ORCID Profile
0000-0001-9955-9696
Current Organisations
University of Birmingham
,
Flinders University
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Publisher: Swets & Zeitlinger Publishers
Date: 1999
Publisher: Elsevier BV
Date: 02-2010
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 28-10-2022
Publisher: Springer Science and Business Media LLC
Date: 27-07-2018
DOI: 10.1038/S41588-018-0176-Y
Abstract: Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide
Publisher: American Chemical Society (ACS)
Date: 29-06-2011
DOI: 10.1021/PR200148K
Abstract: The ocular lens capsule is a smooth, transparent basement membrane that encapsulates the lens and is composed of a rigid network of interacting structural proteins and glycosaminoglycans. During cataract surgery, the anterior lens capsule is routinely removed in the form of a circular disk. We considered that the excised capsule could be easily prepared for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry imaging (MALDI-MSI) analysis. MALDI-MSI is a powerful tool to elucidate the spatial distribution of small molecules, peptides, and proteins within tissues. Here, we apply this molecular imaging technique to analyze the freshly excised human lens capsule en face. We demonstrate that novel information about the distribution of proteins by MALDI-MSI can be obtained from this highly compact connective tissue, having no evident histo-morphological characteristics. Trypsin digestion carried out on-tissue is shown to improve MALDI-MSI analysis of human lens capsules and affords high repeatability. Most importantly, MALDI-MSI analysis reveals a concentric distribution pattern of proteins such as apolipoprotein E (ApoE) and collagen IV alpha-1 on the anterior surface of surgically removed lens capsule, which may indicate direct or indirect effects of environmental and mechanical stresses on the human ocular lens.
Publisher: BMJ
Date: 29-03-2022
DOI: 10.1136/BJOPHTHALMOL-2020-317461
Abstract: Recent research suggests an association between normal-tension glaucoma (NTG) and dementia. This study investigated whether cognitive impairment is more strongly associated with NTG than high tension glaucoma (HTG) using cognitive screening within an Australiasian Glaucoma Disease Registry. The authors completed a case–control cross-sectional cognitive screening involving 290 age-matched and sex-matched NTG participants and HTG controls aged ≥65 randomly s led from the Australian and New Zealand Registry of Advanced Glaucoma. Cognitive screening was performed using the Telephone Version of the Montreal Cognitive Assessment (T-MoCA). The T-MoCA omits points requiring visual interpretation, accounting for confounding factors related to vision loss in visually impaired participants. Cognitive impairment was defined by a T-MoCA score of /22. Cognition was compared between NTG and HTG participants using predetermined thresholds and absolute screening scores. A total of 290 participants completed cognitive assessment. There were no differences in NTG (n=144) and HTG (n=146) cohort demographics or ocular parameters at baseline. Cognitive impairment was more prevalent in the NTG cohort than the HTG cohort (OR=2.2 95% CI 1.1 to 6.7, p=0.030). Though a linear trend was also observed between lower absolute T-MoCA scores in the NTG cohort when compared with the HTG cohort, this association was not statistically significant (p=0.108). This study demonstrated an association between NTG status and poor cognition, supporting the hypothesis that there exists a disease association and shared pathoaetiological features between NTG and dementia.
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.OGLA.2022.06.009
Abstract: To evaluate the association between a polygenic risk score (PRS) for Primary Open Angle Glaucoma (POAG) and the age of first trabeculectomy and the need for bilateral trabeculectomy. The ocular surgical history was reviewed for nine hundred and three genotyped participants with POAG from the Australian New Zealand Registry of Advanced Glaucoma (ANZRAG). Age of diagnosis, age of trabeculectomy and laterality of trabeculectomy were recorded. Multivariate linear regression analyses correlated glaucoma PRS with age of trabeculectomy and laterality of trabeculectomy. For descriptive purposes, participants were additionally stratified into top decile, intermediate group (10 A higher PRS was associated with a younger age at first trabeculectomy (beta: -1.94 years/SD 95% CI: [-0.41, -3.47] P=0.014). Participants in the top decile underwent their first trabeculectomy approximately 7 years earlier than participants in the lowest decile (mean difference: -7.04 years [2.82, 11.26]). Participants in the top decile were 1.41 fold more likely to require bilateral trabeculectomy than participants in the bottom decile (OR: 1.41 [1.06, 1.91] P=0.021). This report identified clinically relevant correlations between glaucoma PRS and need for surgical intervention in glaucoma. Further work is required to investigate the association between PRS and other clinical endpoints, such as treatment initiation.
Publisher: Wiley
Date: 22-05-2014
DOI: 10.1111/CEO.12122
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 09-02-2016
DOI: 10.1167/TVST.5.1.3
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 07-10-2015
Abstract: We aimed to determine differentially expressed genes relevant to orbital inflammation and orbital fat expansion in thyroid orbitopathy (TO) using microarray gene profiling in a case-control study. Human orbital adipose s les were obtained from in iduals with active TO (n = 12), inactive TO (n = 21), and normal controls (n = 21). Gene expression profiles were examined using microarray analysis and were compared between active and inactive TO, and between active TO and normal controls. Top ranked differentially expressed genes were validated by real-time RT-PCR in an additional eight active TO, 13 inactive TO, and 11 normal controls and correlated with gene set enrichment analysis (GSEA) and molecular pathways analysis. Seven hundred twenty-one probes (683 genes) and 806 probes (735 genes) were significantly differentially expressed in comparing active to inactive TO and in comparing active TO to healthy controls, respectively. All selected genes were confirmed to be differentially expressed by real-time RT-PCR. Multiple top ranked genes in active versus inactive TO comparison are overrepresented by immune and inflammatory response genes. They include defensins (DEFA1, DEFA1B, DEFA3), which were overexpressed by 3.05- to 4.14-fold and TIMD4 by 4.20-fold. Markers for adipogenesis were overexpressed including SCD, FADS1, and SCDP1. Gene set enrichment analysis revealed dysregulation of epigenetic signatures, T-cell activation, Th1 differentiation, defensin pathway, cell adhesion, cytoskeleton organization, apoptosis, cell cycling, and lipid metabolism in active TO. Active TO is characterized by upregulation of genes involved in cell-mediated immune, innate immune, and inflammatory response and enhanced orbital adipogenesis. TIMD4, DEFA1, DEFA1B, and DEFA3 genes may be involved in the innate immune-mediated orbital inflammation in TO. Epigenetic mechanisms may play a role in the pathogenesis of TO.
Publisher: Public Library of Science (PLoS)
Date: 19-09-2013
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 29-03-2022
DOI: 10.1167/IOVS.63.3.26
Publisher: Springer Science and Business Media LLC
Date: 20-01-2020
Publisher: Springer Science and Business Media LLC
Date: 24-10-2023
Publisher: American Society of Hematology
Date: 15-03-1994
DOI: 10.1182/BLOOD.V83.6.1673.1673
Abstract: A considerable number of deletions of variable size and position that involve the beta-globin gene complex on chromosome 11 are associated with the clinical entities of hereditary persistence of fetal hemoglobin (HPFH) and delta beta thalassemia. Specific deletions appear to be associated with consistent phenotypes and some are known to be recurrent. To facilitate the molecular diagnosis of uncharacterized patients with HPFH and delta beta thalassemia, oligonucleotide primers have been designed to enzymatically lify deletion-specific products for nine known deletions, which include those responsible for HPFH-1, HPFH-2, HPFH-3, Spanish (delta beta)zero thalassemia, hemoglobin (Hb) Lepore, Sicilian (delta beta)zero thalassemia, Chinese G gamma(A gamma delta beta)zero thalassemia, Asian-Indian inversion-deletion G gamma(A gamma delta beta)zero thalassemia, and Turkish inversion-deletion (delta beta)zero thalassemia. Using this approach, we have successfully characterized the molecular basis for delta beta thalassemia in 23 in iduals from 16 families of erse ethnic origins. Thirteen in iduals from this group were shown to be heterozygous for the 13.4- kb Sicilian deletion, two were heterozygous for the 100-kb Chinese G gamma(A gamma delta beta)zero deletion, four were heterozygous for the Turkish form of inversion-deletion delta beta thalassemia, and three were heterozygous for the Asian-Indian form of inversion-deletion G gamma(A gamma delta beta)zero thalassemia. One Vietnamese subject was heterozygous for a 12.6-kb deletion, which we have fully characterized at the molecular level. Sequence analysis of the breakpoint regions of the Chinese deletion and the Turkish rearrangement indicates that, in each case, the mutation is likely to have arisen from a single origin. This hypothesis is supported by the evident geographical clustering of the various deletions described here.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 02-2018
Publisher: Springer Science and Business Media LLC
Date: 07-07-2023
DOI: 10.1038/S41598-023-37855-X
Abstract: Nanophthalmos is characterised by shorter posterior and anterior segments of the eye, with a predisposition towards high hyperopia and primary angle-closure glaucoma. Variants in TMEM98 have been associated with autosomal dominant nanophthalmos in multiple kindreds, but definitive evidence for causation has been limited. Here we used CRISPR/Cas9 mutagenesis to recreate the human nanophthalmos-associated TMEM98 p.(Ala193Pro) variant in mice. The p.(Ala193Pro) variant was associated with ocular phenotypes in both mice and humans, with dominant inheritance in humans and recessive inheritance in mice. Unlike their human counterparts, p.(Ala193Pro) homozygous mutant mice had normal axial length, normal intraocular pressure, and structurally normal scleral collagen. However, in both homozygous mice and heterozygous humans, the p.(Ala193Pro) variant was associated with discrete white spots throughout the retinal fundus, with corresponding retinal folds on histology. This direct comparison of a TMEM98 variant in mouse and human suggests that certain nanophthalmos-associated phenotypes are not only a consequence of a smaller eye, but that TMEM98 may itself play a primary role in retinal and scleral structure and integrity.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 10-05-2021
DOI: 10.1167/TVST.10.6.14
Publisher: BMJ
Date: 09-2002
DOI: 10.1136/FN.87.2.F78
Publisher: Wiley
Date: 28-01-2015
DOI: 10.1002/GEPI.21886
Publisher: Wiley
Date: 08-2012
DOI: 10.1111/J.1442-9071.2011.02742.X
Abstract: Glaucoma is a sight-threatening disease affecting 3% of the population over the age of 50. Glaucoma is treatable, and severe vision loss can usually be prevented if diagnosis is made at an early stage. Genetic factors play a major role in the pathogenesis of the condition, and therefore, genetic testing to identify asymptomatic at-risk in iduals is a promising strategy to reduce the prevalence of glaucoma blindness. Furthermore, unravelling genetic risk factors for glaucoma would also allow a better understanding of the pathogenesis of the condition and the development of new treatments. The Australian and New Zealand Registry of Advanced Glaucoma is a prospective study that aims to develop a large cohort of glaucoma cases with severe visual field loss to identify novel genetic risk factors for glaucoma blindness. Clinical information and blood are collected from participants after referral by eye practitioners. S les are collected across Australia and New Zealand using postage kits. Our registry has recruited just over 2000 participants with advanced glaucoma, as well as secondary and developmental glaucomas. A positive family history of glaucoma is present in more than half of the advanced glaucoma cases and the age at diagnosis is significantly younger for participants with affected relatives, which reinforces the involvement of genetic factors in glaucoma. With the collection of glaucoma cases recruited so far, our registry aims to identify novel glaucoma genetic risk factors to establish risk profiling of the population and protocols for genetic testing.
Publisher: Springer Science and Business Media LLC
Date: 06-01-2013
DOI: 10.1038/NG.2506
Publisher: Elsevier BV
Date: 12-2003
DOI: 10.1016/S0896-1549(03)00066-X
Abstract: As new genes and common mutations are identified, DNA testing can be offered. Like clinical testing used in glaucoma, such as IOP, tonography, disc measurements, nerve fiber layer analysis, and the various methods of visual field analysis, well-designed studies are needed to be able to interpret clearly the meaning of abnormal results. To use DNA testing to identify in iduals at high risk for glaucoma, it is necessary to have solid evidence with sensitivity and specificity parameters, genotype-phenotype correlations, and information on prevalence and penetrance. These data will have to be replicated in several studies using large, population-matched control groups. Mass screening of glaucoma patients for Myocilin mutations may be worthwhile if 3% to 5% of glaucoma patients will be positive. For comparison, screening all cases of colon cancer for gene mutations involved in hereditary nonpolyposis colorectal cancer is considered feasible and desirable with a yield of only 3%. Recent research has shown the value of early treatment of glaucoma. The cost effectiveness of genetics screening will need to be weighed against the cost of conventional screening and the benefits of early treatment considered. Within glaucoma pedigrees with known mutations, DNA mutation-positive in iduals will need more frequent clinical screening, whereas DNA mutation-negative in iduals will need less frequent follow-up. It is likely that, for every positive-mutation glaucoma case identified, there will be on average two siblings and two children to test. In addition to the laboratory costs, the costs of counseling, and, in particular, the availability of suitably trained in iduals who can correctly interpret these test results, must be considered. The risk and benefits of these measures must be calculated and then balanced with the long-term visual outcome of such a strategy. How could genetic testing alter management in glaucoma? If a family member in a Myocilin pedigree with a severe mutation is negative for the mutation, that in idual's risk changes from 50% to that of the general population (ie, -2%), and the frequency of clinical screening can be reduced. There are ethical issues involved in testing, particularly in children, but testing would seem justified in congenital, developmental, and juvenile glaucoma. Issues related to insurance may affect the decision making of some patients. A further consideration, which may regrettably become important in the future, is that of intellectual property and patent issues pertaining to glaucoma gene discovery. In addition to clinical evidence of the value of predictive DNA testing, it is incumbent on those working in the field to evaluate the acceptability of testing to patients and their family members. The authors' experience to date is that predictive DNA testing in glaucoma is well supported in suitable families. As with predictive DNA screening in other ophthalmic conditions, issues relating to insurance, ethics, and confidentiality need to be taken into consideration. Although many of the more recently described genetic associations of POAG require more thorough evaluation, Myocilin gene testing can and should be offered for young-onset severe glaucoma cases with a positive family history.
Publisher: Hindawi Limited
Date: 19-10-2022
DOI: 10.1002/HUMU.24482
Abstract: The standardization of variant curation criteria is essential for accurate interpretation of genetic results and clinical care of patients. The variant curation guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015 are widely used but are not gene specific. To address this issue, the Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEP) have been tasked with developing gene-specific variant curation guidelines. The Glaucoma VCEP was created to develop rule specifications for genes associated with primary glaucoma, including myocilin (MYOC), the most common cause of Mendelian glaucoma. Of the 28 ACMG/AMP criteria, the Glaucoma VCEP adapted 15 rules to MYOC and determined 13 rules not applicable. Key specifications included determining minor allele frequency thresholds, developing an approach to counting probands and segregations, and reviewing functional assays. The rules were piloted on 81 variants and led to a change in classification in 40% of those that were classified in ClinVar, with functional evidence influencing the classification of 18 variants. The standardized variant curation guidelines for MYOC provide a framework for the consistent application of the rules between laboratories, to improve MYOC genetic testing in the management of glaucoma.
Publisher: BMJ
Date: 07-2002
DOI: 10.1136/BJO.86.7.782
Abstract: Paediatric cataract is a major cause of childhood blindness. Several genes associated with congenital and paediatric cataracts have been identified. The aim was to determine the incidence of cataract in a population, the proportion of hereditary cataracts, the mode of inheritance, and the clinical presentation. The Royal Children's Hospital and the Royal Victorian Eye and Ear Hospital have a referral base for almost all paediatric patients with cataracts in south eastern Australia. The database contains cases seen over the past 25 years. The medical histories of these patients were reviewed. 421 patients with paediatric cataract were identified, which gives an estimated incidence of 2.2 per 10,000 births. Of the 342 affected in iduals with a negative family history, 50% were diagnosed during the first year of life, and 56/342 (16%) were associated with a recognised systemic disease or syndrome. Unilateral cataract was identified in 178/342 (52%) of sporadic cases. 79 children (from 54 nuclear families) had a positive family history. Of these 54 families, 45 were recruited for clinical examination and DNA collection. Ten nuclear families were subsequently found to be related, resulting in four larger pedigrees. Thus, 39 families have been studied. The mode of inheritance was autosomal dominant in 30 families, X linked in four, autosomal recessive in two, and uncertain in three. In total, 178 affected family members were examined of these 8% presented with unilateral cataracts and 43% were diagnosed within the first year of life. In the paediatric cataract population examined, approximately half of the patients were diagnosed in the first year of life. More than 18% had a positive family history of cataracts. Of patients with hereditary cataracts 8% presented with unilateral involvement. Identification of the genes that cause paediatric and congenital cataract should help clarify the aetiology of some sporadic and unilateral cataracts.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2017
DOI: 10.1038/SREP46330
Abstract: Epigenetic variation is implicated in a range of non-communicable diseases, including those of the eye. However, investigating the role of epigenetic variation in central tissues, such as eye or brain, remains problematic and peripheral tissues are often used as surrogates. In this study, matched human blood and eye tissue (n = 8) were obtained post-mortem and DNA methylation profiling performed on blood, neurosensory retina, retinal pigment epithelium (RPE)/choroid and optic nerve tissue using the Illumina Infinium HumanMethylation450 platform. Unsupervised clustering and principal components analysis revealed tissue of origin as the main driver of methylation variation. Despite this, there was a strong correlation of methylation profiles between tissues with ,000 CpG sites found to have similar methylation levels. An additional ~16,000 show similarity across ocular tissues only. A small proportion of probes showing inter-in idual variation in blood co-varied with eye tissues within in iduals, however much of this variation may be genetically driven. An improved understanding of the epigenetic landscape of the eye will have important implications for understanding eye disease. Despite a generally high correlation irrespective of origin, tissue type is the major driver of methylation variation, with only limited covariation between blood and any specific ocular tissue.
Publisher: Springer Science and Business Media LLC
Date: 24-01-2019
DOI: 10.1038/S41598-018-37388-8
Abstract: Mitochondrial haplogroups H1, H2 and UK have previously been reported to be associated with proliferative diabetic retinopathy (PDR) in Caucasian patients with diabetes. We aimed to replicate this finding with a larger s le and expand the analysis to include different severities of DR, and diabetic macular edema (DME). Caucasian participants (n = 2935) with either type 1 or type 2 diabetes from the Australian Registry of Advanced Diabetic Retinopathy were enrolled in this study. Twenty-two mitochondrial single nucleotide polymorphisms were genotyped by MassArray and haplogroups reconstructed using Haplogrep. Chi square tests and logistic regressions were used to test associations between haplogroup and DR phenotypes including any DR, non-proliferative DR (NPDR), proliferative DR (PDR) and DME. After stratifying the s les in type 1 and type 2 diabetes groups, and adjusting for sex, age, diabetes duration, concurrent HbA1c and hypertension, neither haplogroups H1, H2, UK, K or JT were associated with any DR, NPDR, PDR or DME.
Publisher: BMJ
Date: 08-2022
DOI: 10.1136/BMJOPHTH-2022-001064
Abstract: Paediatric (childhood or congenital) cataract is an opacification of the normally clear lens of the eye and has a genetic basis in at least 18% of cases in Australia. This study aimed to replicate clinical gene screening to identify variants likely to be causative of disease in an Australian patient cohort. Sixty-three reported isolated cataract genes were screened for rare coding variants in 37 Australian families using genome sequencing. Disease-causing variants were confirmed in eight families with variant classification as ‘likely pathogenic’. This included novel variants PITX3 p.(Ter303LeuextTer100), BFSP1 p.(Glu375GlyfsTer2), and GJA8 p.(Pro189Ser), as well as, previously described variants identified in genes GJA3, GJA8, CRYAA, BFSP1, PITX3, COL4A1 and HSF4 . Additionally, eight variants of uncertain significance with evidence towards pathogenicity were identified in genes: GJA3, GJA8, LEMD2, PRX, CRYBB1, BFSP2, and MIP . These findings expand the genotype–phenotype correlations of both pathogenic and benign variation in cataract-associated genes. They further emphasise the need to develop additional evidence such as functional assays and variant classification criteria specific to paediatric cataract genes to improve interpretation of variants and molecular diagnosis in patients.
Publisher: Public Library of Science (PLoS)
Date: 18-10-2021
Publisher: BMJ
Date: 04-05-2016
DOI: 10.1136/MEDETHICS-2016-103533
Abstract: This response refutes the claim made in a recent article that organs for transplantation in China will no longer be sourced from executed prisoners. We identify ongoing ethical problems due to the lack of transparent data on current numbers of transplants in China implausible and conflicting claims about voluntary donations and obfuscation about who counts as a voluntary donor. The big unanswered question in Chinese transplant ethics is the source of organs, and until there is an open and independently audited system in China, legitimate concerns remain about organ harvesting from prisoners of conscience.
Publisher: American Medical Association (AMA)
Date: 03-2014
Publisher: Elsevier BV
Date: 2022
Publisher: Wiley
Date: 30-01-2014
DOI: 10.1111/CEN.12392
Abstract: Selenium is effective in improving quality of life and reducing the progression of active Graves' orbitopathy. The effect of correcting relative selenium deficiency on improving Graves' orbitopathy is unknown, as baseline selenium levels have not previously been measured. The study aims to determine whether serum selenium levels are reduced in patients with Graves' disease with orbitopathy (GO) compared with without orbitopathy (GD). A prospective, case-control study performed between 2009 and 2012 at endocrine and ophthalmology clinics in Australia. A total of 198 patients with Graves' disease participated in the study: 101 with Graves' orbitopathy and 97 without Graves' orbitopathy. Serum selenium levels in both groups. Mean serum selenium levels were significantly lower in GO (1·10 ± 0·18 μm) than in GD (1·19 ± 0·20 μm) (P = 0·001). Mean selenium levels appeared to decrease in parallel with increasing severity of GO selenium level was 1·19 ± 0·20 μm in GD, 1·10 ± 0·19 μm in moderate-to-severe GO and 1·09 ± 0·17 μm in sight-threatening GO (P = 0·003). Serum selenium levels remained significantly lower in GO after adjusting for age, smoking status, thyroidectomy, radioactive iodine treatment and residential location. Serum selenium levels are lower in patients with GO compared with GD in an Australian study population with marginal selenium status. Relative selenium deficiency may be an independent risk factor for orbitopathy in patients with Graves' disease.
Publisher: Wiley
Date: 03-10-2016
DOI: 10.1002/MGG3.248
Publisher: Wiley
Date: 20-02-2019
DOI: 10.1111/CEO.13466
Abstract: Five-year survival rates in patients undergoing vitrectomy for diabetic retinopathy (DR) vary from 68% to 95%. No study has been conducted in an Australian population. We aimed to determine the survival rates of patients undergoing diabetic vitrectomy in an Australian population. Retrospective audit, tertiary centre hospitals and private practices. All in iduals in South Australia and the Northern Territory who underwent their first vitrectomy for diabetic complications between January 1, 2007 and December 31, 2011. An audit of all eligible participants has been completed previously. Survival status as of July 6, 2018 and cause of death were obtained using SA/NT DataLink. Kaplan-Meier survival curves and multivariate cox-regressions were used to analyse survival rates and identify risk factors for mortality. Five-, seven- and nine-year survival rates. The 5-, 7- and 9-year survival rates were 84.4%, 77.9% and 74.7%, respectively. The most common cause of death was cardiovascular disease. Associated with increased mortality independent of age were Indigenous ethnicity (HR = 2.04, 95% confidence interval [CI]: 1.17-3.57, P = 0.012), chronic renal failure (HR = 1.76, 95% CI: 1.07-2.89, P = 0.026) and renal failure requiring dialysis (HR = 2.32, 95% CI: 1.25-4.32, P = 0.008). Long-term survival rates after diabetic vitrectomy in Australia are similar to rates reported in other populations. Indigenous ethnicity and chronic renal failure were the most significant factors associated with long-term mortality. This information can guide allocation of future resources to improve the prognosis of these high risk groups.
