Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression (original) (raw)
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Redefining clinical outcomes and endpoints in glaucoma
Expert Review of Ophthalmology, 2018
Introduction: Increasing life expectancy and ageing populations across the world are causing the number of glaucoma patients to rise dramatically. With longer lifespans also comes the need to improve the timeframe and accuracy with which we can diagnose, monitor and treat patients, ensuring longevity of vision contributes to a meaningful quality of life. Current markers used in glaucoma practice are in many cases suboptimal in their ability to accurately identify glaucomatous damage in time to prevent irreversible optic neuropathy. Areas covered: This review summarises the important properties of successful biomarkers and surrogates, and relates this to how intraocular pressure, visual field testing, and imaging have been refined to improve early diagnosis and progression analysis of glaucoma patients. Secondly, we discuss newer concepts in imaging, genetics, and quality of life measures which may provide biomarkers and surrogate endpoints with which to develop novel treatments in the future. Expert commentary: We summarise the key relevant points in glaucoma research, and the current techniques being trialled that are most likely to lead to valuable biomarkers for the future.
Glaucoma: Past, Present, and Future
Revista Brasileira De Oftalmologia, 2020
P rimary open-angle glaucoma (POAG) is an age-old disease that remains enigmatic. Millions of people worldwide still lose their sight due to POAG and the prediction is that, with longer life expectancy, more people will be diagnosed with it. (1) Over the years, glaucoma has undergone changes in concept, workup and treatment. Up to now, the concept of this disease is not consensual. (2) Would it be a brain disease? Initially, glaucoma was synonymous with elevated intraocular pressure (IOP). The elevated IOP would cause the excavation of the optic disc (glaucomatous excavation) (3) and visual field (VF) loss, characterizing the glaucoma triad. (2) Conceptual changes occurred in 1996 when glaucoma was defined as an optic neuropathy being the elevated IOP its main risk factor. (4) Since then, optic neuropathy and VF loss characterize the manifest glaucoma. However, some patients may have an elevated IOP without VF loss nor retinal nerve fiber layer (RNFL) loss-ocular hypertension (OH). (5) Others may present preperimetric glaucoma characterized by RNFL loss detected by optical coherence tomography (OCT) in the absence of VF loss. (6) It is surprising that elevated IOP, the only known modifiable condition, has been considered as the principal risk factor taking in view that, for avoiding glaucoma progression, the treatment is the IOP normalization even when IOP is statistically normal. It is a big mistake to think that the IOP level is important for POAG and normal tension glaucoma treatment, but at the same time, not as a criterion for its diagnosis. It is known that elevated IOP is the result of impairment of drainage of the aqueous humor (AH) independently of the type of glaucoma. Uncontrolled IOP causes glaucoma progression with irreversible and progressive loss of RNFL and VF. This implies that elevated IOP seems to be or is a fundamental part of the disease and needs a detailed investigation. Taking into consideration that IOP is a highly dynamic parameter with many influence factors, it is an absurd to manage glaucoma with single IOP measurement. The major challenge is to find out the target IOP for each preperimetric or glaucomatous patient. Workup The workup of glaucoma has also changed over time. New tonometers have appeared, but none of them has overcome the gold standard Goldmann applanation tonometer since 1957. (7) In 1997, the measurement of central corneal thickness (CCT) was introduced, but there is no algorithm that directly relates it to the value of IOP. (8,9) Also, the role of corneal hysteresis (CH) in glaucoma has not been fully elucidated. CH may be more significantly associated with glaucoma than CCT. (10) OCT and OCT angiography (OCTA) have been used in last decades. (11,12) Diniz-Filho et al. reported that "higher levels of IOP during follow-up were associated with faster rates of RNFL loss over time measured by SD OCT". (10) OCTA allows for simultaneous in vivo imaging of the morphology and vasculature of the eye. (12) IOP assessment The 24-hour IOP investigation still remains a challenge. It is performed for detecting IOP peaks but it is not performed by most ophthalmologists around the world because of expense and inconvenience. (12) Many provocative and functional tests have been used to diagnose early glaucoma. The water-drinking and ibopamine tests failed to diagnose early POAG because of high rates of false-positive and false-negative results. (13,14) Some authors have monitored 24-hour IOP with the SENSIMED Triggerfish contact lens, but the results are not convincing yet. (15) Corneal hysteresis (CH) and lamina cribrosa Although there are some controversies about CH in glaucoma, some authors reported that lower CH measurements were significantly associated with increased risk of developing glaucomatous visual field defects over time.(10) Studies using Swept-Source OCT (SS-OCT) have demonstrated that the lamina cribrosa is likely biomechanically active and that significant changes occur in glaucoma. (16) VF examination In the past, blue-yellow perimetry was performed for early glaucoma diagnosis. This technique was completely abandoned. (14) Frequency-doubling perimetry (FDP) has been less used than in thepast, presenting a tendency of abandon. (14) Nowadays, all scientific works use the 24-2 test VF. Recently, some authors have advised performing the 10-2 test could be essential for some glaucoma patients. (17) Other authors reported that further studies are needed to determine the potential advantages of the 10-2 test in relation to the 24-2. (18)
Glaucoma: the retina and beyond
Acta neuropathologica, 2016
Over 60 million people worldwide are diagnosed with glaucomatous optic neuropathy, which is estimated to be responsible for 8.4 million cases of irreversible blindness globally. Glaucoma is associated with characteristic damage to the optic nerve and patterns of visual field loss which principally involves the loss of retinal ganglion cells (RGCs). At present, intraocular pressure (IOP) presents the only modifiable risk factor for glaucoma, although RGC and vision loss can continue in patients despite well-controlled IOP. This, coupled with the present inability to diagnose glaucoma until relatively late in the disease process, has led to intense investigations towards the development of novel techniques for the early diagnosis of disease. This review outlines our current understanding of the potential mechanisms underlying RGC and axonal loss in glaucoma. Similarities between glaucoma and other neurodegenerative diseases of the central nervous system are drawn before an overview of...
