Primary open-angle glaucoma genes

A substantial fraction of glaucoma has a genetic basis. About 5% of primary open angle glaucoma (POAG) is currently attributed to single-gene or Mendelian forms of glaucoma (ie glaucoma caused by mutations in myocilin or optineurin). Mutations in these genes have a high likelihood of leading to glaucoma and are rarely seen in normal subjects. Other cases of POAG have a more complex genetic basis and are caused by the combined effects of many genetic and environmental risk factors, each of which do not act alone to cause glaucoma. These factors are more frequently detected in patients with POAG, but are also commonly observed in normal subjects. Additional genes that may be important in glaucoma pathogenesis have been investigated using quantitative traits approaches. Such studies have begun to identify genes that control the magnitude of important quantitative features of glaucoma that may also be important risk factors for POAG, such as central corneal thickness. Each of these different approaches to study glaucoma genetics is providing new insights into the pathogenesis of POAG.     

POAG手术治疗进展

POAG在药物或激光控制眼压无效时常需手术治疗。目前小梁切除术是治疗POAG最主要的手术方法,但其术中、术后并发症较常见,如前房出血、术后浅前房、滤过道纤维化等。随着手术技术的不断改进,许多治疗POAG的新方法逐渐涌现。Ex-PRESS植入术以其手术切口小、术后并发症少以及无需组织切除等特点已逐渐被广泛应用。此外,SOLX黄金分流器、人工纳米引流植入物、iStent小梁微旁路系统、Eyepass双向青光眼植入物、Aquaflow青光眼植入物、Schlemm′s管成形术、小梁消融术等也分别从不同角度用于POAG的治疗。     

The genetics of primary open-angle glaucoma: A review

Glaucoma is the major cause of irreversible blindness worldwide. Primary open-angle glaucoma (POAG), as the most prevalent form of glaucoma, is a complex inherited disorder and affects more than 2 million individuals in the United States. It has become increasingly clear that a host of genetic as well as environmental factors are likely to contribute to the phenotype. A number of chromosomal and genetic associations have been reported for POAG. This review examines what is currently known about the underlying genetic structure, what remains to be learned, and how this may affect our medical management of this major blinding disease.     

Screening glaucoma genes in adult glaucoma suggests a multiallelic contribution of CYP1B1 to open-angle glaucoma phenotypes

Background: Despite increasing knowledge of the genetic pathophysiology of glaucoma, mutations in known genes account for less than 15% of disease. Gene screening predominantly remains a research tool rather than an essential part of the clinical work‐up. We aimed to determine the mutational spectrum and frequency in the genes implicated in glaucoma, in a range of glaucoma and ‘glaucoma suspect’ (GS) participants, with a positive family history. Methods: Observational large case series. One hundred fifteen patients recruited from public hospital and private clinics had diagnoses of GS, ocular hypertension, pseudoexfoliative glaucoma (PXG) or primary open‐angle glaucoma (POAG), and at least one affected family member. In a university laboratory, DNA samples were screened for mutations in all coding exons of MYOC and CYP1B1, and OPTN (exons 4, 5 and 16). WDR36 (exons 1, 4, 5, 8, 11, 13 and 17) was screened in those with CYP1B1 changes. LOXL1 risk variants were screened in PXG pedigrees. Cascade screening of family members was undertaken. Results: Seven out of one hundred fifteen (6.1%) individuals had at least one pathogenic or hypomorphic CYP1B1 allele associated with GS, POAG (5) and PXG phenotypes, including two novel sequence variations (p.Ser6Gly, p.Val243Leu). No pathogenic MYOC change was detected. Five individuals (4.3%) carried an OPTN sequence variation. Three of the seven with CYP1B1 changes had polygenic changes. Conclusions: Mutational analysis of known glaucoma genes in a mixed glaucoma population replicates the reported frequency of pathogenic CYP1B1 changes. Heterozygous CYP1B1 changes occurred at a greater frequency than other genes. Glaucoma pathogenesis in the clinic setting is genetically heterogeneous and may be polygenic.     