Publisher: BMJ
Date: 26-07-2011
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 07-10-2020
DOI: 10.1167/IOVS.61.12.6
Publisher: BMJ
Date: 11-2021
DOI: 10.1136/BMJOPHTH-2021-000903
Abstract: To describe the development and implementation of a web-based high-quality data collection tool to track the outcomes of glaucoma treatments in routine practice. This is a prospective observational registry study. An international steering committee undertook an iterative structured process to define a minimum, patient-centred data set designed to track outcomes of glaucoma treatment. The outcomes were coded into a web-based programme allowing easy access for rapid data entry. Clinicians receive personal reports enabling instant audit of their outcomes. Analyses of aggregated anonymised data on real-world outcomes are analysed and periodically reported with the goal of improving patient care. The minimum data set developed by the international steering committee includes the following: a baseline visit captures 13 mandatory fields in order to accurately phenotype each patient’s subtype of glaucoma and to allow comparison between services, and a follow-up visit includes only four mandatory fields to allow completion within 30 s. Currently, there are 157 surgeons in 158 ophthalmology practices across Australia and New Zealand who are registered. These surgeons are tracking 5570 eyes of 3001 patients and have recorded 67 074 visits. The median number of eyes per surgeon is 22 eyes with a range of 1–575. The most common glaucoma procedure, excluding cataract surgery, is iStent inject, with 2316 cases. This software tool effectively facilitates data collection on safety and efficacy outcomes of treatments for different subgroups of glaucoma within a real-world setting. It provides a template to evaluate new treatments as they are introduced into practice.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2023
DOI: 10.1038/S41588-023-01428-5
Abstract: Glaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the most common form, primary open-angle glaucoma. Two key glaucoma-associated traits also show high heritability: intraocular pressure and optic nerve head excavation damage quantified as the vertical cup-to-disc ratio. Here, since much of glaucoma heritability remains unexplained, we conducted a large-scale multitrait genome-wide association study in participants of European ancestry combining primary open-angle glaucoma and its two associated traits (total s le size over 600,000) to substantially improve genetic discovery power (263 loci). We further increased our power by then employing a multiancestry approach, which increased the number of independent risk loci to 312, with the vast majority replicating in a large independent cohort from 23andMe, Inc. (total s le size over 2.8 million 296 loci replicated at P 0.05, 240 after Bonferroni correction). Leveraging multiomics datasets, we identified many potential druggable genes, including neuro-protection targets likely to act via the optic nerve, a key advance for glaucoma because all existing drugs only target intraocular pressure. We further used Mendelian randomization and genetic correlation-based approaches to identify novel links to other complex traits, including immune-related diseases such as multiple sclerosis and systemic lupus erythematosus.
Publisher: Springer Science and Business Media LLC
Date: 13-05-2016
DOI: 10.1038/SREP25853
Abstract: Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7–15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E–08) and 2.3% (P = 6.9E–21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry s les (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4 P = 6.3E–04).
Publisher: Elsevier BV
Date: 2004
DOI: 10.1016/S0002-9394(03)00774-8
Abstract: Interventional case report. In an institutional practice setting, two women, aged 25 and 45, developed acute myopia after starting topiramate for epilepsy. One patient also developed bilateral angle closure glaucoma. Topiramate was discontinued. Anterior chamber shallowing was noted in both patients at presentation. Ultrasonography showed ciliochoroidal effusion. Baseline measurements of anterior chamber depth and lens thickness were obtained. Topiramate may be associated with ciliochoroidal effusion with forward displacement of the lens-iris diaphragm and anterior chamber shallowing, resulting in acute myopia and angle-closure glaucoma. Increased lens thickness contributes only minimally (9%-16%) to anterior chamber shallowing.
Publisher: Elsevier BV
Date: 12-1994
DOI: 10.1016/0268-960X(94)90109-0
Abstract: The synthesis of fetal hemoglobin (HbF) is normally reduced to very low levels of less than 0.6% of the total hemoglobin in adults. The HbF is restricted to a sub-population of erythrocytes termed 'F-cells' 85% of the normal adult population have 0.3% to 4.4% F-cells. The levels of HbF and F-cells vary by more than 10-fold in normal adults family studies show that these levels are genetically controlled but the number and nature of these genetic factors are still poorly understood. HbF levels may be increased in adults in a number of inherited and acquired disorders, accompanied by an increase in both the number of F-cells and the amount of HbF per F-cell. The clinical significance of these conditions with raised HbF relates to their interaction in disorders such as sickle cell disease and beta thalassaemia in which raised levels of HbF can lead to considerable amelioration of disease severity. Study of the 'natural' mutants primarily associated with increased HbF has provided considerable insight into the understanding of the control of globin gene regulation and hemoglobin switching. Currently considerable effort is being channelled into clinical trials and the search for the 'ideal' therapeutic agents which could increase HbF in adult life with minimal drug toxicity.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.EXER.2016.03.013
Abstract: Pseudoexfoliation (PEX) syndrome is a systemic disease involving the extracellular matrix. It increases the risk of glaucoma, an irreversible cause of blindness, and susceptibility to heart disease, stroke and hearing loss. Single nucleotide polymorphisms (SNPs) in the LOXL1 (Lysyl oxidase-like 1) gene are the major known genetic risk factor for PEX syndrome. Two coding SNPs, rs1048861 (G > T Arg141Leu) and rs3825942 (G > A Gly153Asp), in the LOXL1 gene are strongly associated with the disease risk in multiple populations worldwide. In the present study, we investigated functional effects of these SNPs on the LOXL1 protein. We show through molecular modelling that positions 141 and 153 are likely surface residues and hence possible recognition sites for protein-protein interactions the Arg141Leu and Gly153Asp substitutions cause charge changes that would lead to local differences in protein electrostatic potential and in turn the potential to modify protein-protein interactions. In RFL-6 rat fetal lung fibroblast cells ectopically expressing the LOXL1 protein variants related to PEX (Arg141_Gly153, Arg141_Asp153 or Leu141_Gly153), immunoprecipitation of the secreted variants showed differences in their processing by endogenous proteins, possibly Bone morphogenetic protein-1 (BMP-1) that cleaves and leads to enzymatic activation of LOXL1. Immunofluorescence labelling of the ectopically expressed protein variants in RFL-6 cells showed no significant difference in their extracellular accumulation tendency. In conclusion, this is the first report of a biological effect of the coding SNPs in the LOXL1 gene associated with PEX syndrome, on the LOXL1 protein. The findings indicate that the disease associated coding variants themselves may be involved in the manifestation of PEX syndrome.
Publisher: Elsevier BV
Date: 12-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2015
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.JPROT.2013.01.008
Abstract: Pseudoexfoliation (PEX) syndrome is an age-related systemic disease of the extracellular matrix, characterized by the presence of amyloid-like fibrillar deposits on the anterior lens capsule. The pathological deposits (PEX material) can obstruct aqueous outflow leading to increased intraocular pressure that in turn can result in glaucoma. PEX syndrome is the most common risk factor for glaucoma. In our previous work, we reported a protocol for the analysis of human lens capsules by MALDI MS imaging. Here, we extend our previous work applying the developed protocol to the analysis of human lens capsules affected by PEX syndrome. We focus our investigation on known components of the PEX material, namely lysyl oxidase-like 1 (LOXL1) and apolipoprotein E (APOE). Our results show that LOXL1 is more abundant in the deposits in the iris region and, alternatively APOE is concentrated in the PEX material accumulated in the pupillary area of the anterior lens capsule. Furthermore, we identify potentially relevant post-translational modifications which may have an important role in promoting the cross-linking processes in PEX syndrome and stabilize aggregate structures within the proteinaceous PEX material. This paper is about the identification and localization of apolipoprotein E and lysyl oxidase-like 1 in human lens capsules affected by PEX syndrome by MALDI MS imaging. With this study we expand the clinical application of MALDI MSI toward the use of non-sectioned tissue s les analyzed after in situ enzymatic digestion and advance the knowledge regarding a common pathology like PEX syndrome.
Publisher: Informa UK Limited
Date: 11-2017
DOI: 10.1111/CXO.12552
Abstract: Diabetic macular oedema is the major cause of visual impairment in type 1 and type 2 diabetes. As type 2 diabetes becomes more prevalent worldwide, the prevalence of diabetic macular oedema is also expected to rise. Current management of diabetic macular oedema is challenging, expensive and not optimal in a subset of patients. Therefore, it is important to increase our understanding of the risk factors involved and develop preventative strategies. While clinical risk factors for diabetic macular oedema have been identified, few studies have addressed potential genetic risk factors. Epidemiology and family studies suggest genetic influences are of importance. In this review, we summarise known clinical risk factors, as well as discuss the small number of genetic studies that have been performed for diabetic macular oedema.
Publisher: Wiley
Date: 24-03-2011
DOI: 10.1111/J.1442-9071.2011.02507.X
Abstract: To determine the distribution and associations of intraocular pressure (IOP) among the indigenous Australian population living in central Australia. Clinic-based cross-sectional study. 1884 in iduals living in one of 30 remote communities within the statistical local area of 'Central Australia'. This equated to 36% of those aged ≥20 years and 67% of those aged ≥40 years within this district. Participants aged 20 years or over were recruited as they presented to the eye clinic at each remote community. Of those recruited into the study, 1060 underwent IOP measurement using either a Perkins tonometer (Haag-Streit, Koeniz, Switzerland) or an ICare tonometer (Tiolat Oy, Helsinki, Finland) depending on the availability of equipment. Central corneal thickness (CCT) was also measured using ultrasound pachymetry. The distribution and associations of IOP from the right eye of each participant is presented. Mean IOP was 12.8 mmHg (SD 3.2 mmHg) and CCT was 512 µm (SD 36 µm). IOP was strongly associated with CCT (r(2) = 0.14, t = 3.87 P < 0.0001), showing an increase of 0.4 mmHg with every 10 µm increase in CCT. Furthermore, IOP was strongly associated with age, decreasing by 1.9 mmHg for every decade increase in age, but only for eyes with a CCT above the mean. IOP of indigenous Australians is lower than any other racial group previously published. This may relate to the low CCT readings found among this population. Clinicians will need to bear this in mind when examining indigenous Australians and make appropriate allowances for the measured IOP.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Springer Science and Business Media LLC
Date: 19-04-2021
DOI: 10.1038/S41431-021-00889-8
Abstract: Inherited paediatric cataract is a rare Mendelian disease that results in visual impairment or blindness due to a clouding of the eye’s crystalline lens. Here we report an Australian family with isolated paediatric cataract, which we had previously mapped to Xq24. Linkage at Xq24–25 (LOD = 2.53) was confirmed, and the region refined with a denser marker map. In addition, two autosomal regions with suggestive evidence of linkage were observed. A segregating 127 kb deletion (chrX:g.118373226_118500408del) in the Xq24–25 linkage region was identified from whole-genome sequencing data. This deletion completely removed a commonly deleted long non-coding RNA gene LOC101928336 and truncated the protein coding progesterone receptor membrane component 1 ( PGRMC1 ) gene following exon 1. A literature search revealed a report of two unrelated males with non-syndromic intellectual disability, as well as congenital cataract, who had contiguous gene deletions that accounted for their intellectual disability but also disrupted the PGRMC1 gene. A morpholino-induced pgrmc1 knockdown in a zebrafish model produced significant cataract formation, supporting a role for PGRMC1 in lens development and cataract formation. We hypothesise that the loss of PGRMC1 causes cataract through disrupted PGRMC1-CYP51A1 protein–protein interactions and altered cholesterol biosynthesis. The cause of paediatric cataract in this family is the truncating deletion of PGRMC1 , which we report as a novel cataract gene.
Publisher: Wiley
Date: 15-08-2014
DOI: 10.1111/CEO.12388
Publisher: S. Karger AG
Date: 24-10-2019
DOI: 10.1159/000503854
Abstract: Simultaneous bilateral acute angle closure crisis (AACC) is a sight-threatening ocular emergency. Many “cold and flu” preparations contain compounds with sympathomimetic or anticholinergic qualities that confer a risk of inducing AACC. We present a review of cold and flu preparation-induced AACC, and present a case of simultaneous bilateral AACC triggered by a single oral dose of pseudoephedrine. The challenges facing the clinician in recognizing simultaneous bilateral AACC in the context of an upper respiratory tract infection are addressed. An awareness of this uncommon clinical entity, its pertinent clinical features, risk factors, and the drug classes that may precipitate an attack is critical for the timely diagnosis and management of this ocular emergency. Notably, clinicians must be aware that even a single dose of an implicated medication may trigger an attack of AACC.
Publisher: American Medical Association (AMA)
Date: 2022
DOI: 10.1001/JAMAOPHTHALMOL.2022.4688
Abstract: Irreversible vision loss from primary open-angle glaucoma (POAG) can be prevented through timely diagnosis and treatment, although definitive diagnosis can be difficult in early-stage disease. As a consequence, large numbers of in iduals with suspected glaucoma require regular monitoring, even though many of these may never develop disease and other high-risk in iduals with suspected glaucoma may have delayed or inadequate treatment. POAG is one of the most heritable common diseases, and this provides an opportunity to use genetic instruments in risk-stratified screening, diagnosis, and treatment of early glaucoma. To assess the association of glaucoma polygenic risk with glaucoma progression in early-stage disease. This cohort study used clinical and genetic data obtained from a longitudinal cohort study, Progression Risk of Glaucoma: Relevant SNPs With Significant Association (PROGRESSA). Participants of European ancestry with characteristic optic nerve head changes suggestive of glaucoma were included. Data were collected between February 2012 and June 2020. Analysis took place between July 2020 and April 2022. The association of a glaucoma polygenic risk score (PRS) (2673 uncorrelated variants) with rate of peripapillary retinal nerve fiber layer thinning on optical coherence tomography and progression of visual field loss on 24-2 Humphrey visual fields. A total of 1777 eyes from 896 in iduals had sufficient data for structural progression analyses and 1563 eyes from 808 in iduals for functional progression analyses. The mean (SD) age was 62.1 (9.9) years, 488 (44%) were male, and 1087 of 1103 in iduals (98.5%) had European ancestry. An ancestrally matched normative population cohort (n = 17 642) was used for PRS reference. In iduals in the top 5% PRS risk group were at a higher risk of visual field progression compared with the remaining 95% after 5 years (hazard ratio, 1.5 95% CI, 1.13-1.97 P = .005). Conversely, those in the bottom 20% PRS risk group were at a lower risk of visual field progression compared with an intermediate risk group over 3 years (hazard ratio, 0.52 95% CI, 0.28-0.96 P = .04). In this study, high polygenic risk was associated with more rapid structural and functional progression in early POAG, despite more intensive treatment. A PRS may serve as a valuable adjunct to identify in iduals who stand to benefit the most from more frequent surveillance and earlier or more intensive treatment.
Publisher: Elsevier BV
Date: 09-2021
Publisher: American Society of Hematology
Date: 02-1993
Publisher: Wiley
Date: 17-03-2021
DOI: 10.1111/CEO.13913
Abstract: Ocular coherence tomography angiography (OCTA) is available in varying size and resolution. We sought to characterise associations of cardiometabolic factors with retinal microvascular changes using 3 × 3, 6 × 6 and 8 × 8‐mm OCTA scans to determine differences in detection with varying scan size. Cross‐sectional study of 247 cardiovascular patients from a single‐centre tertiary‐care hospital. Demographic, comorbidity and medication data were obtained. Patients underwent 3 × 3, 6 × 6 and 8 × 8‐mm macula OCTA scanning using Carl Zeiss CIRRUS HD‐OCT Model 5000. Angioplex and AngioTool software was used to quantify vascular parameters in the superficial capillary plexus. Increasing age, hypertension, dyslipidaemia, diabetes, chronic kidney disease, coronary artery disease and peripheral vascular disease were associated with reductions in vessel density, vessel perfusion, average vessel length and/or junction density in 3 × 3‐mm OCTA ( P .05 for all). Conversely, smoking was associated with increased vessel density, vessel length and junction density in 3 × 3‐mm OCTA ( P .05 for all). Associations of vessel abnormalities with cardiometabolic factors were progressively weakened and statistically attenuated in 6 × 6 and 8 × 8‐mm OCTA scans. In multivariate analyses, dyslipidaemia remained an independent predictor of reduced vessel density, average vessel length and junction density ( P .05). Cardiometabolic factors are associated with multiple retinal microvascular changes in 3 × 3‐mm OCTA scans. These associations were weakened and progressively attenuated in OCTA scans of larger 6 × 6 and 8 × 8‐mm size. These findings advance our understanding of microcirculatory dysfunction and may have future implications for the screening and management of patients with cardiometabolic risk factors. Additional studies are required to further investigate these important associations.
Publisher: Wiley
Date: 29-10-2013
DOI: 10.1111/J.1442-9071.2012.02817.X
Abstract: To estimate the incidence and causes of visual impairment for the purposes of service provision among the indigenous Australian population within central Australia from its most common causes, namely cataract, diabetic retinopathy and trachoma. Clinic-based cohort study. One thousand eight hundred eighty four in iduals aged ≥20 years living in one of 30 remote communities within the statistical local area of 'Central Australia'. From those initially recruited, 608 (32%) participants were reviewed again between 6 months and 3 years (median 2 years). Patients underwent Snellen visual acuity testing and subjective refraction. Following this, an assessment of their anterior and posterior segments was made. Baseline results were compared with those who were reviewed. The annual incidence rates and causes of visual impairment (vision worse than Snellen visual acuity 6/12 in at least one eye). The incidence of visual impairment in at least one eye was 6.6%, 1.2% and 0.7% per year for cataract, diabetic retinopathy and trachoma, respectively (7.9%, 1.5% and 0.7% per year for those aged ≥40 years). Advancing age was the main risk factor common to all three. It is important to be mindful not only of the prevalence of disease in a community but also of the rate at which new cases are occurring when allocating resources to address the ocular health needs of this region. Compared with historical data, diabetic retinopathy is emerging as a new and increasing threat to vision in this population.
Publisher: Springer Science and Business Media LLC
Date: 28-08-2010
DOI: 10.1007/S00439-009-0729-3
Abstract: Osteogenesis imperfecta (OI) is a rare connective tissue disorder caused by mutations in the type I collagen genes, COL1A1 and COL1A2, and is characterised by low bone mass and bone fragility. In this study, we explored the relationship between type 1 collagen genes and the quantitative trait central corneal thickness (CCT). CCT was measured in a cohort of 28 Australian type I OI patients and mean CCT was found to be significantly lower compared to a normal population (P < 0.001). We then investigated CCT and corneal collagen fibril diameter and density in a mouse model of OI with a col1a2 mutation. Mean CCT was significantly lower in mutant mice (P = 0.002), as was corneal collagen fibril diameter (P = 0.034), whilst collagen fibril density was significantly greater in mutants (P = 0.034). Finally, we conducted a genetic study to determine whether common single nucleotide polymorphisms (SNPs) in COL1A1 and COL1A2 are associated with CCT variation in the normal human population. Polymorphism rs2696297 (P = 0.003) in COL1A1 and a three SNP haplotype in COL1A2 (P = 0.007) were all significantly associated with normal CCT variation. These data implicate type 1 collagen in the determination of CCT in both OI patients and normal in iduals. This provides the first evidence of quantitative trait loci that influence CCT in a normal population and has potential implications for investigating genes involved in glaucoma pathogenesis, a common eye disease in which the severity and progression is influenced by CCT.
Publisher: Public Library of Science (PLoS)
Date: 13-05-2010
Publisher: Wiley
Date: 28-01-2015
DOI: 10.1111/CGE.12558
Abstract: Myocilin glaucoma is an autosomal dominant disorder leading to irreversible blindness, but early intervention can minimize vision loss and delay disease progression. The purpose of this study was to discuss the benefits of predictive genetic testing in minors for Myocilin mutations associated with childhood onset glaucoma. Three families with Myocilin mutations associated with an age of onset before 18 years and six unaffected at-risk children were identified. Predictive genetic testing was discussed with the parents and offered for at-risk minors. Parents opted for genetic testing in half of the cases. None carried the familial mutation. The age of disease onset in the family, the severity of the condition, and the age of the child are all factors that appear to influence the decision of the parent to test their children. Predictive genetic testing for early onset Myocilin glaucoma can facilitate early detection of disease or discharge from routine ophthalmic examinations.
Publisher: Wiley
Date: 23-12-2012
DOI: 10.1111/J.1442-9071.2011.02726.X
Abstract: To report the prevalence of current and previous uveitis within the indigenous population living within Central Australia. Population-based cross-sectional study in Central Australia. One thousand eight hundred and eighty-four subjects who identified themselves as indigenous Australians, presenting to the remote clinics during the 36-month period between July 2005 and June 2008. Clinical assessments for active or previous uveitis were performed. Data were collected using a standardized form. Prevalence of various types of uveitis. Four of 1881 subjects had evidence of previous or current anterior uveitis, giving a prevalence for anterior uveitis of 0.21% (95% confidence interval, 0.01-0.42%). Eleven of 1854 patients had signs of previous posterior uveitis, giving a prevalence for posterior uveitis of 0.59% (95% confidence interval 0.24-0.94%). Nine of the 11 patients with posterior uveitis cases (82%) had presumed toxoplasma retinochoroiditis. There were no cases of intermediate uveitis or panuveitis observed in this study. There were no observed cases consistent with well-recognized clinical uveitic syndromes, such as Behçet's disease or Vogt-Koyanagi-Harada syndrome. A distinct pattern of uveitis appears to be present among indigenous population of remote Central Australia. Posterior uveitis was commoner than anterior uveitis with a predominance of toxoplasma retinochoroiditis. Environmental factors appeared to be more important in this genetically distinct population, with infective causes and ocular trauma being the most common aetiologies of uveitis.
Publisher: Springer Science and Business Media LLC
Date: 22-09-2014
DOI: 10.1038/NCOMMS5883
Abstract: Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 in iduals of European ancestry and 6,784 in iduals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.
Publisher: BMJ
Date: 15-03-2013
Publisher: American Society for Clinical Investigation
Date: 06-06-2016
DOI: 10.1172/JCI85830
Publisher: American Medical Association (AMA)
Date: 2019
Publisher: Public Library of Science (PLoS)
Date: 03-2010
Publisher: American Medical Association (AMA)
Date: 06-2022
Publisher: Wiley
Date: 20-07-2018
DOI: 10.1111/CEO.13009
Abstract: Visual impairment significantly impairs the length and quality of life, but little is known of its impact in Indigenous Australians. To investigate the association of disease-specific causes of visual impairment with all-cause mortality. A retrospective cohort analysis. A total of 1347 Indigenous Australians aged over 40 years. Participants visiting remote medical clinics underwent clinical examinations including visual acuity, subjective refraction and slit-l examination of the anterior and posterior segments. The major ocular cause of visual impairment was determined. Patients were assessed periodically in these remote clinics for the succeeding 10 years after recruitment. Mortality rates were obtained from relevant departments. All-cause 10-year mortality and its association with disease-specific causes of visual impairment. The all-cause mortality rate for the entire cohort was 29.3% at the 10-year completion of follow-up. Of those with visual impairment, the overall mortality rate was 44.9%. The mortality rates differed for those with visual impairment due to cataract (59.8%), diabetic retinopathy (48.4%), trachoma (46.6%), 'other' (36.2%) and refractive error (33.4%) (P < 0.0001). Only those with visual impairment from diabetic retinopathy were any more likely to die during the 10 years of follow-up when compared with those without visual impairment (HR 1.70 95% CI, 1.00-2.87 P = 0.049). Visual impairment was associated with all-cause mortality in a cohort of Indigenous Australians. However, diabetic retinopathy was the only ocular disease that significantly increased the risk of mortality. Visual impairment secondary to diabetic retinopathy may be an important predictor of mortality.
