulus and outer annulus PCMD, as well as peripapillary vessel density (VD), were calculated. One-way analysis of variance was used to compare the vascular parameters of the 3 groups. Pearson correlation analysis or Spearman correlation test was used to evaluate the correlation between PCMD and glaucomatous severity factors. The spatial positional relationship between PCMD and corresponding peripapillary retinal nerve fiber layer (RNFL) thickness and visual field (VF) mean deviation (MD) was also assessed. The average and 4 quadrants of the inner annulus PCMD and peripapillary VD in the 2 glaucomatous groups were significantly lower than in normal eyes ( P <0.05). Strong correlations were found between inner annulus PCMD and VF MD, peripapillary VD, and RNFL in POAG patients. Similarly, the inner annulus PCMD in NTG patients was strongly correlated with peripapillary VD and RNFL (all r >0.5). Strong positional correlations were found between inner superior quadrantal PCMD and RNFL thickness in both POAG and NTG patients ( r =0.566 and 0.731, respectively). Likewise, inner inferior quadrantal PCMD exhibited a strong correlation with RNFL thickness in POAG patients ( r =0.608). Strong positional correlations were also found between inner superior PCMD and VF MD in both POAG and NTG patients ( r =0.589 and 0.622, respectively). Inner inferior PCMD exhibited a moderate correlation with VF MD in both POAG and NTG patients ( r =0.487 and 0.440, respectively). The study found that the inner annulus PCMD decreased to varying degrees in NTG and POAG patients. The inner annulus PCMD was closely related to the structural and visual function parameters of glaucoma in both NTG and POAG. Furthermore, inner PCMD demonstrated a spatial correlation with corresponding RNFL thickness and VF MD.

To explore the mechanical indices used for differential diagnosis and to investigate the relationship between ocular biomechanics and glaucoma severity within each group. This cross-sectional study included 185 eyes from 185 subjects: 62 normal controls, 91 high-tension glaucoma (HTG), and 32 normal-tension glaucoma (NTG) patients. All participants underwent a comprehensive ophthalmic examination that involved ocular biomechanical measurements. Glaucoma severity was assessed using visual field index (VFI), mean deviation (MD), pattern standard deviation (PSD) and retinal nerve fiber layer (RNFL) thickness. Multivariable models were used to compare fifteen biomechanical parameters among the three groups adjusting for age, gender, intraocular pressure (IOP), central corneal thickness (CCT), and axial length (AL). The generalized linear model was utilized for multifactor comparison. Significant differences in first applanation time (AT1), highest concavity time (HC time), stress strain index (SSI), and HC deflection were found among the three groups (P<0.05). AT1 was significantly higher in the HTG group compared to controls (P<0.05), and SSI was higher in HTG than NTG (P<0.05). HC deflection in the HTG group was significantly smaller than in NTG (P<0.05). Furthermore, AT1 levels were observed to be significantly higher in primary open angle glaucoma (POAG) patients compared to controls (P<0.05). Receiver operating charactristic (ROC) analysis showed HC deflection had an area under the curve (AUC) of 0.802 between HTG and NTG. A negatively significant correlation was observed between SSI and VFI in POAG patients. Biomechanical analysis reveals that corneas in POAG patients are stiffer than normal controls, with increased corneal stiffness correlating with more severe glaucomatous damage. Interestingly, stiffer corneas in NTG patients appeares protective. In addition, HC deflection may be useful for differentiating HTG and NTG.

(i) To investigate whether pulsatility index (PI) and mean flow velocities (MFV) are altered in glaucoma patients. (ii) To evaluate the significance of PI in retrobulbar autoregulation capacity. Patients with primary open-angle glaucoma (POAG; n = 49), normal tension glaucoma (NTG; n = 62) and healthy controls (n = 48) underwent colour Doppler imaging measurements of the retrobulbar vasculature. Kruskal-Wallis test was used to compare variables between the three diagnostic groups. Restricted cubic splines were used to determine nonlinearities between the resistive index (RI) and PI correlations. Mean flow velocities (MFV) were lower in both short posterior ciliary arteries (SCPA) and central retinal arteries (CRA) from the two glaucoma groups (p < 0.04 versus healthy controls). No differences were detected in RI or PI in any arteries of the three diagnostic groups (p > 0.08). In healthy individuals, correlations between RI and PI were linear in all arteries. In both POAG and NTG patients, CRA presented a nonlinear curve with a cutpoint at RI 0.77 (p < 0.001) and 0.61 (p = 0.03), respectively, above which the slope increased nearly five- and tenfold (POAG: 1.96 to 10.06; NTG: -0.46-4.06), respectively. A nonlinear correlation in the ophthalmic artery was only observed in NTG patients, with a cutpoint at RI 0.82 (p < 0.001), above which the slope increased from 3.47 to 14.03. Glaucoma patients do not present the linear relationships between RI and PI observed in healthy individuals. Their nonlinear relations may be indicative of an altered autoregulation and suggest a possible threshold RI could be determined above which autoregulatory disturbances become more relevant.