原发性开角型青光眼房水内皮素与眼压的相关关系研究

目的 了解ＰＯＡＧ房水内皮素与眼压有无相关关系。方法 通过放射免疫饱和分析法（ＲＩＡ）测定高眼压状态的原发性开角型青光眼（ＰＯＡＧ）及正常眼压的白内障患者房水内皮素（ＥＴ）。结果 ＰＯＡＧ组明显高于白内障组（Ｐ〈０．０１）。两组术前眼压比较,Ｐ〈０．０１ＰＯＡＧ眼压和ＥＴ回归分析,Ｐ〈０．０５,白内障组眼压与ＥＴ回归分析,Ｐ〉０．０５。结论 ＰＯＡＧ眼压与ＥＴ分泌有相关关系,眼部ＥＴ水平的改变是机     

Primary open-angle glaucoma in blacks: a review

Glaucoma is one of the leading causes of blindness worldwide. Primary open-angle glaucoma (POAG) is the most prevalent form of glaucoma and has a particularly devastating impact in blacks. In the black American population, POAG prevalence is estimated to be six times as high in certain age groups compared to whites. POAG is more likely to result in irreversible blindness, appears approximately 10 years earlier and progresses more rapidly in blacks than in whites. Racial differences in optic disk parameters have been reported and show that blacks have larger optic disks than whites. This finding is robust and may account for the reported differences in other optic disk parameters. The existence of racial differences in intraocular pressure remains to be demonstrated, as conflicting findings are reported in the literature. Intraocular pressure may actually be underestimated in blacks, perhaps because they have thinner corneas. The prevalence of diabetes and hypertension is higher in blacks than in whites, and although no causal relationship has been established between POAG and each of these systemic diseases, some reports suggest that they often occur together, perhaps through an indirect relationship with intraocular pressure. Compounding the problem, there is evidence that blacks are less responsive to both drug and surgical treatment for POAG. Finally, they often have reduced accessibility to treatment and are less aware of the risks of having POAG. This article provides a comprehensive review of the current knowledge pertaining to POAG in blacks.     

Myocilin glaucoma

Genetic factors have long been implicated in the pathophysiology of primary open-angle glaucoma (POAG). Recently, myocilin, a gene of unknown function, was associated with both juvenile open-angle glaucoma (JOAG) and POAG. Forty-three different myocilin mutations have been reported in open-angle glaucoma patients, and several large studies have suggested that as a group these mutations are associated with 3–4% of POAG in patient populations worldwide. Support for the pathogenicity of the individual myocilin mutations has been obtained from in vitro assays, statistical methods, and conservation of gene sequence arguments. Several of these myocilin mutations were observed in multiple patients allowing the identification of mutation-specific glaucoma phenotypes (maximum intraocular pressure and age at diagnosis). Associations between myocilin and other forms of open-angle glaucoma have been explored. At present there is no evidence to link myocilin mutations and steroid-induced ocular hypertension or normal-tension glaucoma. Clinical vignettes of POAG patients from four generations of a family harboring the TYR437HIS myocilin mutation are presented, highlighting the benefits of elucidating the genetics of glaucoma.     

Association of metformin use among diabetics and the incidence of primary open-angle glaucoma – The Chennai Eye Disease Incidence Study

Purpose:Studies have reported the usage of metformin being associated with the reduced risk of progression of glaucoma. The current study aims to determine the association of metformin usage among subjects with diabetes mellitus and the six-year incidence of primary open-angle glaucoma (POAG).Methods:In this prospective cohort study, subjects who did not have glaucoma at the baseline and had a follow-up after a six-year interval were included. Details such as medical and drug history, applanation tonometry, gonioscopy, pachymetry, optic disc evaluation, and automated perimetry were collected. Incident POAG was defined as subjects who do not have glaucoma at baseline and developed glaucoma as classified International Society of Geographical and Epidemiological Ophthalmology Classification at the follow-up. The association between the subjects who were on metformin for treatment of diabetes mellitus and development of incident POAG was assessed.Results:Among the 4302 eligible participants, 128 (3%) had incident POAG. There were 905 (21.0%) subjects who had diabetes mellitus of which 142 (15.7%) were using metformin. Of the subjects with POAG, 92 (71.9%) were nondiabetics and 36 were diabetics (28.1%). Among the diabetics, the incidence of POAG among those on metformin was 5.6% (8 participants) and those not on metformin was 3.6% (28 participants). There was no difference in the incidence of POAG in subjects with diabetes mellitus, with and without metformin use (P = 0.25). Logistic regression showed no association of metformin use with the incidence of POAG (OR: 1.33, 95 CI: 0.58–3.04, P = 0.49) after adjusting for age, gender, and place of residence.Conclusion:The current study did not find any association between the effects of metformin on the incidence of POAG.     