Publisher: Elsevier BV
Date: 2021
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.OGLA.2022.02.005
Abstract: To investigate and report on the quality-of-life (QoL) issues experienced by caregivers of in iduals with childhood glaucoma. Exploratory, qualitative study. Thirty-five caregivers of in iduals with childhood glaucoma (defined as disease onset before 18 years of age) recruited from the Australian and New Zealand Registry of Advanced Glaucoma. A qualitative research methodology (interpretive phenomenology) was applied. Data were collected through semistructured in-depth interviews. NVivo-12 software (QSR International Pty Ltd) was used to analyze, code, and organize data into QoL themes inductively. Quality-of-life themes and their subthemes. The mean caregiver age was 50.2 ± 13.6 years, and 27 of 35 caregivers (77%) were mothers of an in idual with childhood glaucoma. A total of 6 QoL themes were identified. Coping strategies and emotional well-being were the most prominent themes. Caregivers frequently adopted problem-focused adaptive coping strategies including partner or peer support, and normalization. A caregiver's psychosocial well-being was often impacted by feelings of guilt and regret regarding their child's delayed diagnosis, fear and anxiety related to medical and social support, and loss of control as their child developed medical autonomy. The effect of family planning from the perspective of the caregiver formed a novel QoL theme and was associated with normalization and parental confidence in management of the condition. Childhood glaucoma poses a substantial threat to a caregiver's psychosocial well-being. Strategies that promote normalization, peer support, psychotherapeutic intervention, and genetic counseling may be indicated and, indeed, critical to the caregiver as they adapt to supporting their child with glaucoma.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 27-03-2013
Abstract: Recently, several studies have investigated genetic associations between Cytochrome P450 (CYP1B1), Endothelial nitric oxide synthase (eNOS), and Neurotrophin-4 (NTF4) with primary angle-closure glaucoma (PACG) in various ethnic groups. We investigated the association of these candidate genes with PACG in s les from Australia and Nepal. A total of 235 patients with PACG (106 Nepalese and 129 Australian) and 492 controls (204 Nepalese and 288 Australian) was included. Tag single nucleotide polymorphisms (SNPs) were selected to cover the majority of common variation within the candidate genes and genotyped in DNA extracted from peripheral whole blood. Allele and haplotype analyses were conducted in PLINK. Bonferroni correction was applied for the total number of SNPs in this study (P = 0.05/15 = 0.003). In the Australian cohort, one eNOS SNP rs3793342 showed significance association with PACG after Bonferroni correction (P value of 0.003, odds ratio [OR] 0.5, 95% confidence interval [CI] 0.3-0.8). After adjusting the results for sex and age, SNPs rs3793342 and rs7830 showed significance after Bonferroni correction (P value of 0.001 and 0.003, respectively). The eNOS haplotype of all 7 typed SNPs showed significant association with a global P value of 0.019, with the CGCAATC haplotype giving a specific P value of 0.008 and OR of 1.5 (95% CI 0.9-2.4). In the Nepalese cohort, SNPs in CYP1B1 and NTF4 genes showed borderline association with PACG, but did not survive Bonferroni correction. Our data support the involvement of common variations in eNOS with PACG pathogenesis. Differences were observed in the two populations studied, and additional replication studies in other populations are necessary to confirm these associations.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2022
DOI: 10.1186/S12886-022-02325-X
Abstract: To assess whether insulin therapy impacts the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of diabetic macular edema (DME) in type 2 diabetes mellitus. This was a retrospective multi-center analysis. The best-corrected visual acuity (BCVA) at 12 months, BCVA change, central macular thickness (CMT), CMT change, and cumulative injection number were compared between the insulin and the oral hypoglycemic agent (OHA) groups. The mean final BCVA and CMT improved in both the insulin ( N = 137 p 0.001 p 0.001, respectively) and the OHA group ( N = 61 p = 0.199 p 0.001, respectively). The two treatment groups were comparable for final BCVA ( p = 0.263), BCVA change ( p = 0.184), final CMT ( p = 0.741), CMT change ( p = 0.458), and the cumulative injections received ( p = 0.594). The results were comparable between the two groups when stratified by baseline vision ( p 0.05) and baseline HbA1c ( p 0.05). Insulin therapy does not alter treatment outcomes for anti-VEGF therapy in DME.
Publisher: Elsevier BV
Date: 07-2021
Publisher: Elsevier BV
Date: 11-2021
Publisher: Oxford University Press (OUP)
Date: 11-1999
Abstract: We have developed five conventional duplex polymerase chain reaction (PCR) protocols on single lymphocytes and blastomeres from embryos, in order to analyse five exons commonly deleted in deletion-type Duchenne muscular dystrophy (DMD). The five DMD gene exons (17, 19, 44, 45 and 48) can be analysed in separate duplex PCR reactions together with the sex-determining region Y (SRY) gene which enables simultaneous gender assignment. We present here PCR lification results from single lymphocytes isolated from a normal male (220 cells), a normal female (24 cells) and a male DMD patient (40 cells) carrying a deletion of exons 46-49 within the DMD gene. The method failed to produce a PCR signal for the SRY gene in 8/220 normal male cells (3.6%) and for a DMD exon in 0-4.5% of normal male cells. One negative control out of 112 was positive. When this method was used to analyse two blastomeres from each of five embryos, concordant results were obtained for each pair of blastomeres. All embryos produced signals for the DMD exon tested with four of the embryos found to be male and one female. This method is therefore suitable for preimplantation genetic diagnosis and will allow the transfer of healthy embryos (both male and female) in families carrying DMD gene deletions involving at least one of the five exons 17, 19, 44, 45 and 48.
Publisher: Cold Spring Harbor Laboratory
Date: 05-11-2020
DOI: 10.1101/2020.11.03.367623
Abstract: Cupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time-intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach we perform a systematic comparison of the distribution of VCDR and VDD, and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI based gradings increased estimates of heritability by ~50% for VCDR and VDD. Our GWAS identified more than 200 loci for both VCDR and VDD (double the number of loci from previous studies), uncovers dozens of novel biological pathways, with many of the novel loci also conferring risk for glaucoma.
Publisher: Elsevier BV
Date: 09-2010
Publisher: Wiley
Date: 05-2010
DOI: 10.1111/J.1442-9071.2010.02255.X
Abstract: To describe the design and demographic characteristics of a study to determine the prevalence of ocular morbidity among indigenous Australians living within remote central Australia. 1884 in iduals aged 20 years or older, living in one of 30 remote communities within the statistical local area of 'central Australia' were recruited for this study. Participants were recruited as they presented to the eye clinic at each remote community. Patients underwent visual acuity testing and subjective refraction. Following this they had a comprehensive ocular assessment. A baseline description of the participants is presented. 1884 participants were recruited including 689 (36.6%) males and 1195 (63.4%) females. This equates to 36% of those aged 20 years or older and 67% of those aged 40 years or older living in central Australia. 55% of participants were diabetic and 20% of participants were symptomatic of an eye condition, but the majority of these only had presbyopia. Combined, those who presented due to diabetes (regardless of symptoms), due to presbyopia, or without any symptoms made up 95% of the s le. Despite being recruited through clinics, the majority of participants presented for a 'check-up' because the clinic was available and not due to symptoms. Therefore, the data we collected may be used to establish the current prevalence of ocular morbidity within the indigenous community living in remote central Australia with particular reference to those aged 40 years or older. As such, this can help to determine the current and future needs of this population.
Publisher: Wiley
Date: 14-11-2019
DOI: 10.1111/CEO.13375
Abstract: Diabetes mellitus (DM) is highly prevalent among Indigenous Australians and contributes greatly to premature death. The association of diabetic retinopathy (DR) with early mortality, however, has not previously been reported among Indigenous Australians. To investigate associations between 10-y mortality and the presence of DR among Indigenous Australians living in Central Australia. Prospective cohort study. A total of 1257 in iduals aged 40 y or older, living in one of 30 remote communities within Central Australia were recruited through outreach clinics. Fundus examination was performed on all patients at recruitment. The presence of any DR was recorded. Mortality rate and cause were obtained at 10 y, and their association with any DR was determined. Ten-year all-cause mortality was found to be 29.3%. Of those with DM but no DR, 24.0% died during the 10 y after recruitment, compared with 40.1% for those with any DR (P < 0.0001). Those who had any DR were 75% more likely to die (hazard ratio [HR] 1.75 P < 0.0001) and were more likely to die from renal failure (HR 2.71 P = 0.004) or stroke (HR 5.91 P = 0.026). The presence of any DR among those with DM, was associated with a 75% greater 10-y all-cause mortality rate and were more likely to die from renal failure or stroke. We recommend that whenever DR is noted among Indigenous Australians with DM, that they be immediately referred for investigation and management of risk factors, which might predispose to renal failure and stroke.
Publisher: Hindawi Limited
Date: 11-05-2021
DOI: 10.1002/HUMU.24214
Abstract: Gelsolin (GSN) variants have been implicated in amyloidosis of the Finnish type. This case series reports a novel GSN:c.1477T>C,p.(Trp493Arg) variant in a family with ocular and systemic features consistent with Finnish Amyloidosis. Exome sequencing performed on affected in iduals from two families manifesting cutis laxa and polymorphic corneal stromal opacities demonstrated the classic GSN:c.654G>A,p.Asp214Asn variant in single affected in idual from one family, and a previously undocumented GSN:c.1477T>C variant in three affected first-degree relatives from a separate family. Immunohistochemical studies on corneal tissue from a proband with the c.1477T>C variant identified gelsolin protein within histologically defined corneal amyloid deposits. This study reports a novel association between the predicted pathogenic GSN:c.1477T>C variant and amyloidosis of the Finnish type, and is the first to provide functional evidence of a pathological GSN variant at a locus distant to the critical G2 calcium-binding region, resulting in the phenotype of amyloidosis of the Finnish type.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-03-2022
Publisher: Oxford University Press (OUP)
Date: 05-06-2015
DOI: 10.1093/HMG/DDV211
Abstract: Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a s le of 1029 in iduals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent s les from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a s le of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 × 10(-5)).
Publisher: Springer Science and Business Media LLC
Date: 03-08-2015
DOI: 10.1038/NG.3373
Publisher: BMJ
Date: 08-2023
DOI: 10.1136/BMJOPEN-2022-068811
Abstract: Glaucoma, a major cause of irreversible blindness, is a highly heritable human disease. Currently, the majority of the risk genes for glaucoma are unknown. We established the Genetics of Glaucoma Study (GOGS) to identify disease genes and improve genetic prediction of glaucoma risk and response to treatment. More than 5700 participants with glaucoma or a family history of glaucoma were recruited through a media c aign and the Australian Government healthcare service provider, Services Australia, making GOGS one of the largest genetic studies of glaucoma globally. The mean age of the participants was 65.30±9.36 years, and 62% were female. Participants completed a questionnaire obtaining information about their glaucoma-related medical history such as family history, glaucoma status and subtypes, surgical procedures, and prescriptions. The questionnaire also obtained information about other eye and systemic diseases. Approximately 80% of the participants provided a DNA s le and ~70% consented to data linkage to their Australian Government Medicare and Pharmaceutical Benefits Scheme schedules. 4336 GOGS participants reported that an optometrist or ophthalmologist has diagnosed them with glaucoma and 3639 participants reported having a family history of glaucoma. The vast majority of the participants (N=4393) had used at least one glaucoma-related medication latanoprost was the most commonly prescribed drug (54% of the participants who had a glaucoma prescription). A subset of the participants reported a surgical treatment for glaucoma including a laser surgery in 2008 participants and a non-laser operation in 803 participants. Several comorbid eye and systemic diseases were also observed the most common reports were ocular hypertension (53% of the participants), cataract (48%), hypertension (40%), nearsightedness (31%), astigmatism (22%), farsightedness (16%), diabetes (12%), sleep apnoea (11%) and migraines (10%). GOGS will contribute to the global gene-mapping efforts as one of the largest genetic studies for glaucoma. We will also use GOGS to develop or validate genetic risk prediction models to stratify glaucoma risk, particularly in in iduals with a family history of glaucoma, and to predict clinical outcomes (eg, which medication works better for an in idual and whether glaucoma surgery is required). GOGS will also help us answer various research questions about genetic overlap and causal relationships between glaucoma and its comorbidities.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.OPHTHA.2015.05.004
Abstract: To investigate associations between single nucleotide polymorphisms (SNPs) in the VEGFC gene and the development of diabetic retinopathy (DR) in white patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Cross-sectional, case control study. White patients with T1DM or T2DM (n = 2899) were recruited from ophthalmology and endocrine clinics in Australia and the United Kingdom. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be receiving oral hypoglycemic treatment or insulin. Participants were categorized according to their worst-ever DR grading, as having "no DR" (no history of nonproliferative DR [NPDR], proliferative DR [PDR], or diabetic macular edema [DME]) or "any DR" (further subclassified as NPDR or PDR, without or with DME). Clinical characteristics, glycemic control (hemoglobin A1c [HbA1c]), and presence of diabetic complications were determined at recruitment. Genotyping was performed for 13 VEGFC tag SNPs. Odds ratios (ORs) were determined for associations with DR of VEGFC tag SNPs, in idually and within haplotypes. Logistic regression was used to adjust for clinical covariates, including DM type, age, sex, DM duration, hypertension, nephropathy, HbA1c, and smoking. Participants with DM but "no DR" (n = 980) were compared with 1919 participants with DM and "any DR." Three VEGFC SNPs were associated with DR after logistic regression: rs17697419 (P = 0.001 OR, 0.67 confidence interval [CI], 0.52-0.85), rs17697515 (P = 0.001 OR, 0.62 CI, 0.47-0.81), and rs2333526 (P = 0.005 OR, 0.69 CI, 0.54-0.90). rs17697515 Was also specifically associated with DME in those with T2DM (P = 0.004 OR, 0.53 CI, 0.35-0.82). Haplotype analysis revealed 2 significantly associated haplotypes, both protective against DR development. Significant associations were found between VEGFC tag SNPs (in idually and within haplotypes) and the presence of any DR or DME in white participants with T1DM and T2DM.
Publisher: Elsevier BV
Date: 03-2021
Publisher: BMJ
Date: 13-11-2016
DOI: 10.1136/BJOPHTHALMOL-2015-307399
Abstract: Orbital changes in thyroid orbitopathy (TO) result from de novo adipogenesis, hyaluronan synthesis, interstitial oedema and enlargement of extraocular muscles. Cellular immunity, with predominantly CD4+ T cells expressing Th1 cytokines, and overexpression of macrophage-derived cytokines, perpetuate orbital inflammation. Orbital fibroblasts appear to be the major effector cells. Orbital fibroblasts express both thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R) at higher levels than normal fibroblasts. TSHR expression increases in adipogenesis TSHR agonism enhances hyaluronan production. IGF-1R stimulation leads to adipogenesis, hyaluronan synthesis and production of the chemokines, interleukin (IL)-16 and Regulated on Activation, Normal T Cell Expression and Secreted, which facilitate lymphocyte trafficking into the orbit. Immune activation uses a specific CD40:CD154 molecular bridge to activate orbital fibroblasts, which secrete pro-inflammatory cytokines including IL-1β, IL-1α, IL-6, IL-8, macrophage chemoattractant protein-1 and transforming growth factor-β, to perpetuate orbital inflammation. Molecular pathways including adenylyl cyclase/cyclic adenosine monophosphate, phophoinositide 3 kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase are involved in TO. The emergence of a TO animal model and a new generation of TSHR antibody assays increasingly point towards TSHR as the primary autoantigen for extrathyroidal orbital involvement. Oxidative stress in TO resulting from imbalances of the oxidation-reduction state provides a framework of understanding for smoking prevention, achieving euthyroidism and the use of antioxidants such as selenium. Progress has been made in the understanding of the pathogenesis of TO, which should advance development of novel therapies targeting cellular immunity, specifically the CD40:CD40 ligand interaction, antibody-producing B cells, cytokines, TSHR and IGF-1R and its signalling pathways. Further studies in signalling networks and molecular triggers leading to burnout of TO will further our understanding of TO.
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.1586/EOP.12.11
Publisher: Springer Science and Business Media LLC
Date: 05-2011
DOI: 10.1038/NG.824
Abstract: We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 in iduals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010 rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68 rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.
Publisher: American Medical Association (AMA)
Date: 2010
DOI: 10.1001/ARCHOPHTHALMOL.2009.355
Abstract: To determine whether sequence variation in the erythropoietin gene (EPO) is associated with the development of diabetic retinopathy (DR). This was a multicenter study based on 518 subjects with long-standing diabetes mellitus (DM), 173 with type 1 DM (T1DM) and 345 with type 2 DM (T2DM). Study groups consisted of 233 control subjects with no DR, 155 subjects with nonproliferative DR, 126 with proliferative DR, and 90 with clinically significant macular edema. Subjects with end-stage renal disease were excluded. DNA extracted from blood of each subject was genotyped for 3 EPO single-nucleotide polymorphisms (SNPs). All 3 SNPs in EPO were associated with overall DR status in the combined T1DM and T2DM and T2DM alone groups (CC genotype of rs507392, P < .008 GG genotype of rs1617640, P < .008 and CC genotype of rs551238, P < .008) in the multivariate analysis. The GCC haplotype was also associated with overall DR status in the combined DM and T2DM alone groups (P = .008) by multivariate analysis. All SNPs and the GCC haplotype were also associated with proliferative DR and clinically significant macular edema in the combined DM and T2DM alone groups. No associations were found with T1DM alone. Sequence variation in EPO is associated with the risk of DR independent of duration of DM, degree of glycemic control, and nephropathy. Identifying EPO genetic markers for high risk of developing DR could lead to the possibility of developing novel treatments or preventive therapies.
Publisher: Springer Science and Business Media LLC
Date: 19-11-2010
Abstract: A novel phenotype consisting of cataract, mental retardation, erythematous skin rash and facial dysmorphism was recently described in an extended pedigree of Australian Aboriginal descent. Large scale chromosomal re-arrangements had previously been ruled out. We have conducted a genome-wide scan to map the linkage region in this family. Genome-wide linkage analysis using Single Nucleotide Polymorphism (SNP) markers on the Affymetrix 10K SNP array was conducted and analysed using MERLIN. Three positional candidate genes ( ZBTB17, EPHA2 and EPHB2 ) were sequenced to screen for segregating mutations. Under a fully penetrant, dominant model, the locus for this unique phenotype was mapped to chromosome 1p35.3-p36.32 with a maximum LOD score of 2.41. The critical region spans 48.7 cM between markers rs966321 and rs1441834 and encompasses 527 transcripts from 364 annotated genes. No coding mutations were identified in three positional candidate genes EPHA2, EPHB2 or ZBTB17 . The region overlaps with a previously reported region for Volkmann cataract and the phenotype has similarity to that reported for 1p36 monosomy. The gene for this syndrome is located in a 25.6 Mb region on 1p35.3-p36.32. The known cataract gene in this region ( EPHA2 ) does not harbour mutations in this family, suggesting that at least one additional gene for cataract is present in this region.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 12-07-2022
DOI: 10.1167/TVST.11.7.8
Publisher: Wiley
Date: 27-04-2011
DOI: 10.1111/J.1442-9071.2011.02532.X
Abstract: To determine the prevalence of pterygium within the indigenous Australian population living in central Australia. Clinic-based cross-sectional study. A total of 1884 in iduals living in one of 30 remote communities within the statistical local area of 'Central Australia'. This equated to 36% of those aged ≥20 years and 67% of those aged ≥40 years within this district. PARTICIPANTS aged 20 years or over were recruited as they presented to the eye clinic at each remote community. Slit-l examination was performed, and the presence of a pterygium or evidence of previous pterygium surgery was recorded. The prevalence of a pterygium in one or both eyes is presented. Pterygium was present in one or both eyes of 9.3% of in iduals aged 40 years or older. Right and left eyes were affected equally (χ(2) = 0.19 P = 0.91). There was a significant association between the presence of a pterygium and age (t = 3.99 P < 0.0001). There was no association with gender (χ(2) = 1.06 P = 0.30). Pterygium was present in a significantly higher proportion of indigenous Australians compared with non-indigenous Australians. This is similar to previous findings of the National Trachoma and Eye Health Program and may be due to a difference in proportion of hours spent outdoors and consequent exposure to ultraviolet radiation.
Publisher: Elsevier BV
Date: 2022
Publisher: Wiley
Date: 23-12-2012
DOI: 10.1111/J.1442-9071.2011.02725.X
Abstract: To estimate the incidence of diabetic retinopathy (DR) within the indigenous Australian population living in Central Australia. Clinic-based cohort study. One thousand eight hundred eighty-four in iduals aged ≥20 years living in one of 30 remote communities within the statistical local area of 'Central Australia'. Among those with diabetes mellitus (DM) (n = 1040), 432 (42%) were reviewed between 6 months and 3 years (median 21 months) after the initial examination. DR in participants with DM was graded using the Early Treatment of Diabetic Retinopathy Study classification. Baseline results were compared with those at follow-up. The incidence of any DR and vision-threatening DR (clinically significant macular oedema and/or proliferative DR) in at least one eye. Of those with DM but without DR at baseline, 8.41% (9.42% of those aged 40 years or older) per year developed DR. Meanwhile, 0.7% (0.92% for those aged ≥40 years) of those with no DR at baseline developed vision-threatening DR per year, increasing to 8.4% per year for those with minimal or mild non-proliferative DR, and 28.2% per year for those with moderate or severe non-proliferative DR at baseline. Our study has estimated the annual incidence rates of DR among indigenous Australians living within Central Australia. These rates are similar to those from the non-indigenous population, and highlight the need for good surveillance and service provision in a population where the prevalence of diabetes is very high and the logistics of screening are complex.
Publisher: Hindawi Limited
Date: 03-2013
DOI: 10.1002/HUMU.22260
Abstract: Congenital cataract is a heterogeneous disorder causing severe visual impairment in affected children. We screened four South Australian families with autosomal dominant congenital cataract for mutations in 10 crystallin genes known to cause congenital cataract. We identified a novel segregating heterozygous mutation, c.62G>A (p.R21Q), in the CRYΑA gene in one family. Western blotting of proteins freshly extracted from cataractous lens material of the proband demonstrated a marked reduction in the amount of the high-molecular-weight oligomers seen in the lens material of an unaffected in idual. We conclude that the p.R21Q mutation, which is located in the highly conserved and structurally significant N-terminal region of the protein, is responsible for the cataract phenotype observed in the family as this mutation likely reduces the formation of the functional oligomeric alpha-crystallin.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.OPHTHA.2019.03.016
Abstract: To investigate which clinical measures influence whether an in idual demonstrates earliest glaucomatous structural progression on peripapillary retinal nerve fiber layer (pRNFL) or macular ganglion cell-inner plexiform layer (mGCIPL). Prospective, longitudinal cohort study. Two hundred seventy-one eyes from 207 in iduals with statistically significant evidence of glaucomatous progression on OCT Guided Progression Analysis (GPA) software were drawn from a total of 1271 eyes from 686 in iduals categorized as glaucoma suspect or having early manifest glaucoma undergoing glaucoma surveillance. In iduals demonstrating earliest evidence of longitudinal progression on mGCIPL GPA event analysis were compared with in iduals demonstrating evidence of earliest longitudinal progression on pRNFL GPA event analysis. Correlation of OCT event change analysis with intraocular pressure (IOP), clinical variables, and baseline thickness of the pRNFL and mGCIPL. Intraocular pressure, baseline pRNFL thickness, baseline mGCIPL thickness, and systemic hypertension were associated with location of first progression. Eyes demonstrating earliest longitudinal progression on mGCIPL had significantly lower maximum-recorded pretreatment IOP (mean difference, 3.90 mmHg 95% confidence interval [CI], 2.37-5.43 mmHg P < 0.001). The interval between progression on pRNFL and progression on mGCIPL increased by 12.4 months for every 5-mmHg increase in IOP (95% CI, 10.32-15.72 months). Eyes demonstrating earliest longitudinal progression on mGCIPL showed significantly lower baseline average pRNFL thickness than eyes progressing on pRNFL first (mean difference, 7.07 μm 95% CI, 4.38-9.77 μm P < 0.001). Eyes progressing first on mGCIPL parameters were 3.03 times more likely to demonstrate a new paracentral field defect than eyes progressing first on pRNFL parameters (odds ratio, 3.03 95% CI, 1.26-7.28 P = 0.01). Clinical features, particularly pretreatment IOP, influence whether structural glaucoma progression is detected earlier with mGCIPL or pRNFL imaging. These data support the usefulness of mGCIPL imaging in addition to pRNFL analysis for detection of glaucoma progression, particularly in patients with normal IOP.