Purpose: To study the health profiles and behavioral differences between primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) patients.Methods: Confidential mail survey of ICD-9 defined POAG (n = 277) and NTG (n = 116) patients was carried out to collect information regarding age, gender, height, weight, waist circumference, blood pressure (BP), medications [prescription (Rx) and over the counter (OTC)], education, and the Short Health Anxiety Inventory (SHAI).Results: NTG patients (59/116) were significantly more likely to respond to the survey than POAG patients (43/277), p = 0.0001, and to have obtained college level education (70% vs. 42%), p = 0.003. Body weight, waist circumference, body mass index, systolic BP, pulse pressure, and ratio of prescription medications to OTC medications were significantly lower in the NTG group (p < 0.0001). The SHAI score, mean age, and diastolic BP were not different between the two groups. A subgroup analysis of college-educated patients in both groups revealed persisting significant differences in waist circumference, systolic BP, and ratio of Rx to OTC medications.Conclusions: NTG patients do not have significantly greater health anxiety than POAG patients. NTG patients are more likely to have lower BMI, systolic BP, and ratio of Rx to OTC medications than POAG patients. The pilot nature of this study limits generalizability of these findings. Larger studies confirming these findings and elucidating the role of refractive error and medical history on such differences are needed.

To investigate whether normal tension glaucoma (NTG) is associated with increased risk of developing dementia/Alzheimer disease (AD). A total of 69 patients with NTG were identified in the case note files in the Glaucoma Clinic, University Hospital of Copenhagen (Rigshospitalet), Denmark from 1980 to 2001. The rate of a subsequent diagnosis of dementia as recorded in nationwide health care registers from 1980 to 2005 was estimated and compared with the rate for the general population [standard mortality rate (SMR) = observed number of cases of dementia/expected number of cases of dementia]. The 69 patients had a median age of 64 years (quartiles 57 and 73) at the time of the diagnosis, and the average follow-up period was 12.7 years. The SMR(dementia) was 0.20 (95% CI 0.01-1.11). No patient developed AD. Normal tension glaucoma was not associated with an increased risk of developing dementia/AD.

The S1 RNA binding domain 1 (SRBD1) and elongation of long-chain fatty acids family member 5 (ELOVL5) have been reported to be susceptibility genes for early-onset normal-tension glaucoma (NTG). The present study we conducted to assess whether these genes were associated with primary open-angle glaucoma (POAG), including late-onset NTG and high-tension glaucoma (HTG). Three hundred seventy Japanese patients with POAG, including 158 NTG and 212 HTG patients and 191 control subjects were analyzed for SRBD1 (rs3213787) and ELOVL5 (rs735860) gene polymorphisms. The A allele frequencies of rs3213787 were significantly higher in NTG (98.4%, P = 0.0003) and HTG (97.6%, P = 0.0013) patients than in the control subjects (92.7%). The A allele frequency was significantly higher (P = 0.014), even though the NTG patients were limited to those diagnosed at ages older than 60 years. The POAG patients with the CC or CT risk genotypes of rs735860 were significantly older (P = 0.032, analysis of variance, P = 0.043 and P = 0.015, respectively) than were the POAG patients with the TT genotype, and the frequency of a family history of glaucoma in POAG patients with the CC risk genotype was significantly higher (P = 0.015) than that in POAG patients with the TT genotype. SRBD1 gene polymorphism is associated with the development of HTG as well as NTG, including late-onset NTG. Typical POAG associated with ELOVL5 gene polymorphism may have a late rather than an early onset.