Genetic mapping of autosomal dominant primary open-angle glaucoma (POAG) in Sardinia

Primary open-angle glaucoma (POAG) can be subdivided into two groups according to age of onset: (1) the more prevalent middle to late-age-onset chronic open-angle glaucoma (COAG) diagnosed after age 40, and (2) the less common form, juvenile open-angle glaucoma (JOAG), which occurs between 3 years of age and early adulthood. Susceptibility to either COAG or JOAG has been found to be inherited. The discovery of several genetic markers spanning the region 1q21-q24 in genetic linkage with autosomal dominant juvenile open-angle glaucoma (adJOAG) represents a major breakthrough towards the localisation of gene(s) responsible for the disease. Linkage analysis is a powerful means of distinguishing disease loci in large families with dominant disease. However the size of the group of families may represent a crucial factor for the linkage analysis. Sardinia is an island with a relatively isolated ethnic group showing a relatively high frequency of ad JOAG and COAG (Fossarello et al., 1994) and it is genetically more homogeneous than most Western populations. Therefore it represents an ideal ethnic group to search for linkage. We identified 18 families affected by POAG in which the disease appears to be inherited as autosomic dominant trait. In all families but two, occurrence of both JOAG and COAG in the same kindred was observed. Identification of adPOAG locus was performed by linkage analysis using 9 microsatellite markers spanning the region 1q21-q24. No significant linkage was observed. Our findings provide further evidence for genetic heterogeneity in autosomal dominant primary open angle glaucoma, even in a geographic area where a relatively homogeneous genetic background exists.     

选择性激光小梁成形术治疗原发性开角型青光眼

目的评价选择性小梁激光成形术（SLT）治疗各类原发性开角性青光眼（POAG）的疗效观察。方法79例（93眼）根据种族的不同（小梁Seheie色素分级）、年龄及眼压情况分为3组,采用国通公司倍频Q-开关。532nmND：YAG激光器,单脉冲,时间为3ns,波长532nm,光斑直径400μm,脉冲能量设置0．4～1．6mJ。术前在盐酸奥布卡因表麻下放置前房角镜,瞄准功能小梁网,选择相应的脉冲能量、象限范围和激光点数进行治疗或重复治疗。术后随访眼压（1h、1d、1周、1个月、3个月、6个月、1年）、眼底及视野。结果3个组79例（93眼）术前1年平均眼压依次为（23．1±6．3）mmHg、（26．52±6．1）mmHg和（29．52±6．1）mmHg;术后1年眼压依次为（12．52±4．3）mmHg、（15．58±4．7）mmHg和（16．65±4．5）mmHg。术前与术后眼压相比有显著下降（P〈0．01）。3个组眼底C／D比,术前为0．50～0．70±0．15～0．13;术后为0．57～0．68±0．16～0．42。视力：术前0．85～0．57±0．32～0．29;术后0．91～0．58±0．30～0．27,两者比较其差异均无统计学意义。结论SLT对各类POAG均有显著降压作用。     

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Glaucoma is a common, complex, heterogenous disease and it constitutes the major cause of irreversible blindness worldwide. Primary open-angle glaucoma (POAG) is the most common type of glaucoma in all populations. Most of the molecular mechanisms leading to POAG development are still unknown. Gene mutations in various populations have been identified by genetic studies and a genetic basis for glaucoma pathogenesis has been established. Linkage analysis and association studies are genetic approaches in the investigation of the genetic basis of POAG. Genome-wide association studies (GWAS) are more powerful compared with linkage analysis in discovering genes of small effect that might contribute to the development of the disease. POAG links to at least 20 genetic loci, but only 2 genes identified in these loci, myocilin and optineurin, are considered as well-established glaucoma-causing genes, whereas the role of other loci, genes, and variants implicated in the development of POAG remains controversial. Gene mutations associated with POAG result in retinal ganglion cell death, which is the common outcome of pathogenetic mechanisms in glaucoma. In future, if the sensitivity and specificity of genotyping increases, it may be possible to screen individuals routinely for disease susceptibility. This review is an update on the latest progress of genetic studies associated with POAG. It emphasizes the correlation of recent achievements in genetics with glaucoma pathophysiology, glaucoma treatment perspectives, and the possibility of future prevention of irreversible visual loss caused by the disease.     

Red blood cell plasmalogens and docosahexaenoic acid are independently reduced in primary open-angle glaucoma