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.AJO.2012.04.023
Abstract: To ascertain if single nucleotide polymorphisms (SNPs) involved in the determination of central corneal thickness, optic disc area, and vertical cup-to-disc ratio (VCDR) also are associated with open-angle glaucoma (OAG). Retrospective case-control genetic association study. A total of 16 SNPs associated with central corneal thickness, optic disc area, and VCDR were genotyped in 876 OAG cases and 883 normal controls. To determine if the SNPs were also correlated with OAG severity, the cohort was stratified into advanced OAG (n = 326) and nonadvanced OAG (n = 550). Both the cases and controls were of European descent and were recruited from within Australia. Two VCDR SNPs were found to be significantly associated with OAG after correction for multiple testing. The 2 SNPs were rs10483727, found adjacent to the SIX1 gene (P = 6.2 × 10(-06) odds ratio, 1.38 95% confidence interval, 1.20 to 1.59), and rs1063192, found within the CDKN2B gene (P = 2.2 × 10(-05) odds ratio, 0.74 95% confidence interval, 0.64 to 0.85). The CDKN2B variant rs1063192 also was found to be associated more strongly with advanced OAG. The findings from this study indicate that variants influencing VCDR are also risk alleles for OAG in our Australian cohort of European descent. The identification of SIX1 and CDKN2B as susceptibility loci will assist in understanding the pathologic mechanisms involved in the development of OAG.
Publisher: Public Library of Science (PLoS)
Date: 06-03-2017
Publisher: Springer Science and Business Media LLC
Date: 16-12-2020
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 10-03-2017
Abstract: Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of in iduals with advanced early-onset POAG. The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninety-three previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes. Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] = 16.62, P = 6.31×10-16). Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.
Publisher: Oxford University Press (OUP)
Date: 14-02-2018
DOI: 10.1093/HMG/DDY053
Publisher: Springer Science and Business Media LLC
Date: 30-03-2017
DOI: 10.1038/NCOMMS14898
Abstract: The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance ( P × 10 −8 ): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1 , with greater risk in women, and TCF4 , with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying pathogenic basis of FECD.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2016
DOI: 10.1038/NG.3482
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 03-03-2023
DOI: 10.1167/IOVS.64.3.11
Publisher: Oxford University Press (OUP)
Date: 20-09-2016
DOI: 10.1093/HMG/DDW319
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 28-06-2016
Abstract: Many genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at the 9p21 glaucoma locus (CDKN2B/CDKN2B-AS1) to be significantly associated with primary open-angle glaucoma (POAG), with association being stronger in normal tension glaucoma (NTG) and advanced glaucoma. We aimed to determine whether any observed differences in genetic association at the 9p21 locus are influenced by sex. Sex was assessed as a risk factor for POAG for 2241 glaucoma participants from the Australian and New Zealand Registry of Advanced Glaucoma, the Glaucoma Inheritance Study in Tasmania, and the Flinders Medical Centre. A total of 3176 controls were drawn from the Blue Mountains Eye Study and South Australia: 1523 advanced POAG and 718 nonadvanced POAG cases were genotyped along with 3176 controls. We selected 13 SNPs at the 9p21 locus, and association results were subanalyszd by sex for high-tension glaucoma (HTG) and NTG. Odds ratios (ORs) between sexes were compared. A sex bias was present within advanced NTG cases (57.1% female versus 42.9% male, P = 0.0026). In all POAG cases, the strongest associated SNP at 9p21 was rs1063192 (OR, 1.43 P = 4 × 10-18). This association was stronger in females (OR, 1.5 P = 5 × 10-13) than in males (OR, 1.35 P = 7 × 10-7), with a statistically significant difference in female to male OR comparison (P = 1.0 × 10-2). An NTG to HTG subanalysis yielded statistically significant results only in females (OR, 1.63 P = 1.5 × 10-4) but not in males (OR, 1.15 P = 2.8 × 10-1), with a statistically significant difference in female to male OR comparison (P = 1.4 × 10-4). This study demonstrated that female sex is a risk factor for developing advanced NTG. The stronger genetic signals at the 9p21 locus among females may contribute at least in part to the observed sex bias for NTG.
Publisher: MDPI AG
Date: 12-12-2019
Abstract: Type 2 diabetes mellitus (T2DM) poses significant challenges to in iduals and broader society, much of which is borne by disadvantaged and marginalised population groups including Indigenous people. The increasing prevalence of T2DM among Indigenous people has meant that rates of diabetes-related complications such as blindness from end-stage diabetic retinopathy (DR) continue to be important health concerns. Australia, a high-income and resource-rich country, continues to struggle to adequately respond to the health needs of its Indigenous people living with T2DM. Trends among Indigenous Australians highlight that the prevalence of DR has almost doubled over two decades, and the prevalence of diabetes-related vision impairment is consistently reported to be higher among Indigenous Australians (5.2%–26.5%) compared to non-Indigenous Australians (1.7%). While Australia has collated reliable estimates of the eye health burden owing to T2DM in its Indigenous population, there is fragmentation of existing data and limited knowledge on the underlying risk factors. Taking a systems approach that investigates the social, environmental, clinical, biological and genetic risk factors, and—importantly—integrates these data, may give valuable insights into the most important determinants contributing to the development of diabetes-related blindness. This knowledge is a crucial initial step to reducing the human and societal impacts of blindness on Indigenous Australians, other priority populations and society at large.
Publisher: Wiley
Date: 14-08-2020
DOI: 10.1111/CEO.13826
Publisher: Hindawi Limited
Date: 2007
DOI: 10.1002/HUMU.9501
Abstract: Hereditary hyperferritinemia cataract syndrome (HHCS) is characterized by distinctive cataracts and high serum ferritin in the absence of iron overload. It is caused by mutations in the iron response element (IRE) of the Ferritin Light Chain (FTL) gene. Here we investigate the genetics of HHCS in a three generation Australian kindred with typical HHCS ocular lens morphology and high ferritin levels. Initial sequencing of the IRE failed to detect any mutations. Sequencing of the entire gene including the promoter region revealed a novel 25 bp deletion upstream of the IRE abolishing the transcription start site. In lymphoblastoid cells, the deletion allele was transcribed from an alternate start site within the lower stem of the IRE and mutation carriers had high cellular L-ferritin levels. This novel deletion in the promoter encompassing the transcription start site of the FTL gene is responsible for HHCS in this kindred. The initial primers for lifying the IRE similar to those used by other researchers failed to detect this mutation. Therefore the genomic region assessed in HHCS cases for diagnosis should be expanded to include mutations of this type.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 07-2010
DOI: 10.1167/IOVS.09-4786
Publisher: Hindawi Limited
Date: 24-09-2002
DOI: 10.1002/HUMU.9066
Publisher: Springer Science and Business Media LLC
Date: 13-12-2022
Publisher: Informa UK Limited
Date: 20-04-2017
DOI: 10.3109/13816810.2016.1164195
Abstract: Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal dominant Mendelian disorder characterized by early onset cataracts and elevated levels of serum ferritin in the absence of iron overload. Numerous mutations associated with the development of HHCS have been reported in the 5' non-coding region of the ferritin light chain (FTL) gene in family studies. We present an FTL mutation in an Australian family with 10 HHCS-affected members spanning three generations. Blood and saliva s les were collected from affected and unaffected family members and DNA was extracted using commercially available kits (Qiagen). The complete sequencing of the iron-responsive element (IRE) of the FTL gene was analyzed using bi-directional genomic sequencing. A heterozygous single nucleotide substitution (c.-167 C>T) was identified in the proband and five affected family members (logarithm of the odds score [Z] = 3.61, recombination distance [θ = 0]). All affected in iduals had previously been found to have high ferritin levels and early onset cataracts. This is the first Australian report of the c.-167 C>T mutation in a large family with multiple affected in iduals. This finding raises the possibility that identification of HHCS mutations may be an effective means of disease detection and may aid in facilitating appropriate genetic counseling.
Publisher: Springer Science and Business Media LLC
Date: 06-04-2016
DOI: 10.1038/NCOMMS11008
Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry in iduals, we identify six novel loci ( FAM150B-ACP1 , LINC00340 , FBN1 , DIS3L-MAP2K1 , ARID2-SNAT1 and SLC14A2 ) associated with refractive error. In Asian populations, three genome-wide significant loci AREG , GABRR1 and PDE10A also exhibit strong interactions with education ( P .5 × 10 −5 ), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
Publisher: Wiley
Date: 04-09-2018
DOI: 10.1111/AOS.13769
Publisher: Public Library of Science (PLoS)
Date: 28-06-2013
Publisher: Springer Science and Business Media LLC
Date: 24-11-2017
DOI: 10.1038/S41467-017-00837-5
Abstract: Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1 , that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically erse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2018
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.ULTRAMIC.2011.03.008
Abstract: The phenomenon of protein aggregation is of considerable interest to various disciplines, including the field of medicine. A range of disease pathologies are associated with this phenomenon. One of the ocular diseases hallmarked by protein aggregation is the Pseudoexfoliation (PEX) Syndrome. This condition is characterized by the deposition of insoluble proteinaceous material on the anterior human lens capsule. Genomic and proteomic analyses have revealed an association of specific genetic markers and various proteins, respectively, with PEX syndrome. However, the ultrastructure of the protein aggregates is poorly characterized. This study seeks to build capacity to determine the molecular nature of PEX aggregates on human lens capsules in their native state by AFM-based antibody recognition imaging. Lysyl oxidase-Like 1 (LOXL1), a protein identified as a component of PEX aggregates, is detected by an antibody-modified AFM probe. Topographical AFM images and antibody recognition images are obtained using three AFM-based techniques: TREC, phase and force-volume imaging. LOXL1 is found to be present on the lens capsule surface, and is localized around fibrous protein aggregates. Our evaluation shows that TREC imaging is best suited for human tissue imaging and holds significant potential for imaging of human disease tissues in their native state.
Publisher: Springer Science and Business Media LLC
Date: 19-03-2020
DOI: 10.1038/S42003-020-0802-Y
Abstract: Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 in iduals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11 / FBLN2 rs2630445, RBP3 rs11204213) others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.
Publisher: Wiley
Date: 05-03-2020
DOI: 10.1111/CGE.13722
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 07-2004
DOI: 10.1167/IOVS.03-1044
Abstract: Mutations in the frizzled-4 gene (FZD4) have recently been associated with autosomal dominant familial exudative vitreoretinopathy (FEVR) in families linking to the EVR1 locus on the long arm of chromosome 11. The purpose of this study was to screen FZD4 in a panel of 40 patients with FEVR to identify the types and location of mutations and to calculate what proportion of this heterogeneous condition is attributable to FZD4 mutations. PCR products were generated from genomic DNA with primers designed to lify the coding sequence of FZD4. The PCR products were screened for mutations by single-strand conformational polymorphism-heteroduplex analysis (SSCP-HA) and by direct sequencing. In total, eight mutations were identified, seven of which were novel. Three were deletions (c957delG, c1498delA, and c1501-1502delCT), one was a nonsense mutation (Q505X), and four were missense mutations (G36D, M105T, M157V, and S497F). Eight mutations have been identified in the FZD4 gene in a cohort of 40 unrelated patients with FEVR. This result indicates that FZD4 mutations are responsible for only 20% of FEVR index cases and suggests that the other FEVR loci may account for more cases than previously anticipated.
Publisher: Wiley
Date: 05-2010
DOI: 10.1111/J.1442-9071.2010.02288.X
Abstract: To determine the prevalence and associations of blinding trachoma within the indigenous Australian population living in central Australia. A total of 1884 in iduals aged 20 years or older, living among 30 remote communities within the statistical local area of 'Central Australia', were recruited for this study. This equated to 36% of those aged 20 years or older and 67% of those aged 40 years or older within this district. Participants were recruited as they presented to the eye clinic at each remote community. Anterior segment examination was performed and the rates of trachomatous trichiasis (TT) and trachomatous corneal opacification (CO) were documented. The prevalence of TT and CO in one or both eyes was presented. There were 6.1% (95% CI 5.0-7.2) (8.3% of those aged 40 years or older) who had TT and 3.3% (95% CI 2.5-4.1) (4.4% of those aged 40 years or older) who had CO. Both TT and CO were associated with advancing age and female sex. Prevalence varied widely between communities, from 0% to 33% for TT and 0% to 27% for CO. Our study has shown that blinding trachoma remains endemic among indigenous Australians in central Australia. However, compared with previous estimates, the prevalence of TT and CO appears to be decreasing.
Publisher: Public Library of Science (PLoS)
Date: 10-08-2011
Publisher: BMJ
Date: 07-2022
DOI: 10.1136/BMJOPEN-2022-062754
Abstract: Childhood glaucoma is a chronic vision-threatening condition that may significantly impact an in idual’s psychosocial well-being. There is a paucity of literature investigating the quality of life (QoL) in children with glaucoma. The aim of this study was to investigate and report on the QoL issues encountered by children with glaucoma. This is a qualitative interview study. Data were collected through semistructured interviews. NVivo V.12 software (QSR International Pty Ltd, Melbourne, Australia) was used to analyse and code data to identify QoL themes. The prominence of QoL themes was determined by the number of children who raised issues connected to the corresponding theme. Interviews were conducted via telephone or videoconferencing between April 2020 and July 2021. Eighteen children with glaucoma, aged 8–17 years, who resided in Australia, were recruited from the Australian and New Zealand Registry of Advanced Glaucoma. Median child age was 12.1 years (IQR: 9.7–14.5 years) and 33% were female. Seven QoL themes were identified: ‘coping’, ‘inconveniences’ and ‘emotional well-being’ were more prominent themes than ‘symptoms’, ‘ocular health concerns’, ‘social well-being’ and ‘autonomy’. Adaptive coping strategies included resilience throughout clinical examinations and establishing positive relationships with ophthalmologists. These minimised inconveniences related to clinic waiting times and pupillary dilatation. External to the clinical setting, children often dissociated from their glaucoma but struggled with glare symptoms and feeling misunderstood by fellow peers. Older children aged 13–17 years commonly disengaged from their glaucoma care and expressed an unwillingness to attend ophthalmic appointments. Older children further raised issues with career options, obtaining a driver’s licence and family planning under the theme of autonomy. The psychosocial impact of childhood glaucoma extends beyond the clinical environment and was minimised using coping strategies. Older children may require additional social and ophthalmic support as they transition into adulthood.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2021
DOI: 10.1186/S12864-021-07782-0
Abstract: Glaucoma is a leading cause of visual disability and blindness. Release of iris pigment within the eye, pigment dispersion syndrome (PDS), can lead to one type of glaucoma known as pigmentary glaucoma. PDS has a genetic component, however, the genes involved with this condition are largely unknown. We sought to discover genes that cause PDS by testing cohorts of patients and controls for mutations using a tiered analysis of exome data. Our primary analysis evaluated melanosome-related genes that cause dispersion of iris pigment in mice ( TYRP1 , GPNMB , LYST , DCT , and MITF ). We identified rare mutations, but they were not statistically enriched in PDS patients. Our secondary analyses examined PMEL (previously linked with PDS), MRAP , and 19 other genes. Four MRAP mutations were identified in PDS cases but not in controls ( p = 0.016). Immunohistochemical analysis of human donor eyes revealed abundant MRAP protein in the iris, the source of pigment in PDS. However, analysis of MRAP in additional cohorts (415 cases and 1645 controls) did not support an association with PDS. We also did not confirm a link between PMEL and PDS in our cohorts due to lack of reported mutations and similar frequency of the variants in PDS patients as in control subjects. We did not detect a statistical enrichment of mutations in melanosome-related genes in human PDS patients and we found conflicting data about the likely pathogenicity of MRAP mutations. PDS may have a complex genetic basis that is not easily unraveled with exome analyses.
Publisher: BMJ
Date: 08-2004
Publisher: Wiley
Date: 26-07-2022
DOI: 10.1111/CEO.14134
Abstract: Vascular dysfunction plays a considerable role in glaucoma pathogenesis. Previous glaucoma case studies described localised wedge-shaped vascular defects, similar to retinal nerve fibre layer (RNFL) wedge defects. This study investigates the prevalence and quantification of this vessel loss, in relation to primary open angle glaucoma (POAG) parameters. This study included 608 eyes (351 participants): 192 PROGRESSA study participants (342 eyes) with suspect, preperimetric or early manifest POAG, observed for vascular wedge defect presence (cohort one) an additional 114 in iduals (cohort two-208 eyes) with POAG at various stages of progression for wedge characterisation and 38 controls (56 eyes). Vascular wedge defects were observed using optical coherence tomography angiography (OCTA). Wedge parameters and vessel densities were quantified using ImageJ software. RNFL and ganglion cell layer inner plexiform layer (GCLIPL) from OCT scans, and mean deviation (Humphrey visual field 24-2) were also assessed. Vascular wedge defects were found in 45/342 eyes (13.2%) in cohort one, in 41/208 eyes (19.7%) in cohort two and were not found in controls. Wedge defects were mostly inferotemporal (80%), and present at all disease stages. They were associated with visual field loss in the opposite hemisphere, thinner RNFL (p < 0.001), thinner GCLIPL (p = 0.003), and focal RNFL loss corresponding with the vascular defect region. Vascular wedge defects are present at all POAG stages even before functional change and are strongly concordant with focal RNFL loss. Further research is needed to explore these defects in particular their temporal relationship with clinical measures of POAG.
Publisher: American Medical Association (AMA)
Date: 02-2020
Publisher: American Medical Association (AMA)
Date: 04-2019
Publisher: Wiley
Date: 13-02-2020
DOI: 10.1111/CEO.13724
Publisher: Informa UK Limited
Date: 1996
DOI: 10.3109/03630269609005848
Abstract: This paper reviews the methodology used by the World Economic Forum (WEF) to create the Global Competitiveness Index (WEF-GCI). We propose an alternative competitiveness index that only includes the objective data (hard data) from the WEF-GCI and is created by applying a multivariate statistical procedure (Exploratory Factor Analysis) that allows us to determine the weights from the implicit data structure. The rankings obtained from this index have a high degree of association with those provided by the WEF. The main benefit of this index over the WEF index is that it does not include valuations from opinion surveys given to business executives and/or entrepreneurs of the countries included in the index (soft data). Consequently, the rankings from this alternative index are not affected by political biases or in idual interests as it is elaborated only including officially published objective data.
Publisher: Oxford University Press (OUP)
Date: 10-04-2015
DOI: 10.1093/HMG/DDV128
Publisher: Springer Science and Business Media LLC
Date: 14-03-2020
Publisher: Springer Science and Business Media LLC
Date: 04-11-2014
Publisher: Elsevier BV
Date: 07-2023
Publisher: AMPCo
Date: 02-2013
DOI: 10.5694/MJA12.10607
Abstract: To assess the accuracy of grading diabetic retinopathy (DR) using single-field digital fundus photography compared with clinical grading from a dilated slit-l fundus examination in Indigenous Australians living in Central Australia. Cross-sectional study comparing DR grades in participants with diabetes mellitus presenting for examination at remote community clinics from 1 July 2005 to 30 June 2008. Sensitivity and specificity of grading using digital photography compared with the clinical gold standard of slit-l fundus examination. Of the 1884 participants recruited for the study, 1040 had self-reported diabetes mellitus and, of those, 360 had fundus photographs available (706 eyes) that were able to be graded. On clinical grading, 163 eyes had any DR and 51 eyes had vision-threatening DR (VTDR). The sensitivity and specificity for detecting any DR were 74% (95% CI, 67%-80%) and 92% (95% CI, 90%-94%), respectively. The sensitivity and specificity for detecting VTDR were 86% (95% CI, 77%-96%) and 95% (95% CI, 93%-97%), respectively. Single-field digital fundus photography is a valid screening tool for DR in remote communities of central Australia and may be used to provide eye care services to this region with acceptable accuracy.
Publisher: Wiley
Date: 30-01-2017
DOI: 10.1111/CEO.12880
Abstract: No studies to date have explored the association of vision with mortality in Indigenous Australians. We aimed to determine the 10-year all-cause mortality and its associations among Indigenous Australians living in Central Australia. Prospective observational cohort study. A total of 1257 (93.0%) of 1347 patients from The Central Australian Ocular Health Study, over the age of 40 years, were available for follow-up during a 10-year period. All-cause mortality and its associations with visual acuity, age and gender were analysed. All-cause mortality. All-cause mortality was 29.3% at the end of 10 years. Mortality increased as age of recruitment increased: 14.2% (40-49 years), 22.6% (50-59 years), 50.3% (60 years or older) (χ = 59.15 P < 0.00001). Gender was not associated with mortality as an unadjusted variable, but after adjustment with age and visual acuity, women were 17.0% less likely to die (t = 2.09 P = 0.037). Reduced visual acuity was associated with increased mortality rate (5% increased mortality per one line of reduced visual acuity t = 4.74 P < 0.0001) after adjustment for age, sex, diabetes and hypertension. The 10-year all-cause mortality rate of Indigenous Australians over the age of 40 years and living in remote communities of Central Australia was 29.3%. This is more than double that of the Australian population as a whole. Mortality was significantly associated with visual acuity at recruitment. Further work designed to better understand this association is warranted and may help to reduce this disparity in the future.
Publisher: Elsevier BV
Date: 09-2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-09-2020
Publisher: American Medical Association (AMA)
Date: 05-2018
Publisher: Cold Spring Harbor Laboratory
Date: 22-10-2021
DOI: 10.1101/2021.10.19.21264544
Abstract: Integrating polygenic risk scores (PRS) into healthcare has the potential to stratify an in idual’s risk of glaucoma across a broad population. Glaucoma is the most common cause of irreversible blindness worldwide, therefore effective screening for glaucoma endorsed by the population is highly important. This study assessed the attitude of unaffected in iduals towards PRS testing for glaucoma, and sought to identify factors associated with interest in testing. We surveyed 418 unaffected in iduals including those with a first-degree relative with glaucoma (n=193), those who had a recent eye examination (n=117), and general members of the community (n=108). Overall, 71.3% indicated an interest in taking a polygenic risk test for glaucoma. Interest was more likely in those who believed glaucoma to be a severe medical condition (OR 14.58, 95%CI (1.15-185.50), p=0.039), those concerned about developing glaucoma (OR 4.37, 95%CI (2.32-8.25), p .001), those with an intention to take appropriate measures regarding eye health (OR 2.39, 95%CI (1.16-4.95), p=0.019), and those preferring to know if considered to be at-risk or not (OR 4.52, 95%CI (2.32-8.83), p .001). These findings represent a valuable assessment of general public interest in glaucoma polygenic risk testing, which will be integral to the implementation and uptake of novel PRS based tests into clinical practice.
Publisher: Wiley
Date: 28-06-2019
DOI: 10.1002/MGG3.774
Abstract: CYP1B1 variants and deletions are the most common cause of primary congenital glaucoma (PCG). We investigated an in idual with PCG from the Australian and New Zealand Registry of Advanced Glaucoma. We performed sequencing of the CYP1B1 gene, followed by Multiplex Ligation‐dependent Probe Amplification and SNP array. We identified a homozygous deletion of the CYP1B1 gene by Multiplex Ligation‐dependent Probe Amplification and confirmed that the father was heterozygous for a CYP1B1 deletion but the mother had normal gene copy number. SNP array identified paternal uniparental isodisomy of the entire chromosome 2. This study is the first report of a homozygous CYP1B1 whole gene deletion due to paternal uniparental isodisomy of chromosome 2 as a cause of PCG. These results illustrate the importance of genetic testing in providing appropriate genetic counseling regarding the risks of recurrence.