AimThe purpose of this study was to evaluate the influence of polymorphisms of the eNOS gene on the clinical status of patients with normal and high tension glaucoma.Methods266 Polish Caucasian patients with primary open angle glaucoma were studied. Of the 266, 156 had normal tension glaucoma (NTG) and 110 high tension glaucoma (HTG). DNA material was isolated from peripheral venous blood using commercial kits. Real-time PCR reaction was used to amplify the promoter site of the endothelial nitric oxide synthase (eNOS) gene, including the single nucleotide polymorphism (SNP) site T-786C and part of the 7th exon of eNOS, including G894T SNP. Genotypes were determined with TaqMan SNP Genotyping Assays.ResultsThere were no significant differences in frequencies of the allelic variants of both polymorphisms. In G894T SNP, however, the wild GG form was more common in the HTG group. The SNP of the eNOS gene did not significantly influence the progression rate in either of the groups studied. There were no differences in variants of the eNOS gene regarding the necessity for and success of surgery and the progression of the disease. In the NTG group, no statistical correlation was observed between G894T, T786C polymorphism variants, and risk factors such as optic disc haemorrhages, optic disc notches, and peripapillary atrophy. Mean diastolic and systolic pressure during the day and night were lowest in NTG patients with the CC variant of the T786C polymorphism. No statistical correlation was observed between the G894T and T786C polymorphisms and capillaroscopic examination results.ConclusionsGenotype frequencies are similar for both the eNOS G894T and T-786C polymorphisms in NTG and HTG patients. These polymorphisms do not correlate with risk factors and do not influence the state of the capillary system in NTG patients. Systolic blood pressure is lower in NTG patients with mutated alleles of both polymorphisms.

Purpose: To compare the macular choroidal thickness, ganglion cell complex thickness, peripapillary choroidal thickness and retinal nerve fiber layer thickness among normal, primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) patients using RTVue (Fourier-domain optical coherence tomography; Optovue, Fremont, CA, USA).Methods: A retrospective analysis of 32 normal controls, 32 POAG and 52 NTG patients was performed.Choroidal thickness, ganglion cell complex thickness and retinal nerve fiber layer thickness were compared among normal controls, POAG and NTG subjects.Additionally, the factors influencing choroidal thickness (age, axial length, spherical equivalent, central corneal thickness, mean deviation, nocturnal dip, blood pressure variability) were analyzed.Results: A total of 32 normal controls, 32 POAG and 52 NTG patients were enrolled in this study.Macular and peripapillary choroidal thicknesses were significantly thinner in the NTG patients.In NTG subjects, the significant influencing factors associated with macular and peripapillary choroidal thicknesses were age, axial length, nocturnal dip (diastolic blood pressure), diastolic blood pressure variability and ganglion cell complex thickness.In POAG patients, significant influencing factors associated with macular and peripapillary choroidal thicknesses were age and axial length.Conclusions: Choroidal thickness was significantly thinner in NTG patients compared with normal controls and POAG patients.Factors influencing choroidal thickness in NTG patients were age, axial length, nocturnal dip (diastolic blood pressure), diastolic blood pressure variability and ganglion cell complex thickness.In POAG patients, significant factors influencing choroidal thickness were age and axial length.

Normal tension glaucoma patients had softer corneas than normal controls, whereas high-tension glaucoma and ocular hypertension patients had stiffer corneas. To comprehensively identify the corneal biomechanical differences of patients with primary open angle glaucoma (POAG) and ocular hypertension (OHT) using the Ocular Response Analyzer or the Corvis ST. The electronic databases PubMed, Embase, and Web of Science were comprehensively searched for studies comparing corneal biomechanical differences between POAG and OHT patients with normal controls by Ocular Response Analyzer or Corvis ST. The weighted mean differences and 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed according to the subtypes of POAG, including high-tension glaucoma (HTG) and normal tension glaucoma (NTG). Thirty-one case-control studies were ultimately included, with 2462 POAG patients, 345 OHT patients, and 3281 normal controls. The corneal hysteresis (CH), corneal resistance factor (CRF), and highest concavity time (HC-t) were all lower in POAG patients than in normal controls. The CH, time at the second applanation (A2t), HC-t, highest concavity radius (HC-R), and deformation amplitude at the highest concavity (HC-DA) were lower in OHT patients, while the CRF, time at the first applanation (A1t), and stiffness parameter at the first applanation (SP-A1) were greater in OHT patients than in normal controls. The subgroup analyses showed that the CH, A2t, length at the second applanation (A2L), and HC-DA were lower in HTG, and the CH, CRF, A1t, and HC-t were lower in NTG patients than in normal controls. The corneas of NTG patients are more deformable than normal controls, whereas the corneas of HTG and OHT patients are stiffer.