Among several theories involved in the pathogenesis of primary open-angle glaucoma (POAG), the vascular theory considers the disease to be a consequence of reduced ocular blood flow associated with red blood cell abnormalities. Red blood cell membrane structure and function are influenced by their phospholipid composition. We investigated whether specific lipid entities that may affect the membrane physiology, namely, polyunsaturated fatty acids (PUFAs) and plasmalogens, are modified in POAG and whether these potential variations are related to the stage of glaucoma. Blood samples were collected from 31 POAG patients and 10 healthy individuals. The stage of glaucoma was determined according to the Hodapp and Parrish classification. Lipids were extracted from red blood cell membranes and individual phospholipid species were quantified by liquid chromatography combined with mass spectrometry using triple quadrupole technology. POAG patients had reduced erythrocyte levels of phosphatidyl-choline (PC) carrying docosahexaenoic acid (DHA). POAG patients also displayed lower levels of choline plasmalogens (PlsC) carrying PUFAs other than DHA. These differences were greater as the severity of the disease increased. Linear regressions predicted that red blood cell PlsC levels would decrease years before clinical symptoms, whereas the levels of PC carrying DHA were linearly correlated to visual field loss. Our data demonstrate the selective loss of some individual phospholipid species in red blood cell membranes, which may partly explain their loss of flexibility in POAG.     

原发性开角型青光眼疾病基因的研究进展

随着分子生物学技术在眼科领域的应用,目前已发现至少11个染色体位点与原发性开角型青光眼(POAG)发病有关。本文就POAG的相关基因,尤其是已确认的MYOC,OPTN,WDR36三种致病基因的定位、结构、功能和突变等方面进行综述。     

Association of catalase polymorphisms with primary open-angle glaucoma in a Chinese population

Purpose: Many genes have been associated with primary open-angle glaucoma (POAG). This study was conducted to investigate whether catalase (CAT) polymorphisms play a significant role in POAG in a Chinese population.

Methods: A cohort of 416 unrelated POAG patients and 997 unrelated control subjects was included in this case–control association study. CAT functional single-nucleotide polymorphisms (SNPs), including rs1001179, rs7943316, and rs769217, were genotyped by SNaPshot method. The genotype and allele frequencies were evaluated using the χ² tests. The linkage disequilibrium (LD) and haplotype block structure association were examined using the program Haploview (Broad Institute, Cambridge, MA).

Results: There was a statistically significant difference for CAT functional SNP rs769217 between POAG cases and controls in the allelic model (p = 0.004, OR = 1.27, 95% CI 1.08–1.49). At this SNP, the allele frequency of the C allele in POAG cases was 0.587, which was higher than that in controls (0.528). However, no association was found for rs1001179 and rs7943316 with POAG. Pairwise LD analysis showed high LD between rs769217 and rs7943316 (D’ = 0.857, r² = 0.252, confidence bounds 0.71–0.93). After the association analysis for haplotype block structure generated from rs769217 with rs7943316, the data showed no significant association between the cases and controls.

Conclusions: This study showed that CAT functional SNP rs769217 was significantly associated with POAG, implying that the CAT gene variants may play a role in the pathogenesis of POAG in the Chinese population.     

Peripapillary and fovea avascular zone optical coherence tomography angiography parameters in exfoliation glaucoma versus primary open-angle glaucoma versus healthy eyes

Purpose:To examine the differences in the peripapillary vascular parameters and foveal-avascular-zone (FAZ) vascularity parameters between primary open-angle-glaucoma (POAG) patients versus exfoliation-glaucoma (XFG) patients versus healthy subjects.Methods:This is cross-sectional study and a comparative clinical study. POAG and XFG patients and healthy subjects underwent a comprehensive ophthalmic examination, including visual field optical coherence tomography (OCT) and OCT angiography (OCTA) of the optic disc and FAZ. Differences in peripapillary vessel density (VD), perfusion density (PD), and FAZ area and circularity were examined between all groups, as well as correlations between clinical parameters and vascularity parameters for each glaucoma group.Results:A total of 109 subjects (one eye for each patient) were analyzed, including 45 with POAG, 30 with XFG, and 34 controls. The average peripapillary VDs were the lowest among the XFG patients and the highest among the controls (P < 0.05, ANOVA). The average peripapillary PD of the central ring was the lowest in the XFG group and the highest in the control group (P = 0.02, ANOVA). A significant negative correlation was found between the average peripapillary VDs and PDs of the inner ring and full ring and disease severity of the POAG patients. There was a significant positive correlation between the average peripapillary PDs of the central rings and full ring and the central macular thickness of the XFG patients (P < 0.01 and P < 0.04, respectively, Pearson correlation).Conclusion:The peripapillary vascular parameters of the POAG and XFG patients were lower compared to those of normal participants. A correlation between clinical characteristics of POAG and XFG patients and PD was found. This may hint to a vascular mechanism in glaucoma either primary or secondary to intra-ocular pressure/OAG damage.     