Publisher: Elsevier BV
Date: 07-2021
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 15-06-2016
Abstract: Thyroid-associated orbitopathy (TO) is an autoimmune-mediated orbital inflammation that can lead to disfigurement and blindness. Multiple genetic loci have been associated with Graves' disease, but the genetic basis for TO is largely unknown. This study aimed to identify loci associated with TO in in iduals with Graves' disease, using a genome-wide association scan (GWAS) for the first time to our knowledge in TO. Genome-wide association scan was performed on pooled DNA from an Australian Caucasian discovery cohort of 265 participants with Graves' disease and TO (cases) and 147 patients with Graves' disease without TO (controls). Top-ranked single nucleotide polymorphisms (SNPs) then were genotyped in in idual DNA s les from the discovery cohort, and two replication cohorts totaling 584 cases and 367 controls. In the GWAS of pooled DNA s les, several SNPs showed suggestive association with TO at genome-wide P ≤ 10-6 rs953128 located on chr10q21.1, rs2867161 on chr7q11.22, rs13360861 on chr5q12.3, rs7636326 on chr3q26.2, rs10266576 on chr 7q11.22, rs60457622 on chr3q23, and rs6110809 on chr20p12.1. However, the only SNP consistently associated with TO on in idual genotyping in the discovery and replication cohorts was rs6110809, located within MACROD2 on chromosome 20p12.1. On combined analysis of discovery and replication cohorts, the minor A allele of rs6110809 was more frequent in TO than in Graves' disease controls without TO (P = 4.35 × 10-5 odds ratio [OR] = 1.77 95% confidence interval [CI], 1.35-2.32) after adjusting for age, sex, duration of Graves' disease, and smoking. In patients with Graves' disease, a common genetic variant in MACROD2 may increase susceptibility for thyroid-associated orbitopathy. This association now requires confirmation in additional independent cohorts.
Publisher: BMJ
Date: 04-08-2023
Abstract: To evaluate the effect of an intraoperative dose of intravitreal bevacizumab (Avastin) on surgical success following trabeculectomy with mitomycin-C (MMC) over 12 months. A single centre, parallel, double-blinded randomised, placebo-controlled trial recruiting patients requiring trabeculectomy for progressing glaucoma. Patients were randomised to intravitreal bevacizumab or placebo. The primary outcome of treatment success was defined by ‘complete success’ when intraocular pressure (IOP) remained less than a predefined target IOP without the requirement of topical medication, or ‘qualified success’ where topical medication was required to meet the predefined target IOP threshold. Secondary outcomes included the need for subsequent IOP-lowering interventions, and structural parameters associated with bleb function. From 131 patients randomised to bevacizumab (n=65) or placebo (n=66), 128 patients completed 12 months of follow-up (98%). At 12 months, success rates were higher in the bevacizumab group (complete success: 94% vs 83% p=0.015 qualified success: 98% vs 90% p=0.033). Within the placebo group, the requirement for topical therapy was higher at 6 months (p=0.045) and 12 months (p=0.045), and the requirement for bleb needling was higher at 1 month (p=0.035). Blebs within the bevacizumab group were larger at 1 month (p .001) and demonstrated less vessel inflammation (p .0001). Bevacizumab given as a single intravitreal dose during trabeculectomy with MMC resulted in improved surgical success as 12 months. Furthermore, bevacizumab was associated with a significant reduction in the need for additional medication or further surgery to achieve target IOP. Bevacizumab was also associated with larger blebs that were less inflamed and required fewer subsequent interventions. ACTRN12614000375651.
Publisher: Elsevier BV
Date: 2015
Publisher: Elsevier BV
Date: 12-2021
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 18-05-2018
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.OPHTHA.2012.02.004
Abstract: Genetic variation at the 9p21 locus encompassing the CDKN2B-AS1, CDKN2A, and CDKN2B genes has been associated with primary open-angle glaucoma (POAG) in several independent studies. This study aimed to dissect the association further and to determine genotype-phenotype correlations between genetic variation at this locus and a range of glaucoma-related traits in a large cohort of POAG patients. Comparative case series and case-control study. One thousand four hundred thirty-two POAG patients and 595 unaffected controls recruited from 2 population-based and 2 cross-sectional studies. Each patient was genotyped at 9 single nucleotide polymorphisms (SNPs) previously associated with POAG at the 9p21 locus. Each SNP was assessed for association with each outcome measure using linear regression under an additive genetic model. Associated traits were explored further including adjustment for relevant covariates. Highest recorded intraocular pressure (IOP) also was analyzed both with and without correction for central corneal thickness (CCT) and was dichotomized into high-tension glaucoma and normal-tension glaucoma (NTG). Intraocular pressure and vertical cup-to-disc ratio (VCDR). Glaucoma risk alleles at 9p21, particularly, rs7049105 and rs10120688, were associated with the presence of both NTG and advanced POAG. The SNP rs10120688 was associated with greater VCDR after adjustment for covariates (P = 0.003 β = 0.016 standard error, 0.006). In addition, multiple SNPs in the region were associated with reduced IOP, before and after adjustment for CCT. The SNP most significantly associated with IOP was also rs10120688 (P = 0.001 β = -2.135 standard error, 0.634) after adjustment for covariates under an additive model. In a comparison of high-tension versus low-tension glaucoma, this SNP was also the most significantly associated, particularly when IOP was corrected for CCT before classification of the type of glaucoma (P = 0.0009 odds ratio, 0.63 95% confidence interval, 0.48-0.83). Patients with POAG carrying the glaucoma risk alleles at the 9p21 locus have larger VCDR and lower IOP than POAG patients without these alleles. Carriers of these alleles seem to be predisposed to POAG developing at lower IOP levels and exhibit stronger associations with NTG and advanced glaucoma phenotypes. This may be of relevance when setting target pressures in patients carrying these risk alleles.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.OPHTHA.2012.11.029
Abstract: To determine the proportion of all Myocilin coding mutations responsible for advanced primary open-angle glaucoma (POAG) in early-age-at-onset in iduals and to investigate the prevalence of exon 3 Myocilin mutations in advanced POAG at any age at onset in a large Australasian cohort. Cross-sectional study using a national disease registry. One thousand sixty in iduals with advanced POAG (103 with age at onset of 40 years or younger) and 320 with nonadvanced POAG all recruited by the Australian and New Zealand Registry of Advanced Glaucoma. Participants were examined and referred by their eye practitioner, and Myocilin genetic testing was performed by direct sequencing. Cascade genetic testing was made available for relatives of participants found to carry a Myocilin mutation. Advanced glaucoma diagnosis based on strict visual field entry criteria. Prevalence and spectrum of Myocilin mutations in in iduals with advanced and nonadvanced POAG. This is the first study to report Myocilin mutations in an advanced POAG cohort. No pathogenic Myocilin mutations were identified in exons 1 and 2 in early-age-at-onset advanced POAG cases. Exon 3 Myocilin mutations were identified in 45 advanced POAG patients (4.2%), which is significantly higher (P = 0.02) compared with nonadvanced POAG patients (1.6%). A novel mutation (Trp373X) and a new variant of uncertain pathogenicity (Ala447Thr) also were reported. The prevalence of Myocilin mutations rose from 16% to 40% in selected advanced POAG subgroups based on different thresholds of maximum recorded intraocular pressure, age at diagnosis, and the presence and strength of positive family history. Twenty-six in iduals with Myocilin mutations were identified through cascade genetic testing of first-degree relatives of affected mutation carriers. The prevalence of Myocilin mutations in glaucoma cases with severe visual field loss is significantly greater than in nonadvanced glaucoma patients. Myocilin screening in phenotypically selected cases can have a much higher yield than in previous unselected series. Identifying in iduals who have Myocilin mutations provides an opportunity to screen at-risk clinically unaffected relatives and to reduce glaucoma blindness through early management and intervention. The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Publisher: Wiley
Date: 11-06-2019
DOI: 10.1111/AOS.14142
Publisher: Wiley
Date: 27-03-2012
DOI: 10.1111/J.1442-9071.2012.02764.X
Abstract: To estimate the incidence and causes of visual impairment and blindness among indigenous Australians living in Central Australia. Clinic-based cohort study. A total of 1884 in iduals aged ≥20 years living in one of 30 remote communities within the statistical local area of 'Central Australia'. From those initially recruited, 608 (32%) participants were reviewed again between 6 months and 3 years (median 2 years). Patients underwent Snellen visual acuity testing and subjective refraction. Following this, an assessment of their anterior and posterior segments was made. Baseline results were compared with those who were reviewed. The annual incidence rates and causes of bilateral visual impairment (vision worse than Snellen visual acuity 6/12 in the better eye) and bilateral blindness (Snellen visual acuity worse than 6/60 in the better eye). The annual incidence of bilateral visual impairment and blindness was 6.82% (8.12% for those aged ≥40 years) per year and 0.50% (0.62% for those aged ≥40 years) per year, respectively. Refractive error, followed by cataract and diabetic retinopathy, were the main causes for incident bilateral visual impairment and blindness. This study has demonstrated rates of incident bilateral blindness and visual impairment among the indigenous Australian population within Central Australia, which are substantially higher than those from the non-indigenous population. Services need to address the underlying causes of this incident vision loss to reduce visual morbidity in indigenous Australians living in central Australia.
Publisher: Oxford University Press (OUP)
Date: 05-1999
DOI: 10.1093/HMG/8.5.899
Abstract: A glaucoma locus, GLC1A, was identified previously on chromosome 1q. A gene within this locus (encoding the protein myocilin) subsequently was shown to harbor mutations in 2-4% of primary open angle glaucoma patients. A total of 1703 patients was screened from five different populations representing three racial groups. There were 1284 patients from primarily Caucasian populations in Iowa (727), Australia (390) and Canada (167). A group of 312 African American patients was from New York City and 107 Asian patients from Japan. Overall, 61 different myocilin sequence variations were identified. Of the 61 variations, 21 were judged to be probable disease-causing mutations. The number of probands found to harbor such mutations in each population was: Iowa 31/727 (4.3%), African Americans from New York City 8/312 (2.6%), Japan 3/107 (2.8%), Canada 5/167 (3.0%), Australia 11/390 (2.8%) and overall 58/1703 (3. 4%). Overall, 16 (76%) of 21 mutations were found in only one population. The most common mutation observed, Gln368Stop, was found in 27/1703 (1.6%) glaucoma probands and was found at least once in all groups except the Japanese. Studies of genetic markers flanking the myocilin gene suggest that most cases of the Gln368Stop mutations are descended from a common founder. Although the specific mutations found in each of the five populations were different, the overall frequency of myocilin mutations was similar ( approximately 2-4%) in all populations, suggesting that the increased rate of glaucoma in African Americans is not due to a higher prevalence of myocilin mutations.
Publisher: Wiley
Date: 16-05-2018
DOI: 10.1002/MGG3.406
Publisher: Elsevier BV
Date: 09-2023
Publisher: Oxford University Press (OUP)
Date: 30-01-2015
DOI: 10.1093/HMG/DDV027
Abstract: Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (β = 0.44, P-value = 1.87 × 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (β = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls odds ratio (OR) = 1.53, P-value = 1.99 × 10(-8)], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10(-9) for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.
Publisher: Asia Pacific Academy of Ophthalmology
Date: 2015
Publisher: Wiley
Date: 06-1996
DOI: 10.1046/J.1365-2141.1996.D01-1682.X
Abstract: A sensitive F-cell assay has been used to examine the production of fetal haemoglobin (Hb F) in a group of 77 adult patients with myelodysplastic syndrome (MDS), and a control group composed of 100 normal blood donors. Although the mean F-cell percentage in the MDS group (6.0%) is not statistically different from that in the normal blood donors (3.1%), a higher proportion of myelodysplastic patients have elevated F-cell values and the magnitude of the increases is greater than that observed in blood donors. In order to investigate the association further, the karyotypes of the MDS patients have been examined. 13/21 (61.9%) of the MDS patients with karyotypic abnormalities have F-cell values > 5%, compared to only 6/56 (10.9%) of the MDS patients with a normal karyotype and 11/100 (11%) of the blood donors. The observed difference in the distributions of F cells between the two subgroups of patients with MDS is highly significant (P < 0.0001).
Publisher: Springer Science and Business Media LLC
Date: 27-04-2020
Publisher: Springer Science and Business Media LLC
Date: 29-05-2013
DOI: 10.1038/NG0613-712B
Publisher: Wiley
Date: 05-2010
DOI: 10.1111/J.1442-9071.2010.02257.X
Abstract: To determine the prevalence and associations of cataract within the indigenous Australian population living in central Australia. 1884 in iduals aged > or =20 years, living in one of 30 remote communities within the statistical local area of 'central Australia' were recruited for this study. This equated to 36% of those aged > or =20 years and 67% of those aged > or =40 years within this district. Slit-l examination was performed. The degree and subtype of cataract was graded using the Lens Opacities Classification System III criteria. A cataract was defined as a nuclear opalescence > or =4.0, a cortical opacity > or =3.0, a posterior subcapsular opacity > or =2.0, a visual acuity worse than 6/12 or a visual acuity worse than 6/60 due to cataract. The prevalence of cataract in one or both eyes was presented for each of the definitions. Nuclear opalescence cataract was present in 13.5% (18.5% of those > or =40 years) cortical opacity cataract was present in 13.1% (17.7% of those > or =40 years) and posterior subcapsular cataract was present in 15.8% (21.0% of those > or =40 years). 12.6% of patients (17.3% of those > or =40 years) and 4.4% of patients (5.9% of those > or =40 years) had a cataract that resulted in a visual acuity of worse than 6/12 and worse than 6/60, respectively. All cataracts were associated with advancing age. Posterior subcapsular cataract was associated with self-reported diabetes. There is a higher prevalence of cataract among indigenous Australians living within remote central Australia compared with the non-indigenous population. Services for this population need to be designed with this in mind when planning resource allocation.
Publisher: Elsevier BV
Date: 08-2023
Publisher: Public Library of Science (PLoS)
Date: 20-06-2018
Publisher: Wiley
Date: 10-2010
DOI: 10.1111/J.1742-6723.2010.01338.X
Abstract: We present a case of a 63-year-old woman who presented to an ED with bifrontal headache, nausea and vomiting and reduced visual acuity. Examination revealed bilateral elevated intraocular pressures, corneal haze, shallow anterior chambers and poorly reactive, mid-dilated pupils. Diagnosis was made of simultaneous bilateral acute angle closure glaucoma. A complete drug history revealed that she had been using an over-the-counter cold and flu remedy whose active ingredients included atropa belladonna, an herb with anticholinergic properties. It is likely that drug-induced dilatation of the in idual's pupils precipitated this angle closure emergency. In the report we discuss the risk factors for angle closure glaucoma, and review the local and systemic drugs known to trigger this sight-threatening emergency.
Publisher: Oxford University Press (OUP)
Date: 1999
DOI: 10.1093/MOLEHR/5.1.5
Abstract: The tumour necrosis factor (TNF)2 allele appears to be linked with increased insulin resistance and obesity, conditions often found in overweight patients with polycystic ovary syndrome (PCOS). The significance of TNFalpha polymorphism in relation to the clinical and biochemical parameters associated with PCOS was investigated in 122 well-characterized patients with polycystic ovaries (PCO). Of these, 84 had an abnormal menstrual cycle and were classified as having PCOS, while the remaining 38 had a normal menstrual cycle and were classified as having PCO. There were a further 28 in iduals without PCO (non-PCO) and 108 in iduals whose PCO status was undetermined (reference population). The promoter region of the TNFalpha gene was lified by polymerase chain reaction (PCR), and the presence or absence of the polymorphism at -308 was determined by single-strand conformational polymorphism (SSCP) analysis. The less common TNF allele (TNF2) was found as TNF1/2 or TNF2/2 in 11/38 (29%) of PCO subjects, 25/84 (30%) of PCOS subjects, 7/28 (25%) of non-PCO subjects, and 45/108 (42%) of the reference population. There was no significant difference in the incidence of the TNF2 allele between the groups. The relationship of TNF genotype to clinical and biochemical parameters was examined. In both the PCO group and the PCOS group, the presence of the TNF2 allele was significantly associated with lower glucose values obtained from the glucose tolerance testing (P<0.05). The TNF genotype was not significantly associated with any clinical or biochemical parameter measured in the PCO, PCOS or non-PCOS groups. Thus, the TNFalpha -308 polymorphism does not appear to strongly influence genetic susceptibility to polycystic ovaries.
Publisher: American Diabetes Association
Date: 27-04-2010
DOI: 10.2337/DC09-1893
Abstract: Aldose reductase (ALR) is involved in diabetic microvascular damage via the polyol pathway. A recent meta-analysis found genetic variation in the ALR gene (AKR1B1) to be significantly associated with diabetic retinopathy (DR). We investigated the genetic association of AKR1B1 with DR. The study enrolled 909 in iduals with diabetes. Participants were genotyped for an AKR1B1 (CA)n microsatellite and 14 tag single nucleotide polymorphisms, and ophthalmological assessment was performed. A total of 514 in iduals were found to have DR. rs9640883 was significantly associated with DR (P = 0.0005). However, AKR1B1 variation was not independently associated with DR development after adjusting for relevant clinical parameters. rs9640883 was associated with duration of diabetes (P = 0.002). Many previous reports have failed to account for known risk factors for DR. The commonly reported association of AKR1B1 with DR may be due to an association of the gene with younger age at onset of diabetes.
Publisher: Springer Science and Business Media LLC
Date: 21-12-2015
DOI: 10.1038/NG.3448
Publisher: BMJ
Date: 22-04-2012
Abstract: To determine the prevalence of glaucoma within the indigenous Australian population living in central Australia. 1884 in iduals aged ≥20 years, living in one of 30 remote communities within the statistical local area of 'Central Australia,' were recruited for this study. This equated to 36% of those aged ≥20 years and 67% of those aged ≥40 years within this district. Slit-l examination of the anterior segment and intraocular pressure measurement, followed by stereoscopic slit-l funduscopy of the optic nerve, was performed. Selected patients underwent automated visual-field testing. The diagnosis of glaucoma was based on pre-existing definitions. Glaucoma prevalence data are presented. Seventeen in iduals had glaucoma (0.90%). Causes of secondary glaucoma were found in four with neovascular glaucoma, two with uveitic glaucoma and four who had developed glaucoma subsequent to trauma or surgery. The remaining seven had no identifiable cause for their glaucoma and were thus classified as open-angle glaucoma equating to a prevalence of 0.52% (95% CI 0.14% to 0.90%) for those aged ≥40 years. Of these, four had an intraocular pressure ≤21 mm Hg, and three had an intraocular pressure >21 mm Hg. The prevalence of open-angle glaucoma among indigenous Australians within central Australia was 0.52% for those aged ≥40 years. After adjustment for the age distribution of our s le, this is one-third the prevalence seen among the non-indigenous Australian population and is despite a higher prevalence of ocular parameters considered to be associated with glaucoma.
Publisher: Oxford University Press (OUP)
Date: 06-09-2019
DOI: 10.1093/HMG/DDZ193
Abstract: Optic nerve head morphology is affected by several retinal diseases. We measured the vertical optic disc diameter (DD) of the UK Biobank (UKBB) cohort (N = 67 040) and performed the largest genome-wide association study (GWAS) of DD to date. We identified 81 loci (66 novel) for vertical DD. We then replicated the novel loci in International Glaucoma Genetic Consortium (IGGC, N = 22 504) and European Prospective Investigation into Cancer–Norfolk (N = 6005) in general the concordance in effect sizes was very high (correlation in effect size estimates 0.90): 44 of the 66 novel loci were significant at P & 0.05, with 19 remaining significant after Bonferroni correction. We identified another 26 novel loci in the meta-analysis of UKBB and IGGC data. Gene-based analyses identified an additional 57 genes. Human ocular tissue gene expression analysis showed that most of the identified genes are enriched in optic nerve head tissue. Some of the identified loci exhibited pleiotropic effects with vertical cup-to-disc ratio, intraocular pressure, glaucoma and myopia. These results can enhance our understanding of the genetics of optic disc morphology and shed light on the genetic findings for other ophthalmic disorders such as glaucoma and other optic nerve diseases.
Publisher: BMJ
Date: 24-06-2010
Abstract: Evidence in the recent literature has highlighted the importance of central corneal thickness (CCT) in relation to several ocular and non-ocular conditions. Most notably, thinner CCT has been identified as a risk factor for open-angle glaucoma. Despite having an extensive knowledge of the structure and function of the cornea, little is known about the pathways that determine CCT. There are data to suggest however that CCT has a strong genetic component. Heritability studies conducted in twins and family pedigrees indicate that CCT is one of the most highly heritable human traits, whereas data from a erse range of ethnic groups show clear ethnic-related differences in CCT. Extreme CCT measurements have also been associated with rare genetic diseases. Although there is strong evidence supporting a genetic component to normal CCT variation, to date, no genes have been identified. This review investigates the current literature surrounding this topic and explores the significance of understanding the genetics of CCT and how this might benefit the field of open-angle glaucoma treatment and research.
Publisher: Informa UK Limited
Date: 02-01-2019
DOI: 10.1080/13816810.2018.1561904
Abstract: Stability of the crystalline lens requires formation of microfibril bundles and their higher-order structures of ciliary zonules. Trauma, malformation, or degeneration of the ciliary zonules can lead to dislocation or displacement of the lens, which in turn can cause transient or permanent loss of visual acuity. The purpose of this study was to identify the predicted substrates of aspartyl/asparaginyl hydroxylase (ASPH), a 2-oxoglutarate- and Fe A single proband of European ancestry with spherophakia and high myopia was subjected to exome sequencing. Proteins containing the ASPH hydroxylation motif were identified within the SwissProt protein database. We identified 105 putative substrates of ASPH-mediated hydroxylation in the human proteome, of which two (fibrillin-1 and latent transforming growth factor beta binding protein-2) are associated with inherited ectopia lentis syndromes, and are essential for microfibril and ciliary zonule development. Our results implicate ASPH-mediated hydroxylation in the formation of FBN1/LTBP2 microfibril bundles and competent ciliary zonules.
Publisher: Informa UK Limited
Date: 2007
Publisher: Elsevier BV
Date: 02-2017
Publisher: Springer Science and Business Media LLC
Date: 08-05-2018
Publisher: Wiley
Date: 05-2010
DOI: 10.1111/J.1442-9071.2010.02256.X
Abstract: To determine the prevalence and associations of diabetic retinopathy (DR) within the indigenous Australian population living in central Australia. 1884 in iduals aged 20 years or older, living in one of 30 remote communities within the statistical local area of 'central Australia' were recruited for this study. This equated to 36% of those aged 20 years or older and 67% of those aged 40 years or older within this district. Participants were recruited as they presented to the eye clinic at each remote community. Following dilated slit-l fundoscopy, the amount of DR in participants with diabetes mellitus (DM) was quantified using the Early Treatment of Diabetic Retinopathy Study criteria. The presence of any DR and vision-threatening DR (clinically significant macular oedema and/or proliferative DR) in one or both eyes was presented. Of those with diabetes, 22.2% (25.4% of those aged 40 years or older) had any DR and 7.0% (8.4% of those aged 40 years or older) had vision-threatening DR. Both the presence of any DR and vision-threatening DR were associated with advancing age and HbA1c level, but neither subcategory was associated with sex or self-reported hypertension. Our study has shown similar prevalence rates for DR in indigenous Australians compared with non-indigenous Australians. However, as DM is far more prevalent among indigenous Australians, the proportion of those affected by DR across the population should be considerably higher when compared with non-indigenous Australians.