BackgroundTo determine the association of the ANGPT2 gene with primary open-angle glaucoma (POAG) in Chinese.MethodsSix single-nucleotide polymorphisms (SNPs) in ANGPT2 (rs2515487, rs2922869, rs13255574, rs4455855, rs13269021, and rs11775442) were genotyped in a total of 2601 study subjects from two cohorts. One is a Hong Kong Chinese cohort of 484 high tension glaucoma (HTG) and 537 normal tension glaucoma (NTG) patients, and 496 non-glaucoma control subjects. Another cohort is a Shantou Chinese cohort of 403 HTG and 135 NTG patients, and 543 non-glaucoma control subjects. Subgroup analysis by sex was conducted. Outcomes from different cohorts were combined for meta-analysis.ResultsThe association of SNP rs11775442 with NTG in the Hong Kong cohort [P = 0.0498, OR = 1.24, 95% confidence interval (CI) 1.00–1.55] after adjusting for age and sex did not reach statistical significance after Bonferroni correction. Other SNPs were not significantly associated with NTG, HTG and POAG in individual cohort or in the combined analyses (P > 0.05). In the subgroup analysis by sex, SNP rs13269021 in the Shantou cohort, but not in the Hong Kong cohort, was significantly associated with NTG in males (P = 0.0081, OR = 1.67, 95% CI: 1.14–2.43) but not in females (P = 0.874). In the combined analyses by sex, no SNPs were significantly associated with NTG, HTG and POAG.ConclusionsIn the subgroup analysis by sex, a significant association was shown in SNP rs13269021 with NTG in Shantou males, but not in Hong Kong males. Further studies are needed to verify the association between ANGPT2 locus (rs13269021) and NTG in Chinese males.

BackgroundThere are limited data concerning the optic disc topography in normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG) patients living in Southeast Asian countries. This study aims to compare optic disc parameters in patients with NTG and POAG in Malaysia and to discuss the results in comparison with studies of NTG and POAG in other Asian countries.MethodsThis prospective cross-sectional study was performed in two hospitals with glaucoma service in Malaysia from 2010 to 2012. Seventy-seven patients of Malay ethnicity were enrolled in this study, including 32 NTG patients and 45 POAG patients. Using the Heidelberg Retinal Tomograph III, we measured optic disc area, cup area, rim area, cup volume, rim volume, cup-to-disc area ratio, mean cup depth, maximum cup depth, cup shape measure, height variation contour, mean retinal nerve fiber layer thickness, and retinal nerve fiber layer cross-sectional area.ResultsThe eyes for NTG patients had significantly larger optic disc areas (2.65 [standard deviation, 0.41] vs 2.40 [standard deviation, 0.36] mm2, respectively; P=0.006) and cup areas (1.54 [standard deviation, 0.43] vs 1.32 [standard deviation, 0.40] mm2, respectively; P=0.027) compared with the eyes of POAG patients. Comparison of the other parameters between the two groups revealed no significant difference (P>0.050). The moderate and severe NTG patients showed significantly deeper cups and larger disc and cup areas when compared with the moderate and severe POAG patients (P<0.050).ConclusionThe NTG patients in this study have notably larger optic disc and cup areas than the POAG patients. Our observations are consistent with those reported in studies of NTG and POAG patients in Korea. The deeper cups and larger disc and cup areas may serve as indicators of severity when comparing NTG with POAG. However, these findings require verification with IOP and visual field results.

To investigate in parallel the systemic glutathione levels of patients suffering from primary open angle glaucoma (POAG) or normal tension glaucoma (NTG) with comparable functional loss. Thirty-four POAG patients, 30 NTG patients, and 53 controls were subjected to blood analysis to detect the level of circulating glutathione in its reduced (GSH) and oxidized (GSSG) forms. Systemic blood pressure (BP) and ocular perfusion pressure (OPP) parameters were also determined. Independent of age, POAG and NTG patients demonstrated significantly lower GSH and t-GSH levels than age-matched controls (P < 0.001). Additionally, a lower redox index was found, but in POAG patients only, in comparison to both NTG and control groups (P = 0.020). GSSG levels were, however, similar between all study groups (P > 0.05). This study demonstrates, for the first time, that both POAG and NTG patients exhibit lower GSH and t-GSH levels than age-matched controls, indicating a similar general compromise of the antioxidant defense systems may exist in both conditions.