Optic disc morphology in primary open-angle glaucoma versus primary angle-closure glaucoma in South India

Purpose:The aim of this study was to investigate the optic disc morphology in primary angle-closure glaucoma (PACG) versus primary open-angle glaucoma (POAG) in South Indians.Methods:A total of 60 patients (60 eyes) with PACG and 52 patients (52 eyes) with POAG were included in a cross-sectional observational study. The glaucoma diagnosis was based on a glaucomatous appearance of the optic disc correlating with visual field defects. The glaucoma was graded as early, moderate, or severe, depending upon perimetric loss. All patients underwent an ophthalmic evaluation, including visual field examination and planimetric analysis of 30° stereoscopic color optic disc photographs.Results:The POAG and PACG groups did not differ significantly in a disc or rim area, rim width, and frequencies of disc hemorrhages or rim notches. However, early POAG group (n = 15) had a significantly deeper cup depth (P = 0.01), larger beta zone (P = 0.01), and a higher frequency of localized retinal nerve fiber layer (RNFL) defects (P = 0.02) than early PACG (n = 20).Conclusion:In the early stage of the disease, POAG compared to PACG may be characterized by deeper disc cupping, a larger beta zone of peripapillary atrophy, and a higher frequency of localized RNFL defects. Such differences in early glaucoma may suggest differences in pathophysiology in POAG and PACG.     

Economic impact of primary open-angle glaucoma in Australia

Background: Glaucoma is the World's leading cause of irreversible blindness, and poses serious public health and economic concerns. Design: Review. Samples: Published randomized trials and population‐based studies since 1985. Methods: We report the economic impact of primary open‐angle glaucoma and model the effect of changes in detection rates and management strategies. Main Outcome Measures: The cost‐effectiveness of different interventions to prevent vision loss from primary open‐angle glaucoma was measured in terms of financial cost (Australian dollars) and disability‐adjusted life years. Results: The prevalence of glaucoma in Australia is expected to increase from 208 000 in 2005 to 379 000 in 2025 because of the aging population. Health system costs over the same time period are estimated to increase from $AU355 million to $AU784 million. Total costs (health system costs, indirect costs and costs of loss of well‐being) will increase from $AU1.9 billion to $AU4.3 billion in Australia. Conclusion: Primary open‐angle glaucoma poses a significant economic burden, which will increase substantially by 2025. This dynamic model provides a valuable tool for ongoing policy formulation and determining the economic impact of interventions to better prevent visual impairment and blindness from glaucoma.     

开角型青光眼相关基因的研究

近年来国外在开角型青光眼遗传学方面的研究已取得显著进展，已确定了许多染色体位点与开角型青光眼发病有关，并且进行了相关基因的定位与克隆，以及其突变位点的分析，本文就开角型青光眼相关基因的研究进行综述。     

Clinical and genetic characterization of a large primary open angle glaucoma pedigree

Purpose: To both characterize the clinical features of large primary open angle glaucoma (POAG) pedigree from a village in southern India and to investigate the genetic basis of their disease.

Materials and methods: Eighty-four members of a large pedigree received complete eye examinations including slit lamp examination, tonometry, gonioscopy, and ophthalmoscopy. Some were further studied with perimetry. Those diagnosed with POAG were tested for disease-causing mutations in the myocilin and optineurin genes with Sanger sequencing.

Results: Fourteen of 84 family members were diagnosed with POAG, while eight were clinically judged to be POAG-suspects. The family structure and the pattern of glaucoma in the pedigree are complex. Features of glaucoma in this pedigree include relatively early age at diagnosis (mean 50 ± 14 years) and maximum intraocular pressures ranging from 14 to 36 mm Hg with a mean of 23 mm Hg ± 6.5 mm Hg. Patients had an average central corneal thickness (mean 529 ± 37.8 microns) and moderate cup-to-disc ratios (0.74 ± 0.14). No mutations were detected in myocilin, optineurin, or TANK binding kinase 1 (TBK1).

Conclusions: We report a five-generation pedigree with a complex pattern of POAG inheritance that includes 22 POAG patients and glaucoma suspects. Although the familial clustering of POAG in this pedigree is consistent with dominant inheritance of a glaucoma-causing gene, mutations were not detected in genes previously associated with autosomal dominant glaucoma, suggesting the involvement of a novel disease-causing gene in this pedigree.     

外泌体在原发性开角型青光眼中的研究进展

外泌体同原发性开角型青光眼(POAG)的发病及诊疗过程有着多种关联.POAG相关蛋白及细胞因子可经外泌体释放调节房水循环;外泌体通过侵袭性伪足及基质金属蛋白酶活性调控细胞外基质降解和重塑影响小梁网的稳定性,外泌体还可与小胶质细胞相互作用介导视神经损伤.由于外泌体内容物的特异性使其可能作为POAG的诊断标志物.治疗方面通...