Publisher: Wiley
Date: 05-02-2016
DOI: 10.1111/CEO.12661
Abstract: The nucleolus has emerged as a key regulator of cellular growth and the response to stress, in addition to its traditionally understood function in ribosome biogenesis. The association between nucleolar function and neurodegenerative disease is increasingly being explored. There is also recent evidence indicating that the nucleolus may well be crucial in the development of the eye. In this present review, the role of the nucleolus in retinal development as well as in neurodegeneration with an emphasis on the retina is discussed.
Publisher: Elsevier BV
Date: 09-2018
Publisher: Wiley
Date: 17-10-2018
DOI: 10.1111/CEO.13079
Publisher: Wiley
Date: 12-1992
DOI: 10.1111/J.1365-2141.1992.TB06952.X
Abstract: A family of Asian-Indian descent has a variant form of beta-thalassaemia characterized by unusually high levels of Hb A2 in the heterozygous state. The propositus who is homozygous for the mutation has thalassaemia intermedia. Restriction endonuclease mapping suggested the presence of a 10.3 kilobase (kb) deletion removing the whole of the beta-globin gene. Subsequently, molecular analysis was performed by directly sequencing a specifically lified region of genomic DNA. A 10329 basepair deletion was precisely defined which results in the loss of the 5' beta promoter region and the entire beta-globin gene. The deletion extends from 3011 bp 5' to the mRNA cap site to an L1 repeat element downstream of the beta-globin gene and is very similar to the 12.6 kb deletion of Dutch beta zero-thalassaemia. In common with four other mutations, both these deletions remove the 5' promoter region of the beta gene and all are associated with unusually elevated levels of Hb A2 in the heterozygous state.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 14-04-2016
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.OPHTHA.2016.11.011
Abstract: To assess the difference in severity of disease in primary open-angle glaucoma (POAG) patients with a Myocilin (MYOC) disease-causing variant who presented through normal clinical pathways (Clinical cases) versus those who were examined following genetic testing (Genetic cases). Retrospective clinical and molecular study. Seventy-three MYOC mutation carriers identified through the Australian and New Zealand Registry of Advanced Glaucoma. In iduals were classified based on how they first presented to an ophthalmologist: Clinical cases were referred by their general practitioner or optometrist, and Genetic cases were referred following positive results from genetic testing for the previously identified familial MYOC variant (cascade genetic testing). All cases were then sub-classified into 4 groups (unaffected, glaucoma suspect, glaucoma, advanced glaucoma) according to the severity of disease at the time of their first examination by an ophthalmologist. Glaucoma clinical parameters and age at presentation. At their first examination, 83% of Genetic cases were unaffected and 17% were glaucoma suspect, whereas among Clinical cases 44% were glaucoma suspect, 28% had glaucoma, and 28% had advanced glaucoma. Genetic cases were significantly younger at presentation than Clinical cases (40.6±12.5 vs. 47.5±16.7 years P = 0.018). The mean highest intraocular pressure (32.2±9.7 vs. 17.6±3.6 mmHg P < 0.001), cup-to-disc ratio (0.65±0.27 vs. 0.48±0.13 P = 0.006), and mean deviation on visual field testing (-10.0±10.3 vs. -1.2±1.2 P < 0.001) were all significantly worse in Clinical cases compared with Genetic cases. In iduals with common MYOC p.Gln368Ter variant were further analyzed separately to account for the phenotypic variability of different disease-causing variants. All findings remained significant after adjusting for the common MYOC p.Gln368Ter variant. Our findings demonstrated that MYOC cascade genetic testing for POAG allows identification of at-risk in iduals at an early stage or even before signs of glaucoma are present. To our knowledge, this is the first study to demonstrate the clinical utility of predictive genetic testing for MYOC glaucoma.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 19-07-2019
Publisher: Oxford University Press (OUP)
Date: 15-04-2010
DOI: 10.1093/HMG/DDQ144
Publisher: Wiley
Date: 30-06-2016
DOI: 10.1111/CEO.12784
Publisher: Springer Science and Business Media LLC
Date: 21-03-2016
DOI: 10.1007/S00592-016-0850-4
Abstract: This study aimed to investigate whether the single-nucleotide polymorphism (SNP) rs2910164 residing within microRNA-146a (miR-146a) is associated with diabetic microvascular complications diabetic nephropathy (DN), proliferative diabetic retinopathy (PDR) or diabetic macular oedema (DME) in either Caucasian patients with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus. Caucasian patients with T1DM (n = 733) or T2DM (n = 2215) were recruited from ophthalmology, renal and endocrine clinics in Australia and the UK. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be on treatment with oral hypoglycaemic drugs or insulin. In total, 890 participants had DN (168 with T1DM and 722 with T2DM), 731 had PDR (251 with T1DM and 480 with T2DM) and 1026 had DME (170 with T1DM and 856 with T2DM). Participants were genotyped for SNP rs2910164 in miR-146a. Analyses investigating association were adjusted for relevant clinical covariates including age, sex, DM duration, HbA1c and hypertension. A significant association was found between the C allele of rs2910164 and DN in the T1DM group (OR 1.93 CI 1.23-3.03 P = 0.004), but no association found in the T2DM group (OR 1.05 CI 0.83-1.32 P = 0.691). In the subset of T2DM patients, the C allele was specifically associated with DME (OR 1.25 CI 1.03-1.53 P = 0.025). No association with DME was found in the T1DM group (OR 0.87 CI 0.54-1.42) P = 0.583), or with PDR for either type of DM. Rs2910164 is significantly associated with microvascular complications DN in patients with T1DM and DME in patients with T2DM.
Publisher: Informa UK Limited
Date: 1998
DOI: 10.3109/03630269809071538
Abstract: Hb F and F cell values in normal adults vary considerably with a continuous distribution that is substantially skewed to the right implicating a polygenic influence. The high values of Hb F and F cells are transmitted in the condition referred to as heterocellular hereditary persistence fetal hemoglobin which should be regarded as a multifactorial quantitative trait, quite distinct from the classical pancellular hereditary persistence of fetal hemoglobins. Several factors have been shown to influence F cell/Hb F levels in normal adults including age, gender, genetic determinants linked and unlinked to the beta-globin locus on chromosome 11p. Two trans-acting quantitative trait loci for F cell variance have been mapped, one on 6q and the other on Xp, with at least one other implicated. As an initial step towards hunting for the other quantitative trait loci we have carried out a preliminary analysis of F cell variance in 182 pairs of monozygotic and 373 pairs of dizygotic twins. The correlation coefficient of F cell variance in monozygotic twins was 0.89, while that in the dizygotic twins was 0.51. Overwhelming evidence for a strong genetic component in the control of Hb F/F cell levels is provided by a heritability of 0.87. However, the role and extent of contribution from the quantitative trait loci on 6q and Xp are still not known.
Publisher: Springer Science and Business Media LLC
Date: 04-04-2023
DOI: 10.1186/S40942-023-00453-0
Abstract: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are the standard of care for diabetic macular edema (DME), a common complication of diabetes. This study aimed to identify factors influencing DME intravitreal anti-VEGF treatment outcomes in real-world practice. This was a multi-center retrospective observational study using medical chart review of participants receiving anti-VEGF injections for DME (N = 248). Demographic and clinical variables were assessed for association with best corrected visual acuity (BCVA) and central macular thickness (CMT) outcomes using regression models. There was a significant improvement in BCVA (p 0.001) and CMT (p 0.001) after 12 months of treatment, although 21% of participants had decreased BCVA, and 41% had a 10% CMT reduction at 12 months. Higher baseline BCVA (p = 0.022, OR=-0.024, 95% CI=-0.046,-0.004) and longer duration of diabetic retinopathy (p = 0.048, OR=-0.064, 95% CI=-0.129,-0.001) were negative predictors for BCVA response, whereas Aflibercept treatment (p = 0.017, OR = 1.107, 95% CI = 0.220,2.051) compared with other drugs and a positive “early functional response” (p 0.001, OR=-1.393, 95% CI=-1.946,-0.857) were positive predictors. A higher baseline CMT (p 0.001, OR = 0.019, 95% CI = 0.012,0.0261) and an “early anatomical response”, (p 0.001, OR=-1.677, 95% CI=-2.456, -0.943) were predictors for greater reduction in CMT. Overall, the variables could predict only 23% of BCVA and 52% of CMT response. The study shows a significant proportion of DME patients do not respond to anti-VEGF therapy and identifies several clinical predictors for treatment outcomes. The study was approved through the Human Research Ethics Committee, University of Tasmania (approval number H0012902), and the Southern Adelaide Clinical Human Research Ethics Committee (approval number 86 − 067).
Publisher: Optica Publishing Group
Date: 14-05-2010
DOI: 10.1364/OE.18.011347
Publisher: Springer Science and Business Media LLC
Date: 18-11-2016
Publisher: American Medical Association (AMA)
Date: 08-2014
DOI: 10.1001/JAMAOPHTHALMOL.2014.946
Abstract: Nanophthalmos is a congenital disorder characterized by small eyes, with the main complications being severe hyperopia and angle-closure glaucoma. To perform a clinical and genetic investigation of a large white family with autosomal dominant nanophthalmos. Detailed clinical evaluation and a genome-wide linkage scan was conducted in the family NNO-SA1. Linkage was evaluated with a 10K single-nucleotide polymorphism array, followed by whole exome sequencing, to identify novel segregating coding variants within the linked region. The candidate gene was screened for mutations in additional independent families by direct sequencing of the coding exons and intron/exon boundaries. The expression pattern of the candidate gene in ocular tissues was analyzed by reverse transcriptase-polymerase chain reaction. Participants were recruited through ophthalmology clinics at Flinders Medical Centre, Adelaide, South Australia, Australia. Nanophthalmos was defined as an axial length less than 20.0 mm and/or refractive error greater than +7.00. Of the 35 available in iduals from family NNO-SA1, 16 participants (46%) had a diagnosis of nanophthalmos, with mean refraction of +11.8 D and mean axial length of 17.6 mm. Unaffected unrelated in iduals serving as controls were screened for the identified mutation. Additional independent families with clinically diagnosed nanophthalmos were also recruited. Nanophthalmos status. Significant linkage was detected on chromosome 17 between single-nucleotide polymorphism markers rs2323659 and rs967293, with a maximum location score of 4.1. Exome sequencing identified a single novel segregating missense variant within the linkage region located in exon 8 of the transmembrane-98 (TMEM98) gene c.577G>C (p.Ala193Pro), which was absent in the Exome Variant Server database and among 285 local white in iduals serving as controls. The TMEM98 gene was expressed in all ocular tissues tested including sclera and optic nerve head. A novel gene associated with nanophthalmos, TMEM98 most likely represents the cause of the disease in this family. To our knowledge, this represents the first gene identified causing autosomal dominant nanophthalmos.
Publisher: Informa UK Limited
Date: 16-06-2020
Publisher: Public Library of Science (PLoS)
Date: 12-05-2021
DOI: 10.1371/JOURNAL.PGEN.1009497
Abstract: Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.
Publisher: SAGE Publications
Date: 28-01-2016
Abstract: To investigate, in a large cohort of 2494 in iduals with diabetes mellitus, whether functional single nucleotide polymorphisms in the promoter region of tumour necrosis factor ( TNF) and lymphotoxin-alpha ( LTA) genes are associated with type of diabetes or presence of diabetic retinopathy. A total of 334 type 1 diabetes and 999 type 2 diabetes participants with sight-threatening diabetic retinopathy, and 260 type 1 diabetes and 901 type 2 diabetes participants with no diabetic retinopathy or minimal non-proliferative diabetic retinopathy, were genotyped for two single nucleotide polymorphisms (rs1800629 and rs361525). The A allele of rs1800629 was associated with type 1 diabetes ( p 0.001 odds ratio = 0.62). After adjustment for age, sex, diabetes duration, HbA1c, hypertension and nephropathy, no significant association was found between rs1800629 or rs361525 and sight-threatening diabetic retinopathy. An association between the A allele of rs1800629 and type of diabetes was found. No association was found between two promoter variants of TNF and LTA, and diabetic retinopathy in a large cohort of Caucasian patients with type 1 diabetes and type 2 diabetes.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2018
DOI: 10.1038/S41467-018-03646-6
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, % of the CCT-loci are near or within Mendelian disorder genes. These included FBN1 , ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus ( r = −0.62, P = 5.30 × 10 −5 ) but not between CCT and primary open-angle glaucoma ( r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.OGLA.2021.11.002
Abstract: Glaucoma is the leading cause of irreversible blindness worldwide however, vision loss resulting from glaucoma generally can be prevented through early identification and timely implementation of treatment. Recently, polygenic risk scores (PRSs) have shown promise in stratifying in idual risk and prognostication for primary open-angle glaucoma (POAG) to reduce disease burden. Integrating PRS testing into clinical practice is becoming increasingly realistic however, little is known about the attitudes of patients toward such testing. Cross-sectional, questionnaire-based study. Among the participants in the Australian and New Zealand Registry of Advanced Glaucoma, 2369 were invited to participate who fit the inclusion criteria of adults with a diagnosis of POAG who had not received genetic results that explain their condition, were not known to be deceased, resided in Australia, and had agreed to receive correspondence. One thousand one hundred sixty-nine in iduals (response rate, 49%) with POAG completed the survey evaluating their attitudes towards polygenic risk testing for glaucoma. Sociodemographic, health, perception, and emotional factors were examined to assess associations with interest in PRS testing. Interest in PRS testing was evaluated through assessing likelihood to take the test to predict personal risk of disease and disease severity, and whether the in idual would recommend the test to family members or others. Our results show strong interest in the test, with 69.4% of in iduals (798 of 1150) indicating a keenness in testing before diagnosis, had it been available. In particular, interest was seen in those from an urban area (odds ratio [OR], 1.70 95% confidence interval [CI], 1.15-2.49 P = 0.007), those who perceived their risk of developing glaucoma as higher (OR, 2.05 95% CI, 1.28-3.29 P = 0.003), and those who were worried about developing glaucoma (OR, 2.07 95% CI, 1.27-3.37 P = 0.004). People who were interested in testing were more likely to change their eye health-seeking intentions and to recommend testing to family members and others, as well as to undergo testing for prognostication. These findings will help to facilitate the clinical implementation of PRS testing for glaucoma to reduce irreversible vision loss.
Publisher: MDPI AG
Date: 06-04-2022
DOI: 10.3390/IJMS23074042
Abstract: Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME) however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p 5 × 10−8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8) one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8) and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 24-07-2012
DOI: 10.1167/IOVS.11-9047
Abstract: Glaucoma is the leading cause of irreversible blindness worldwide. Primary open angle glaucoma (POAG) is the most common subtype. We recently reported association of genetic variants at chromosomal loci, 1q24 and 9p21, with POAG. In this study, we determined association of the most significantly associated single nucleotide polymorphism (SNP) rs4656461, at 1q24 near the TMCO1 gene, with the clinical parameters related to glaucoma risk and diagnosis, and determined ocular expression and subcellular localization of the human TMCO1 protein to understand the mechanism of its involvement in POAG. Association of SNP rs4656461 with five clinical parameters was assessed in 1420 POAG cases using linear regression. The TMCO1 gene was screened for mutations in 95 cases with a strong family history and advanced disease. Ocular expression and subcellular localization of the TMCO1 protein were determined by immunolabeling and as GFP-fusion. The data suggest that in iduals homozygous for the rs4656461 risk allele (GG) are 4 to 5 years younger at diagnosis than noncarriers of this allele. Our data demonstrate expression of the TMCO1 protein in most tissues in the human eye, including the trabecular meshwork and retina. However, the subcellular localization differs from that reported in other studies. We demonstrate that the endogenous protein localizes to the cytoplasm and nucleus in vivo and ex vivo. In the nucleus, the protein localizes to the nucleoli. This study shows a relationship between genetic variation in and around TMCO1 with age at diagnosis of POAG and provides clues to the potential cellular function/s of this gene.
Publisher: Wiley
Date: 16-11-2018
DOI: 10.1111/CEO.13083
Abstract: Visual outcomes following diabetic vitrectomy have not previously been studied in an Australian population. This analysis aimed to determine the rate of, and factors associated with visual success following diabetic vitrectomy performed for Indigenous and non-Indigenous Australians, and investigate factors predisposing to early progression to diabetic retinopathy (DR) requiring vitrectomy. Retrospective, population-based audit. All patients undergoing vitrectomy for the complications of DR in South Australia (SA) and the Northern Territory (NT) between 2007 and 2011. Medical records were audited and data collected, including demographics, diabetic history, past treatment for DR, indication for vitrectomy and visual acuity pre and postoperatively. Visual success (gain of ≥15 ETDRS letters) at 6 and 12 months, postoperatively. A total of 495 diabetic vitrectomies, for 404 eyes of 335 patients were performed in SA and NT between 2007 and 2011. 77 (23%) patients requiring diabetic vitrectomy were Indigenous Australians. 87% of patients undergoing diabetic vitrectomy had stable or improved vision at 1 year, postoperatively. There was no significant difference between indigenous and non-indigenous eyes achieving visual success (P = 0.929). Timely preoperative laser treatment (P = 0.03) and preoperative visual acuity (P = 0.01) were the predominant factors associated with visual success. Indigenous patients are just as likely to have improved vision following diabetic vitrectomy as non-Indigenous Australians. However, the small subset of indigenous patients with blind eyes prior to vitrectomy are significantly less likely to improve from surgery. The underlying factors associated with poor outcomes in this group requires further exploration.
Publisher: Wiley
Date: 05-1993
DOI: 10.1111/J.1365-2141.1993.TB03032.X
Abstract: Single-base substitutions in the immediate 5'-flanking region of the fetal G gamma and A gamma globin genes have been associated with non-deletional forms of hereditary persistence of fetal haemoglobin (HPFH). Previously, the sole promoter mutation associated with HPFH in British in iduals has been the T to C substitution at position -198 relative to the A gamma globin gene CAP site. We have investigated a British family with G gamma HPFH and found a T to C substitution at position -175 of the G gamma globin gene. The mutation was first detected by examining the lified 5' regions of both the G gamma and A gamma globin genes for heteroduplex formation after electrophoresis in a Hydrolink gel. The potential of such a system for the study of sequence variations in the gamma gene promoter regions associated with elevated HbF expression has been evaluated. Previously reported cases of an identical mutation in an American-Black and a Sardinian family display haematological phenotypes remarkably similar to that of the British family described here.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2012
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.GENE.2014.04.033
Abstract: MYOC gene variants are associated with autosomal dominant primary open angle glaucoma (POAG). In this study, we describe a previously unreported MYOC variant segregating with a POAG phenotype in an Australian family. Two in iduals affected with POAG and three unaffected in iduals from the same family were recruited through the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Direct sequencing of all MYOC coding exons identified the novel heterozygous single nucleotide transition MYOC:c.1119G>A, p.(Trp373), predicted to encode an aberrant truncated MYOC protein in two affected siblings. Two unaffected siblings and an unaffected niece were negative for the MYOC sequence variant.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.EXER.2019.107806
Abstract: Age-related cataract is the major cause of blindness worldwide. Both genetic and environmental factors contribute to the disease. Genetic variation in the Ephrin type-A receptor 2 (EPHA2) gene is associated with the risk of age-related cataract in multiple populations, and exposure to ultraviolet-B (UV-B) radiation is a well-established risk factor for the disease. Epha2 knockout and UV-B radiation independently lead to cataract in mice, and UV-B radiation reportedly alters EPHA2 expression in cultured cells. We hypothesised that an interaction between UV-B radiation exposure and Epha2 signalling may influence cataract development. To test this hypothesis, 5-week-old Epha2
Publisher: BMJ
Date: 06-2002
DOI: 10.1136/BJO.86.6.696
Publisher: Wiley
Date: 04-11-2012
DOI: 10.1111/J.1442-9071.2011.02696.X
Abstract: Pseudoexfoliation syndrome (XFS) has been found to occur more commonly among indigenous Australians. This paper was designed to determine the prevalence of XFS within the indigenous Australian population living in central Australia. Clinic-based cross-sectional study. One thousand eight hundred eighty-four in iduals living in one of 30 remote communities within the statistical local area of 'Central Australia' were recruited. This equated to 36% of those aged 20 years or older and 67% of those aged 40 years or older within this district. Participants aged 20 years or over were recruited as they presented to the eye clinic at each remote community. Slit-l examination was performed, and the presence of XFS in each eye was recorded and presented. Prevalence and associations of XFS. XFS was present in one or both eyes of 4.7% of the in iduals recruited into the study. Prevalence increased with age (5.9% of those ≥40 years and 12.7% ≥ 60 years). There was a significant association between the presence of XFS and climatic keratopathy (χ(2) = 240.13 P < 0.00001). Notably, none of those with XFS had ocular hypertension or glaucoma. XFS was present in a significantly higher proportion of indigenous Australians compared with previously reported prevalence estimates among non-indigenous Australians. The association found between XFS and climatic keratopathy may represent a common causal link between the two conditions. The lack of association of XFS with ocular hypertension and glaucoma appears to be a unique feature of the indigenous Australian population, and this merits further investigation.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Wiley
Date: 08-10-2015
DOI: 10.1111/CEO.12433
Abstract: Increase in intraocular pressure is a recognized complication of corticosteroid treatment via intravitreal or periocular injections for treatment of a range of conditions including macular oedema and retinal neovascularization. This surveillance study was designed to determine the incidence and nature of severe intraocular pressure elevation as a complication of intravitreal or periocular corticosteroid injections in Australia and New Zealand. Seventeen cases meeting the defined criteria of severe intraocular pressure elevation, above 35 mmHg, following an intravitreal or periocular corticosteroid injection were included in the study. Over an 18-month period, ophthalmologists were invited to report cases to the Australian and New Zealand Ophthalmic Surveillance Unit. After reporting, further demographic and clinical information was sought via a follow-up questionnaire. Intraocular pressure elevation above 35 mmHg. Follow-up questionnaires were received for 20 cases of 34 initially reported to the unit. Seventeen met the defined criteria. Triamcinolone acetonide was used in all 17 cases, with 16 delivered as a 4-mg intravitreal injection. There was an absence of identified underlying risk factors in the majority of cases with personal history of glaucoma in 2 of 17 cases. No cases reported a positive family history of glaucoma. Trabeculectomy was performed in 8 of 17 patients (47%) for intraocular pressure management. Severe intraocular pressure elevation following intravitreal or periocular corticosteroid injection can occur in the absence of risk factors such as personal and family history of glaucoma. The severe intraocular pressure elevation may ultimately require trabeculectomy.
Publisher: Springer Science and Business Media LLC
Date: 08-03-2017
DOI: 10.1038/EJHG.2017.33
Publisher: Springer Science and Business Media LLC
Date: 04-04-2016
DOI: 10.1038/NG.3540
Abstract: Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.
Publisher: Springer Science and Business Media LLC
Date: 08-05-2017
Publisher: Elsevier BV
Date: 06-2022
Publisher: Springer Science and Business Media LLC
Date: 31-05-2016
DOI: 10.1038/SREP26885
Abstract: Primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) are leading causes of irreversible blindness. Several loci have been mapped using genome-wide association studies. Until very recently, there was no recognized overlap in the genetic contribution to AMD and POAG. At genome-wide significance level, only ABCA1 harbors associations to both diseases. Here, we investigated the genetic architecture of POAG and AMD using genome-wide array data. We estimated the heritability for POAG (h 2 g = 0.42 ± 0.09) and AMD (h 2 g = 0.71 ± 0.08). Removing known loci for POAG and AMD decreased the h 2 g estimates to 0.36 and 0.24, respectively. There was evidence for a positive genetic correlation between POAG and AMD (r g = 0.47 ± 0.25) which remained after removing known loci (r g = 0.64 ± 0.31). We also found that the genetic correlation between sexes for POAG was likely to be less than 1 (r g = 0.33 ± 0.24), suggesting that differences of prevalence among genders may be partly due to heritable factors.
Publisher: MDPI AG
Date: 02-03-2021
Abstract: In the special issue “Molecular Genetics of Retinal Dystrophies”, Morales–Cámara and colleagues reported the association of a new candidate gene with primary congenital glaucoma (PCG) [...]
Publisher: Springer Science and Business Media LLC
Date: 14-01-2019
DOI: 10.1038/S41467-018-08078-W
Abstract: The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.
Publisher: Elsevier BV
Date: 09-2001
DOI: 10.1016/S0161-6420(01)00654-6
Abstract: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the most common Myocilin mutation (Gln368STOP). Cross-sectional genetic study. Eight pedigrees carrying the Gln368STOP mutation were ascertained from 1730 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania. Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Gln368STOP mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. From the eight pedigrees, 29 Gln368STOP mutation-carrying in iduals with either ocular hypertension (OHT) or POAG were found, with a mean age at diagnosis of 52.4 +/- 12.9 years and a mean peak intraocular pressure (IOP) of 28.4 +/- 4.7 mmHg. A further 11 mutation carriers older than 40 years have been studied, who as yet show no signs of OHT or POAG. Within the 8 pedigrees, a further 31 in iduals with OHT or POAG were identified who did not carry the Gln368STOP mutation. For these in iduals the mean age at diagnosis was higher (62.3 +/- 13.7 years, P < 0.01), and the mean peak IOP was lower (25.4 +/- 6.4 mmHg, P = 0.01). For Gln368STOP carriers, age-related penetrance for OHT or POAG was 72% at age 40 years and 82% at age 65 years. A positive family history of POAG was present in all index cases. Five of the eight pedigrees had a positive family history on both maternal and paternal sides. Seven of the eight pedigrees had one or more in iduals with POAG who did not carry the mutation. Eight of the 29 Gln368STOP carriers with OHT or POAG had undergone trabeculectomy. The GLC1A Gln368STOP mutation is associated with POAG, which in the pedigrees studied is of a younger age of onset and higher peak IOP than non-mutation glaucoma cases. In addition, Gln368STOP mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. We have not observed simple autosomal dominant inheritance patterns for POAG in these pedigrees. Other factors, as yet uncharacterized, are involved in expression of the POAG phenotype in Gln368STOP pedigrees.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 09-04-2014
Abstract: Macular diseases may be associated with an altered retinal vasculature. We describe and test new software for the measurement of retinal vascular fractal dimension to quantify the complexity of retinal vasculature at the macula (D mac) and to compare this with fractal dimension measured around the optic disc (D disc). A total of 342 macular-centered and optic disc-centered digital retinal photographs from 171 subjects was selected randomly from a population-based study. Retinal vascular fractional dimension (Df) was measured by two trained graders using a computer-assisted program (SIVA-FA, software version 1.0, National University of Singapore) on macula-centered (D mac) and optic disc-centered (D disc) photographs, to assess intergrader reliability. Measurements were repeated after two weeks to determine intragrader reliability. A separate 50 pairs of consecutively repeated images were selected and measured using SIVA-FA to assess intrasession reliability. Reliability analyses were conducted using intraclass correlation coefficients (ICC), and multiple linear regression analyses were performed to compare factors associated with D mac and D disc measurements. The mean (SD) D mac and D disc values were 1.453 (0.060) and 1.484 (0.043), respectively, and were highly correlated (r = 0.70, P < 0.001). Intragrader, intergrader, and intrasession reliability for both Df measures was high (ICCs ranging from 0.88-0.99). In multiple regression analyses, age (both β = -0.03, P < 0.001) and hypertension (β = -0.02, P = 0.011 β = -0.02, P = 0.021, respectively) were independently associated with D mac and D disc. The complexity of the retinal vasculature in the macula can be measured reliably and may be a useful tool to study parafoveal vascular networks in macula diseases, such as diabetic maculopathy.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2009
DOI: 10.1038/EYE.2009.37
Abstract: The aim of this study was to investigate the causes of mortality in in iduals with open-angle glaucoma (OAG). All-cause mortality data from the Registry of Births, Deaths and Marriages for the Australian state of Tasmania, for all people who were at least 40 years of age at the time of death, were classified using International Classification of Diseases-10 guidelines. This information was cross-referenced to identify participants in the Glaucoma Inheritance Study in Tasmania (GIST) who had died. Contingency tables were used for crude analysis and then models were constructed, adjusting for age at death as well as gender. Between 1996 and 2005, a total of 33 879 deaths were recorded. Data were unavailable for 4868 (14.4%) people. The mean age at death for the study s le was 78.4+/-11.5 (range 41-109) years. Of those cases known to have OAG by their participation in GIST (n=2409), full mortality data were available for 741 (92.0%). Following adjustment for the age at death and male gender, the odds ratio for death due to ischaemic heart disease in people with OAG compared to the general population not known to have OAG was significant (OR=1.30, 95% CI: 1.08-1.56 P=0.006). Crude analysis revealed that there were significantly fewer people with OAG who died due to metastatic cancer (P<0.001) however, this did not remain significant following adjustment for age and gender. The pathoaetiological relationship between OAG and ischaemic heart disease is unclear and requires further investigation. Increased awareness of the association between cardiovascular disease and OAG is warranted.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2018
DOI: 10.1038/S41598-018-20435-9
Abstract: Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis s le size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1 , LINC02052 and CRYGS , LMX1B , and LMO7 using single variant tests, one additional locus ( C9 ) using gene-based tests, and two genetic pathways - “response to fluid shear stress” and “abnormal retina morphology” - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2017
Publisher: Informa UK Limited
Date: 21-12-2018
DOI: 10.1080/13816810.2017.1413659
Abstract: Recent genome-wide association studies reported strong association of genetic variation at the CDKN2B/CDKN2B-AS1 locus on 9p21 with normal-tension glaucoma (NTG) in multiple populations. The mechanism by which this locus causes disease remains to be elucidated. We investigated the association of DNA methylation of CpG islands at this locus with NTG. We conducted a retrospective case-control study of 178 NTG cases and 202 unaffected controls from Australia. CDKN2B and CDKN2B-AS1 promoter methylation was measured quantitatively using the MassCleave assay, and assessed for association with the disease, and the genotype of the associated risk variants using IBM SPSS statistics 22.0 CpG sites at which methylation status was associated with NTG were validated using pyrosequencing. We identified one CpG site (F1:13-14) in the CDKN2B promoter which showed significant association with NTG (p = 0.001). The association was highly significant in female cases (p = 0.006) but not in male cases (p = 0.054). The association was validated using an independent method confirming the likely association of DNA methylation with NTG in females (p = 0.015), but not in males (p = 0.497). In addition, methylation at CpG sites in CDKN2B was also associated with genotype at rs1063192, which is known to confer risk for NTG. This study reveals an association of methylation status in the CDKN2B promoter with NTG, particularly in females. This suggests that the observed genetic association with the disease at this locus could be in part due to epigenetic mechanisms, and is likely to be independent of the association of nonsynonymous coding variation within the gene.
Publisher: Springer Science and Business Media LLC
Date: 19-07-2015
DOI: 10.1007/S00125-015-3697-2
Abstract: Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study. Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot. The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina. Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 03-08-2015
Publisher: American Society of Neuroradiology (ASNR)
Date: 07-09-2023
DOI: 10.3174/AJNR.A7995
Publisher: American Society for Clinical Investigation
Date: 12-2022
DOI: 10.1172/JCI156967
Publisher: Elsevier BV
Date: 08-2022
Publisher: Wiley
Date: 15-04-2014
DOI: 10.1111/CEO.12327
Publisher: Elsevier BV
Date: 08-2023
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 15-02-2018
DOI: 10.1167/TVST.7.1.18
Publisher: Wiley
Date: 27-07-2015
DOI: 10.1111/CEO.12569
Abstract: An ibopamine challenge is a novel technique for assessing glaucoma using ibopamine, a topical drug which temporarily increases aqueous production. We aimed to determine whether change in intraocular pressure (IOP) and/or optic cup volume (OCV) during the test differentiated between glaucoma patients at different stages of disease namely, glaucoma suspects (GS), glaucoma patients who are stable (SG) and glaucoma patients who have demonstrated rapid progression (PG). Non-randomized clinical trial evaluating a diagnostic test. Sixty-one patients were recruited through glaucoma clinics at the Flinders Medical Centre (24 GS, 24 SG and 13 PG). Patients underwent IOP measurement and OCV assessment using optical coherence tomography. Two drops of ibopamine 2% solution were instilled into the study eye of each patient. After 45 min, IOP and OCV were reassessed. Changes from baseline were compared between groups. Change in IOP and OCV after ibopamine challenge. Following the ibopamine challenge, IOP increased by 1.8 mmHg for GS patients, 4.5 mmHg for SG patients (P = 0.003) and 8.1 mmHg for PG patients (P < 0.0001). OCV increased by 0.2% for GS patients, 0.6% for SG patients and 5.5% for PG patients. This was not significantly different between GS patients and SG patients however, it was significantly different between GS patients and PG patients (P < 0.0001), and between SG and PG patients (P = 0.001). GS patients may be differentiated from those with SG or PG by their IOP response, and SG may be differentiated from PG patients by their change in OCV following an ibopamine challenge.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 22-11-2016
Publisher: Wiley
Date: 08-10-2014
DOI: 10.1111/CEO.12200
Abstract: Many countries face the challenge of a rising number of patients with or at risk of developing glaucoma. A test to differentiate between people who are unlikely to develop glaucoma and those at risk for the disease could be clinically useful. Ibopamine, when administered topically, temporarily increases aqueous production. Normal eyes with healthy trabecular meshwork show no significant change in intraocular pressure (IOP) following an ibopamine challenge however, those with glaucoma demonstrate elevated IOP. The study was designed as a prospective case-control study in a tertiary hospital. Patients were recruited consecutively as they presented to glaucoma clinics at Flinders Medical Centre (n = 39) the s le included 18 glaucoma suspects and 21 patients with glaucoma. All patients had open anterior chamber angles and no evidence of secondary glaucoma. Patients underwent IOP measurements followed by instillation of ibopamine 2% solution and subsequent repeated IOP assessment. The difference between the baseline measurement and that taken at 45 min was determined and compared between groups. The outcome measure was the positivity of the ibopamine challenge test, defined by an increase in IOP > 3 mmHg. We observed a mean increase in IOP of 1.9 ± 1.6 mmHg or 12.5 ± 10.3%) for glaucoma suspects and 7.4 ± 4 mmHg or 52.4 ± 26.5% for glaucoma patients (P < 0.0001). Four glaucoma suspects (22%) and 19 glaucoma patients (90%) tested positive (P < 0.0001). This study demonstrates that ibopamine has potential as a test to differentiate glaucoma suspects from patients with glaucoma.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2016
DOI: 10.1097/IOP.0000000000000297
Abstract: The authors describe a case of T-cell large granular lymphocytic leukemia nodular lesion of the eyelid. To their knowledge, this has not been reported previously to occur in the eyelids. They have also reviewed previous literature reports on similar skin lesions in areas elsewhere.
Publisher: Wiley
Date: 12-02-2016
DOI: 10.1111/CEO.12684
Abstract: The ibopamine challenge test correlates well with a patient's peak diurnal intraocular pressure (IOP) measurement. We aimed to investigate the effect that a functioning trabeculectomy has on the ibopamine challenge test. Non-randomized prospective clinical trial evaluating a diagnostic test. Thirteen patients were recruited through glaucoma clinics at the Flinders Medical Centre. Of these, seven required surgical management with trabeculectomy surgery, whilst the remainder were managed medically. Patients underwent IOP measurement, and then two drops of Ibopamine 2% solution were instilled into the study eye of each patient. After 45 min, IOP was reassesed. A positive challenge test was considered to be a rise in IOP of greater than 3 mmHg. Changes from baseline were determined and compared between groups. Twelve months later, this test was then repeated in all patients. Change in IOP after ibopamine challenge. Following the ibopamine challenge, IOP increased by 9.2 mmHg (SD 2.8) (100% positive) for medically managed patients and 7.2 mmHg (SD 2.0) (100% positive) for surgically managed patients (P = 0.18). The surgically managed group then underwent trabeculectomy surgery. Twelve months later, the ibopamine challenge was repeated. Following the repeat ibopamine challenge, IOP increased by 7.2 mmHg (SD 2.3) for medically managed patients and 0.3 mmHg (SD 1.3) for surgically managed patients (P < 0.0001). The medically managed group remained 100% positive, whilst the surgically manage group became 0% positive (Fisher Exact P = 0.044). A glaucoma patient with a positive ibopamine challenge will show a negative challenge result when re-tested following trabeculectomy surgery.
Publisher: Wiley
Date: 21-05-2019
DOI: 10.1111/CEO.13531
Publisher: Public Library of Science (PLoS)
Date: 26-09-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-09-2022
Publisher: American Medical Association (AMA)
Date: 07-2015
DOI: 10.1001/JAMAOPHTHALMOL.2015.0980
Abstract: Juvenile open-angle glaucoma (JOAG) is a severe neurodegenerative eye disorder in which most of the genetic contribution remains unexplained. To assess the prevalence of pathogenic CYP1B1 sequence variants in an Australian cohort of patients with JOAG and severe visual field loss. For this cohort study, we recruited 160 patients with JOAG classified as advanced (n = 118) and nonadvanced (n = 42) through the Australian and New Zealand Registry of Advanced Glaucoma from January 1, 2007, through April 1, 2014. Eighty in iduals with no evidence of glaucoma served as a control group. We defined JOAG as diagnosis before age 40 years and advanced JOAG as visual field loss in 2 of the 4 central fixation squares on a reliable visual field test result. We performed direct sequencing of the entire coding region of CYP1B1. Data analysis was performed in October 2014. Identification and characterization of CYP1B1 sequence variants. We identified 7 different pathogenic variants among 8 of 118 patients with advanced JOAG (6.8%) but none among the patients with nonadvanced JOAG. Three patients were homozygous or compound heterozygous for CYP1B1 pathogenic variants, which provided a likely basis for their disease. Five patients were heterozygous. The allele frequency among the patients with advanced JOAG (11 in 236 [4.7%]) was higher than among our controls (1 in 160 [0.6%] P = .02 odds ratio, 7.8 [95% CI, 0.02-1.0]) or among the control population from the Exome Aggregation Consortium database (2946 of 122 960 [2.4%] P = .02 odds ratio, 2.0 [95% CI, 0.3-0.9]). In iduals with CYP1B1 pathogenic variants, whether heterozygous or homozygous, had worse mean (SD) deviation on visual fields (-24.5 [5.1] [95% CI, -31.8 to -17.2] vs -15.6 [10.0] [95% CI, -17.1 to -13.6] dB F1,126 = 5.90 P = .02 partial ηp2 = 0.05) and were younger at diagnosis (mean [SD] age, 23.1 [8.4] [95% CI, 17.2-29.1] vs 31.5 [8.0] [95% CI, 30.1-33.0] years F1,122 = 7.18 P = .008 ηp2 = 0.06) than patients without CYP1B1 pathogenic variants. Patients with advanced JOAG based on visual field loss had enrichment of CYP1B1 pathogenic variants and a more severe phenotype compared with unaffected controls and patients with nonadvanced JOAG.
Publisher: The Endocrine Society
Date: 07-2016
DOI: 10.1210/JC.2015-4294
Abstract: Previous association studies suggest the development of Graves' orbitopathy (GO) is variably influenced by environmental risk factors. To determine the risk factors and predict odds for developing GO in Graves' hyperthyroidism (GH). Case-control study. Multi-centre Australian Thyroid-associated Orbitopathy Research group consisting of tertiary endocrinology and ophthalmology outpatients and related private practices. A total of 1042 participants with GH were designated as cases if they had GO (n = 604) and controls if they did not have GO (n = 438). Primary outcome was GO risk factors and secondary outcome was dysthyroid optic neuropathy (DON) with the effects of risk factors measured by odds ratio (OR) using multiple logistic regression, adjusted for known risk factors and exploratory variables. The odds of GO increased by 17% for each decade increase in the age of onset of GH (OR 1.17, confidence interval (CI): 1.06-1.29 P = .002) and by 7% for each year increase in the duration of GH (OR 1.07, CI: 1.05-1.10 P < .001). Smoking increased the odds for GO by 2.22 for current smoker and 2.07 for exsmoker (P < .001), compared with never smoking. The odds of GO are 86% less in Graves' patients using antithyroid medication than those not (OR 0.14, CI: 0.06-0.34 P < .001). Predictors for DON were older age, oculomotility restriction, strabismus, reduced palpebral aperture, and active GO. This study identified increase age of onset, duration of GH, and smoking as risk factors for GO. Usage of antithyroid medication was negatively related to GO. Older patients with restricted ocular motility, strabismus, and active GO are at higher risk of DON and may benefit from early medical intervention.
Publisher: American Diabetes Association
Date: 28-11-2018
DOI: 10.2337/DB18-0567
Abstract: To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value & × 10−5 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 × 10−9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein–protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity (P = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein–protein interaction network that includes genes implicated in inflammation, may influence risk for DR.
Publisher: Wiley
Date: 24-11-2021
DOI: 10.1002/AJMG.A.61982
Abstract: Axenfeld‐Rieger syndrome is a genetic condition characterized by ocular and systemic features and is most commonly caused by variants in the FOXC1 or PITX2 genes. Facial dysmorphism is part of the syndrome but the differences between both genes have never been systematically assessed. Here, 11 facial traits commonly reported in Axenfeld‐Rieger syndrome were assessed by five clinical geneticists blinded to the molecular diagnosis. In iduals were drawn from the Australian and New Zealand Registry of Advanced Glaucoma in Australia or recruited through the Genetic and Ophthalmology Unit of l'Azienda Socio‐Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Italy. Thirty‐four in iduals from 18 families were included. FOXC1 variants were present in 64.7% of in iduals and PITX2 variants in 35.3% of in iduals. A thin upper lip (55.9%) and a prominent forehead (41.2%) were common facial features shared between both genes. Hypertelorism/telecanthus (81.8% vs 25.0%, p = 0.002) and low‐set ears (31.8% vs 0.0%, p = 0.036) were significantly more prevalent in in iduals with FOXC1 variants compared with PITX2 variants. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.
Publisher: American Diabetes Association
Date: 26-09-2017
DOI: 10.2337/DB17-0398
Abstract: Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.
Publisher: Elsevier BV
Date: 06-2023
Publisher: IEEE
Date: 11-2013
Publisher: Springer Science and Business Media LLC
Date: 12-09-2010
DOI: 10.1038/NG.661
Publisher: Elsevier BV
Date: 09-2021
Publisher: Wiley
Date: 30-10-2014
DOI: 10.1111/CEO.12451
Publisher: Elsevier BV
Date: 03-2016
Publisher: Elsevier BV
Date: 07-2023
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.JDIACOMP.2012.03.022
Abstract: Asymmetric dimethylarginine (ADMA) levels are elevated in diabetes and likely contribute to diabetic complications such as retinopathy and nephropathy. The DDAH enzymes are primarily responsible for ADMA metabolism. Polymorphisms in the dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 genes have been previously associated with serum ADMA levels in type 2 diabetes (T2DM). We sought to determine whether they are also associated with ADMA levels in in iduals with type 1 diabetes (T1DM). Serum ADMA concentrations were measured in 196 in iduals with T1DM. Twenty-six tag SNPs in the DDAH1 gene and 10 in the DDAH2 gene were genotyped. One SNP in the DDAH1 gene (rs3738111) and one in the DDAH2 gene (rs805293) showed a correlation with serum ADMA levels however, neither survived correction for multiple testing. We found limited evidence that genetic polymorphisms in DDAH genes influence serum ADMA levels in in iduals with T1DM. This differs to findings in T2DM and may be due to underlying differences in the cohorts or to fundamental differences in the pathogenesis of the two types of diabetes.
Publisher: Wiley
Date: 05-05-2014
DOI: 10.1111/CEO.12338
Abstract: The purpose of this review is to compare the prevalence of diabetic retinopathy (DR) between Indigenous and non-Indigenous Australians with Diabetes Mellitus (DM). Australian DR prevalence data from 6 Indigenous studies (n = 2865) and 5 non-Indigenous studies (n = 9801) conducted between 1985 and 2013 were included for analysis. Estimated prevalence of any DR among Indigenous Australians with DM was 23.4% compared with 28.9% for non-Indigenous Australians (χ(2) = 26.9, P < 0.001). In studies performed after 1990, a significantly higher rate of diabetic macular edema was found in Indigenous compared with non-Indigenous Australians with DM (7.6% versus 4.9%, χ(2) = 6.67, P = 0.01). Although there are limitations in comparing these studies, one explanation for the observed data could be a model in which Indigenous Australians are relatively resistant to early stage DR, but with a subset progressing to sight threatening DR due to in idual genetic and environmental susceptibility factors coupled with poor glycemic control.
Publisher: BMJ
Date: 07-06-2010
Abstract: To determine the prevalence and causes of visual impairment and blindness among indigenous Australians living in central Australia. 1884 in iduals aged 20 years or older, living in one of 30 remote communities within the statistical local area of "Central Australia", were recruited for this study, from which 1883 were assessable. This equated to 36% of those > or =20 years old and 67% of those > or =40 years old within this district. Participants were recruited as they presented to the eye clinic at each remote community. Patients underwent Snellen visual acuity testing and subjective refraction. After this, an assessment of their anterior and posterior segments was made. Rates and causes of bilateral visual impairment (vision worse than Snellen visual acuity 6/12 in the better eye) and bilateral blindness (Snellen visual acuity worse than 6/60 in the better eye) were presented. 19.4% (365/1883) had bilateral visual impairment (25.1% of those > or =40 years old) and 2.8% (53/1883) had bilateral blindness (3.6% of those > or =40 years old). Refractive error followed by cataract were the main causes for bilateral visual impairment and blindness. Following these, diabetic eye disease and trachomatous corneal opacification were the main causes of bilateral visual impairment and bilateral blindness, respectively. This study indicates that bilateral visual impairment and blindness are, respectively, 25.1% and 3.6% among indigenous Australians, four to seven times higher than among the non-indigenous Australian population. Trachoma is the leading cause of bilateral blindness after refractive error and cataract.
Publisher: Oxford University Press (OUP)
Date: 10-01-2017
DOI: 10.1093/HMG/DDW399
Publisher: Elsevier BV
Date: 05-2021
DOI: 10.1016/J.OGLA.2021.09.007
Abstract: To explore and report on the quality-of-life (QoL) issues encountered by adults with childhood glaucoma. Exploratory qualitative study. Forty-seven participants with childhood glaucoma (defined as disease onset <18 years) recruited from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). A qualitative research methodology (interpretive phenomenology) was applied, and data were collected through semistructured in-depth interviews. NVivo-12 software (QSR International Pty Ltd) was used to inductively analyze and code data to identify QoL themes pertinent to the cohort studied. Quality-of-life themes and subthemes. Mean participant age was 40.0 ± 15.3 years, and 55% of participants were female. We identified 10 QoL themes pertinent to adults living with childhood glaucoma. Coping strategies and emotional well-being were the most prominent themes. Maladaptive coping strategies, including treatment nonadherence, were observed more commonly in in iduals aged <40 years and those without a vision impairment or reviewed less regularly. Emotional well-being was affected by feelings of being misunderstood because of the rarity of the condition, being self-conscious of physical manifestations of the disease, and anxiety related to possible disease progression and vision loss. The effect of childhood glaucoma on family planning formed a novel QoL theme and included worry for their child to inherit the condition and an inability to fulfill parental duties. This often led to genetic counseling-seeking behaviors. Mobility issues were infrequently experienced. Childhood glaucoma poses a substantial impact to the emotional well-being of adults with the condition, which is mediated by the use of coping strategies. Genetic counseling and family planning options may be important. This study supports the development of a childhood glaucoma-specific patient-reported outcome measure for assessment of the psychosocial impact of childhood glaucoma in adults.
Publisher: Springer Science and Business Media LLC
Date: 31-08-2014
DOI: 10.1038/NG.3087
Publisher: Wiley
Date: 19-01-2012
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 20-09-2019
Abstract: Few studies have explored the association of genetic variants in microRNA genes and binding sites with diabetic retinopathy (DR) in type 1 diabetes. We conducted a genome-wide scan for single nucleotide polymorphisms (SNPs) in these genes by using data from a genome-wide association study (GWAS). All known SNPs were imputed from our GWAS data (n = 325) of DR cases and diabetic controls (no DR). Relevant SNPS were extracted using miRNASNP and PolymiRTS (version 2) databases. χ2 tests and logistic regression (adjusting for age, sex, duration of diabetes, HbA1c, and hypertension) were used to test the association between the imputed SNPs and DR phenotypes (any DR, nonproliferative DR [NPDR], proliferative DR [PDR], diabetic macular edema [DME], and sight-threatening DR defined as PDR, severe NPDR, or clinically significant macula edema [CSME]) compared with diabetic controls. Top-ranking SNPs were genotyped in a larger cohort (N = 560) to confirm their association with DR. Three SNPs (rs10061133, rs1049835, rs9501255) were selected and genotyped in the final cohort. Rs10061133 in MIR449b was protective of sight-threatening DR (odds ratio [OR] = 0.32, P = 3.68 × 10-4) and PDR (OR = 0.30, P = 8.12 × 10-4), and the associations became more significant as the cohort increased in size. Rs10061133 in MIR449b is significantly associated with a decreased risk of PDR and sight-threatening DR in Caucasian patients with type 1 diabetes. This can guide future studies on genetic risk profiling and on developing microRNA-related therapies for sight-threatening DR.
Publisher: Springer Science and Business Media LLC
Date: 1996
DOI: 10.1038/NG0196-58
Abstract: The changes in the type of haemoglobin (Hb) produced during embryonic, fetal and adult life, have served as a paradigm for understanding the developmental regulation of human genes. A genetically determined persistence of fetal Hb synthesis has an ameliorating effect on beta thalassaemia and sickle cell anaemia, globally the commonest single gene disorders. The search for the putative gene(s) controlling the level of fetal Hb production has been extremely difficult because this trait may be influenced by several factors. We have studied a large kindred with hereditary persistence of fetal haemoglobin (HPFH). Using a genetic mapping strategy and statistical methods that account simultaneously for the effects of several genetic factors, we have demonstrated that in addition to the two factors (beta thalassaemia and Xmn I-G gamma site) on chromosome 11p, there is a third major genetic determinant for fetal Hb production localized on chromosome 6q.
Publisher: BMJ
Date: 11-06-2014
Publisher: Springer Science and Business Media LLC
Date: 14-10-2019
DOI: 10.1007/S10787-019-00647-9
Abstract: Diabetic retinopathy (DR) is a frequent complication of diabetes mellitus, and a common cause of vision impairment and blindness in these patients, yet many aspects of its pathogenesis remain unresolved. Furthermore, current treatments are not effective in all patients, are only indicated in advanced disease, and are associated with significant adverse effects. This review describes the microvascular features of DR, and how pericyte depletion and low-grade chronic inflammation contribute to the pathogenesis of this common ophthalmic disorder. Existing, novel and investigational pharmacological strategies aimed at modulating the inflammatory component of DR and ameliorating pericyte loss to potentially improve clinical outcomes for patients with diabetic retinopathy, are discussed.
Publisher: Wiley
Date: 16-12-2011
DOI: 10.1111/J.1442-9071.2010.02429.X
Abstract: To describe the methodology and baseline data of a population-based study designed to determine the prevalence of glaucoma and to study the risk factors for glaucoma development in a Nepali population. Population-based cross-sectional study. Subjects 40 years and above residing in Bhaktapur District. Power calculations suggest that a s le size of 4758 is required. Thirty clusters were randomly selected from the 2 municipalities and 16 Village Development Committees of Bhaktapur District in Nepal. A door-to-door census was conducted in the selected clusters to identify citizens 40 years of age and older. Demographic details were collected and a structured interview, regarding awareness for cataract and glaucoma was taken. All in iduals fulfilling the eligibility criteria were recruited and referred to the Tilganga Institute of Ophthalmology in Kathmandu for a detailed clinical examination including glaucoma diagnostic procedures. Peripheral blood s les were taken to facilitate future genetic analysis. Prevalence of glaucoma, risk factors and genetic screening. A total of 4800 people were selected. The mean age of participants was 55.4 ± 12.3 years (range: 40-99) and 51.8% were female. In total, 64.8% of our cohort was aged less than 59 years and 60.5% were illiterate. Among the various ethnic races, 69.7% belonged to the Newar ethnic group. This study will determine the prevalence of glaucoma and allow for an increased understanding of the risk factors for glaucoma development in this region.
Publisher: Informa UK Limited
Date: 05-09-2022
DOI: 10.1080/09286586.2021.1968005
Abstract: In 1989-1991, pregnant women completed questionnaires on their current smoking and alcohol drinking patterns. Following the birth of their offspring, information on household smokers was obtained between the 1- and 13-year follow-ups. At the 20-year follow-up, these offspring underwent an eye examination including optical coherence tomography imaging of the RNFL. Participants (n = 1,287) were 19-22 years old at time of eye examination. Most participants (77%) had no
Publisher: Elsevier BV
Date: 07-2021
Publisher: Public Library of Science (PLoS)
Date: 23-08-2017
Publisher: American Medical Association (AMA)
Date: 09-2021
Publisher: Elsevier BV
Date: 03-2016
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 16-04-2012
DOI: 10.1167/IOVS.11-8420
Abstract: Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are the dimethylated isomeric derivatives of the amino acid L-arginine. ADMA is an endogenous inhibitor of nitric oxide synthase (NOS), while SDMA is a competitive inhibitor of cellular uptake of L-arginine, the substrate for NOS. As such, these metabolites are associated with endothelial dysfunction. As the nitric oxide pathway and endothelial dysfunction have been implicated in glaucoma, the aim of this study was to investigate serum ADMA, SDMA, and L-arginine levels in in iduals with advanced glaucoma compared with normal controls. In addition, we have investigated genetic variation in the DDAH1 and DDAH2 genes, encoding the enzymes responsible for degradation of ADMA, for association with ADMA level in glaucoma patients and controls. Two hundred eleven patients with advanced glaucoma and 295 normal controls were recruited. Liquid chromatography-tandem mass spectrometry was used to measure the serum ADMA, SDMA, and L-arginine levels of participants. Single nucleotide polymorphisms in the DDAH1 and DDAH2 genes reportedly associated with ADMA level were genotyped in all in iduals. A significant increase in both serum ADMA and SDMA concentration was detected in advanced glaucoma cases compared with controls (P ≤ 0.0001). No significant change was detected in serum L-arginine concentration. No association of polymorphisms in DDAH1 and DDAH2 with either ADMA level or glaucoma was detected. The serum levels of two dimethylarginines, ADMA and SDMA, are associated with advanced glaucoma. These data further implicate the nitric-oxide pathway in glaucoma pathogenesis.
Publisher: Wiley
Date: 19-08-2022
DOI: 10.1002/MGG3.2023
Abstract: Corneal dystrophies describe a clinically and genetically heterogeneous group of inherited disorders. The International Classification of Corneal Dystrophies (IC3D) lists 22 types of corneal dystrophy, 17 of which have been demonstrated to result from pathogenic variants in 19 identified genes. In this study, we investigated the diagnostic yield of genetic testing in a well‐characterised cohort of 58 in iduals from 44 families with different types of corneal dystrophy. In iduals diagnosed solely with Fuchs endothelial corneal dystrophy were excluded. Clinical details were obtained from the treating ophthalmologist. Participants and their family members were tested using a gene candidate and exome sequencing approach. We identified a likely molecular diagnosis in 70.5% families (31/44). The detection rate was significantly higher among probands with a family history of corneal dystrophy (15/16, 93.8%) than those without (16/28, 57.1%, p = .015), and among those who had undergone corneal graft surgery (9/9, 100.0%) compared to those who had not (22/35, 62.9%, p = .041). We identified eight novel variants in five genes and identified five families with syndromes associated with corneal dystrophies. Our findings highlight the genetic heterogeneity of corneal dystrophies and the clinical utility of genetic testing in reaching an accurate clinical diagnosis.
Publisher: American Chemical Society (ACS)
Date: 26-01-2012
DOI: 10.1021/ES202807S
Abstract: A Bayesian inversion technique to determine the location and strength of trace gas emissions from a point source in open air is presented. It was tested using atmospheric measurements of N(2)O and CO(2) released at known rates from a source located within an array of eight evenly spaced s ling points on a 20-m radius circle. The analysis requires knowledge of concentration enhancement downwind of the source and the normalized, three-dimensional distribution (shape) of concentration in the dispersion plume. The influence of varying background concentrations of ∼1% for N(2)O and ∼10% for CO(2) was removed by subtracting upwind concentrations from those downwind of the source to yield only concentration enhancements. Continuous measurements of turbulent wind and temperature statistics were used to model the dispersion plume. The analysis localized the source to within 0.8 m of the true position and the emission rates were determined to better than 3% accuracy. This technique will be useful in assurance monitoring for geological storage of CO(2) and for applications requiring knowledge of the location and rate of fugitive emissions.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2017
DOI: 10.1038/EJHG.2017.59
Publisher: American Medical Association (AMA)
Date: 06-2020
Publisher: Oxford University Press (OUP)
Date: 10-2017
Abstract: Pediatric cataract is a leading cause of childhood blindness. This study aimed to determine the genetic cause of pediatric cataract in Australian families by screening known disease-associated genes using massively parallel sequencing technology. We sequenced 51 previously reported pediatric cataract genes in 33 affected in iduals with a family history (cases with previously known or published mutations were excluded) using the Ion Torrent Personal Genome Machine. Variants were prioritized for validation if they were predicted to alter the protein sequence and were absent or rare with minor allele frequency & % in public databases. Confirmed mutations were assessed for segregation with the phenotype in all available family members. All identified novel or previously reported cataract-causing mutations were screened in 326 unrelated Australian controls. We detected 11 novel mutations in GJA3, GJA8, CRYAA, CRYBB2, CRYGS, CRYGA, GCNT2, CRYGA, and MIP and three previously reported cataract-causing mutations in GJA8, CRYAA, and CRYBB2. The most commonly mutated genes were those coding for gap junctions and crystallin proteins. Including previous reports of pediatric cataract-associated mutations in our Australian cohort, known genes account for & % of familial pediatric cataract in Australia, indicating that still more causative genes remain to be identified.
Publisher: Public Library of Science (PLoS)
Date: 05-12-2018
Publisher: Wiley
Date: 29-05-2018
DOI: 10.1111/CEO.13318
Publisher: Springer Science and Business Media LLC
Date: 31-08-2014
DOI: 10.1038/NG.3079
Publisher: Springer Science and Business Media LLC
Date: 29-05-2017
DOI: 10.1038/NG.3875
Publisher: Springer Science and Business Media LLC
Date: 24-02-2021
DOI: 10.1038/S41467-020-20851-4
Abstract: Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638 , CLIC5, SLC2A12, YAP1, MXRA5 , and SMAD6 . Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
Publisher: Public Library of Science (PLoS)
Date: 23-10-2015
Publisher: Wiley
Date: 06-10-2023
DOI: 10.1111/AOS.15775
Publisher: Wiley
Date: 05-1994
DOI: 10.1111/J.1365-2141.1994.TB04881.X
Abstract: A fixation and permeabilization procedure using formaldehyde and acetone has been developed which allows immunostaining of intracellular haemoglobin for fluorescence activated cell sorter (FACS) analysis of erythrocytes. The treatment preserves antigenicity and light-scattering properties. Validation of the method was given by the correlation of F cell number in adults determined by FACS analysis with that assessed by microscopic examination of cell smears, and by the direct relationship between beta chain synthesis and intensity of beta chain/Hb A immunofluorescence within fetal erythrocyte s les known to vary in their beta chain/Hb A content. The procedure is rapid, non-subjective and sensitive, and makes analysis of haemoglobin content, type and distribution amongst red cell populations possible.
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1038/GIM.2013.196
Abstract: Predictive genetic testing of relatives of known myocilin (MYOC) gene mutation carriers is an appropriate strategy to identify in iduals at risk for glaucoma. It is likely to prevent irreversible blindness in this high-risk group because this treatable condition might otherwise be diagnosed late. The Australian and New Zealand Registry of Advanced Glaucoma has established genetic testing protocols for known glaucoma genes, including MYOC. Through the Australian and New Zealand Registry of Advanced Glaucoma, we investigated the experience of 40 unaffected in iduals who had undergone predictive genetic testing for MYOC mutations through questionnaires. The main motivations for being tested were (i) to make appropriate interventions and (ii) to reduce uncertainty. All our respondents perceived strong benefits, either medical or emotional, in being tested. However, different concerns were raised by the respondents that need to be addressed during counseling. Greater family awareness was reported by the majority of the respondents, and the ability to provide information to children was a strong motivation for being tested. This study provides valuable information on the personal and familial impacts of having predictive genetic testing for glaucoma, which will help health professionals to better address the issues faced by patients and provide them adequate support.
Publisher: Wiley
Date: 05-07-2019
DOI: 10.1111/CEO.13569
Abstract: Fuchs endothelial corneal dystrophy (FECD) is a progressive and potentially a sight threatening disease, and a common indication for corneal grafting in the elderly. Aberrant thickening of Descemet's membrane, formation of microscopic excrescences (guttae) and gradual loss of corneal endothelial cells are the hallmarks of the disease. The aim of this study was to identify differentially abundant proteins between FECD-affected and unaffected Descemet's membrane. Label-free quantitative proteomics using nanoscale ultra-performance liquid chromatography-mass spectrometry (nUPLC-MS Quantitative proteomics revealed significantly lower abundance of apolipoprotein E (APOE) and immunoglobulin heavy constant gamma 1 protein (IGHG1) in affected Descemet's membrane. The difference in the distribution of APOE between affected and unaffected Descemet's membrane and of IGHG1 detected by immunohistochemistry support their down-regulation in the disease. Comparative gene expression analysis showed significantly lower APOE mRNA levels in FECD-affected than unaffected corneal endothelium. IGHG1 gene is expressed at extremely low levels in the corneal endothelium, precluding relative expression analysis. This is the first study to report comparative proteomics of Descemet's membrane tissue, and implicates dysregulation of APOE and IGHG1 proteins in the pathogenesis of Fuchs endothelial corneal dystrophy.
Publisher: Springer Science and Business Media LLC
Date: 27-11-2019
DOI: 10.1038/S42003-019-0634-9
Abstract: A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG) intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is h ered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.
Publisher: Wiley
Date: 30-10-2014
DOI: 10.1111/CEO.12234
Abstract: Primary open-angle glaucoma (POAG) is a genetically complex disease. Genome-wide association study (GWAS) is a particularly useful tool in the search for genetic contributions to glaucoma. Recently, chromosome 9p21 has become a major focus of research endeavour, with multiple genome-wide association studies suggesting associations to POAG. Herein, we provide a review of the chromosome 9p21 susceptibility locus as a risk factor for POAG.
Publisher: Medknow
Date: 2020
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 08-09-2021
DOI: 10.1167/IOVS.62.12.3
Publisher: Public Library of Science (PLoS)
Date: 25-01-2018
Publisher: Public Library of Science (PLoS)
Date: 27-08-2013
Publisher: Elsevier BV
Date: 06-2022
Publisher: Springer Science and Business Media LLC
Date: 03-01-2023
DOI: 10.1038/S42003-022-04323-7
Abstract: Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. In iduals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing. Some of this heritability may be explained by rare variants (minor allele frequency [MAF] ≤ 0.01.). We performed multiple gene-based association tests of mean Spherical Equivalent with rare variants in exome array data from the Consortium for Refractive Error and Myopia (CREAM). The dataset consisted of over 27,000 total subjects from five cohorts of Indo-European and Eastern Asian ethnicity. We identified 129 unique genes associated with refractive error, many of which were replicated in multiple cohorts. Our best novel candidates included the retina expressed PDCD6IP , the circadian rhythm gene PER3 , and P4HTM , which affects eye morphology. Future work will include functional studies and validation. Identification of genes contributing to refractive error and future understanding of their function may lead to better treatment and prevention of refractive errors, which themselves are important risk factors for various blinding conditions.
Publisher: Wiley
Date: 28-10-2014
DOI: 10.1111/CEO.12239
Abstract: Diabetic retinopathy (DR) is a blinding disease of increasing prevalence that is caused by a complex interplay of genetic and environmental factors. Here we describe the patient recruitment methodology, case and control definitions, and clinical characteristics of a study s le to be used for genome-wide association analysis to detect genetic risk variants of DR. One thousand six hundred sixty-nine participants with either type 1 (T1) or type 2 (T2) diabetes mellitus (DM) aged 18 to 95 years were recruited in Australian hospital clinics. In iduals with T2DM had disease duration of at least 5 years and were taking oral hypoglycaemic medication, and/or insulin therapy. Participants underwent ophthalmic examination. Medical history and biochemistry results were collected. Venous blood was obtained for genetic analysis. Six hundred eighty-three diabetic cases (178 T1DM and 505 T2DM participants) with sight-threatening DR, defined as severe non-proliferative DR, proliferative DR or diabetic macular oedema were included in this analysis. Eight hundred twelve in iduals with DM but no DR or minimal non-proliferative DR were recruited as controls (191 with T1DM and 621 with T2DM). The presence of sight-threatening DR was significantly correlated with DM duration, hypertension, nephropathy, neuropathy, HbA1C and body mass index. Diabetic macular oedema was associated with T2DM (P < 0.001), whereas proliferative DR was associated with T1DM (P < 0.001). Adoption of a case-control study design involving extremes of the DR phenotype makes this a suitable cohort, for a well-powered genome-wide association study to detect genetic risk variants for DR.
Publisher: Wiley
Date: 02-12-2020
DOI: 10.1111/CEO.13686
Abstract: Monitoring the results of selective laser trabeculoplasty (SLT) on intraocular pressure (IOP) using a home rebound tonometry. To evaluate the role of Icare HOME tonometry in open-angle glaucoma patients being treated with SLT. A clinic-based prospective case study. Fourteen eyes from 14 patients diagnosed with primary open-angle glaucoma were recruited. The trabecular meshwork of each eye was treated 360° with a frequency-doubled Q-switched Nd:YAG laser. IOP was measured four times a day for a week before and after SLT. On the day of SLT, the patients were required to measure the IOP in the evening to record any IOP spikes. The use of Icare HOME in following up patients post-laser trabeculoplasty without the need for clinic attendance. Icare HOME recorded a significant reduction of 5.12 mmHg in the mean IOP post-SLT (95% confidence interval [CI] 3.75-6.50 mmHg, P < .001). The maximum IOP was also reduced by 6.14 mmHg (95% CI 3.07-9.21, P < .001) with no IOP spikes recorded post-SLT. There was a reduction in IOP fluctuation post-SLT by 1.07 mmHg (95% CI 0.24-1.89 mmHg, P = .021). No adverse effects for using the Icare HOME were reported by the study participants. This methodology could be highly useful for facilitating safe follow-up of patients residing in remote and rural areas, thus reducing healthcare cost with better information on IOP.
Publisher: Wiley
Date: 28-01-2010
DOI: 10.1111/J.1755-3768.2009.01786.X
Abstract: This aim of this study was to compare the prevalence of various disease-associated and potentially modifiable risk factors between people with familial and sporadic forms of primary open angle glaucoma (OAG). A cross-sectional, retrospective study design was utilized. A detailed questionnaire enquiring about knowledge of family history, demographic data, current medications, and medical history of systemic disorders was administered. Where possible, living relatives were examined for signs of OAG. A total of 3,800 potential patients with OAG were identified, of whom 2062 were examined. One thousand twelve (59.5%) subjects were found to have familial OAG, and 688 (40.5%) subjects had no known or identified relative with OAG (sporadic glaucoma). One thousand forty-two unaffected family members examined. A past history of migraine was found more often with familial OAG (OR: 1.67 95% CI: 1.15-2.42). This effect was primarily driven by patients who had a first-degree relative also affected by OAG. Following adjustment for male gender and the age at review, the presence of atherosclerosis was also found to be more common in patients with familial glaucoma than in people with sporadic disease (OR: 1.42 95% CI: 1.05-1.92). No significant difference in the prevalence of hypertension, Raynaud's phenomenon, diabetes mellitus or thyroid disease was identified. Patients with a known relative affected by OAG were statistically significantly more likely to have a past history for migraine or presence of atherosclerosis compared to people with no known affected relative. An understanding of such differences and systemic comorbidities will be useful for further work investigating the underlying molecular mechanisms of this disease.
Publisher: Wiley
Date: 05-2010
DOI: 10.1111/J.1442-9071.2010.02258.X
Abstract: To determine the prevalence and associations of refractive error within the indigenous Australian population living in central Australia. 1884 in iduals aged 20 years or older, living in one of 30 remote communities within the statistical local area of 'central Australia' were recruited for this study. This equated to 36% of those aged 20 years or older and 67% of those aged 40 years or older within this district. Participants were recruited as they presented to the eye clinic at each remote community. Participants underwent subjective refraction to determine spherical equivalent and then had a slit-l anterior segment examination. Participants were only included if they were phakic and only the right eye was considered. The prevalence of hypermetropia worse than +1.0 dioptres (D), myopia worse than -0.5 D and astigmatism worse than 1.0 D is presented. From those recruited, 15.2% were hypermetropic 11.1% were myopic and 6.2% had astigmatism. Participants became progressively more hypermetropic with increasing age until the age of 70 years, after which time they become more myopic. Furthermore, there was an increasing likelihood of myopia and a decreasing likelihood of hypermetropia with increasing nuclear opalescent cataract. Our study has shown that indigenous Australians are less likely to be ametropic compared with non-indigenous groups. Variations with age and nuclear opalescent cataract seen in other previous work have also been observed in our s le.
Publisher: Wiley
Date: 18-12-2019
DOI: 10.1111/CEO.13446
Publisher: Springer Science and Business Media LLC
Date: 03-2021
DOI: 10.1038/S42003-021-01784-0
Abstract: Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.AJO.2022.08.006
Abstract: To evaluate the relationship between body mass index (BMI) and glaucoma progression. Multicohort observational study. This study combined a retrospective longitudinal analysis of suspect and early manifest primary open angle glaucoma cases from the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study with 2 replication cohorts from the UK Biobank and the Canadian Longitudinal Study of Ageing (CLSA). In the PROGRESSA study, multivariate analysis correlated BMI with longitudinal visual field progression in 471 participants. The BMI was then associated with glaucoma diagnosis and cross-sectional vertical cup-disc ratio (VCDR) measurements in the UK Biobank, and finally prospectively associated with longitudinal change in VCDR in the CLSA study. In the PROGRESSA study, a lower BMI conferred a faster rate of visual field progression (mean duration of monitoring (5.28 ± 1.80 years (10.6 ± 3.59 visits) (β 0.04 dB/year/SD95% CI [0.005, 0.069] P = .013). In the UK Biobank, a 1 standard deviation lower BMI was associated with a worse cross-sectional VCDR (β -0.048/SD 95% CI [-0.056, 0.96] P < .001) and a 10% greater likelihood of glaucoma diagnosis, as per specialist grading of retinal fundus imaging (OR 0.90 95% CI [0.84, 0.98] P = .011). Similarly, a lower BMI was associated with a greater risk of glaucoma diagnosis as per International Classification of Disease data (OR 0.94/SD 95% CI [0.91, 0.98] P = .002). Body mass index was also positively correlated with intraocular pressure (β 0.11/SD 95% CI [0.06, 0.15] P < .001). Finally, a lower BMI was then associated with greater VCDR change in the CLSA (β -0.007/SD 95% CI [-0.01, -0.001] P = .023). Body mass index correlated with longitudinal and cross-sectional glaucomatous outcomes. This supports previous work illustrating a correlation between BMI and glaucoma.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2016
Publisher: Elsevier BV
Date: 2015
Publisher: Routledge
Date: 08-12-2016
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Jamie Craig.