Ophthalmology
Objective: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. Design: Cross-sectional study. Participants: For the primary analysis, we examined the glaucoma phenotype of 2,154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) including cases recruited from the UK. For replication, we examined an independent cohort of 624 early POAG patients. Methods: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP associated variants and stratified POAG patients into three risk tiers. The lowest and highest quintiles of the score were set as the low and high risk groups respectively and the other quintiles as the intermediate risk group. Main Outcome Measures: Clinical glaucoma phenotype including maximum recorded IOP, age of diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. Results: There was a dose-response relationship between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 (SD 0.62) mmHg than the low genetic risk group (P = 0.006). Compared to the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 (1.0) years (P < 0.001), more family members affected by 0.46 (0.11) members (P < 0.001), and higher rates of incisional surgery (odds ratio 1.5; 95% confidence interval 1.1-2.0; P = 0.007). There was no statistically significant difference in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). Conclusions: The IOP polygenic risk score was positively correlated with maximum IOP, disease severity, need for surgery and number of family members. Genes acting via IOP mediated pathways, when considered in aggregate have clinically important and reproducible implications for glaucoma patients and their close family members.
Evidence-based pathophysiology of glaucoma
Mædica, 2010
Glaucoma, one of the major causes of blindness worldwide, is a chronic neurodegenerative disease of the optic nerve, which consists of progressive loss of the retinal ganglion cell fibers and visual field defects. High intraocular pressure has long been considered the most ...
Predicting the Onset of Glaucoma
Ophthalmology, 2010
Objective-To evaluate the predictive ability of baseline confocal scanning laser ophthalmoscopy (CSLO) Glaucoma Probability Score (GPS) for the development of primary open angle glaucoma (POAG) and to compare it to the Moorfields Regression Analysis (MRA) classification, other topographic optic disc parameters and stereophotograph-based cup-to-disc ratio. Design-Longitudinal randomized clinical trial Participants-857 eyes of 438 participants in the CSLO Ancillary Study to the Ocular Hypertension Treatment Study (OHTS) with good quality baseline CSLO images. Methods-The ability of baseline GPS, MRA and optic disc parameters to predict the development of POAG was evaluated in univariate and multivariable proportional hazard ratio analyses. Likelihood ratios and positive and negative predictive values were compared Main Outcome Measures-POAG end point as determined by repeatable changes in the visual field or optic disc. Results-Sixty-four eyes of 50 CSLO Ancillary Study participants developed POAG. Median time to reach a POAG endpoint was 72.3 months. The 93 eyes of 388 participants not reaching endpoint were followed for a median124.9 months. Baseline GPS identified many more eyes as outside normal limits than the MRA. In multivariable analyses, all regional and global baseline
A review on glaucoma: A silent killer of vision
The Pharma Innovation Journal, 2016
Glaucoma is a neurodegenerative disorder that affects the optic nerve and the inner layers of the retina. Increased intraocular pressure is a major risk factor in the disease. Chronic elevation of intraocular pressure specifically induces the death of retinal ganglion cells. Recent advances have seen a surge of new ideas and technologies to aid in the detection, treatment and further understanding of glaucoma. These technologies and advances are discussed to provide information on risk-factors, diagnosis and treatment. This study reviews current concepts in the goals of glaucoma therapy, and options for the management of glaucoma.
Clinical Challenges and Priorities in Managing Glaucoma Patients
ESASO Course Series, 2016
There are challenges in managing glaucoma patients and priorities need to be determined. Early in the course of the disease, managing subjects with ocular hypertension (OHT) is a challenge. The risk calculator is a useful guide to decide on early preventive treatment in those with OHT and to recommend treatment in patients at high risk for progression to glaucoma. Moreover, although wellaccepted clinical criteria defining glaucomatous optic disk damage contribute to diagnostic accuracy, clinical diagnosis remains subjective relying on qualitative assessment of the optic disk. As a result, even among glaucoma experts, agreement in optic disk assessment is not excellent. In addition, visual field (VF) damage due to glaucoma has recently been associated with quality of life (QoL) measures, although a specific threshold of VF damage beyond which QoL is affected has not been determined yet. On the other hand, risk factors for glaucoma have been identified in major clinical trials, as well as the potential role of setting an individual target in lowering intraocular pressure (IOP). Despite this knowledge, we are not able to predict the rate of VF progression of the individual patient at baseline. In addition, glaucoma progresses at widely different rates among individual patients even within the same glaucoma type. Therefore,
The many faces of glaucomatous optic neuropathy
Clinical and Experimental Optometry, 2000
Background: Glaucoma manifests mostly in the elderly, who frequently have other ocular changes that frustrate clear visualisation of the optic nerve head or nerve fibre layer. In the past, a large or asymmetric cup/disc ratio has been used to indicate the possibility of glaucoma. In this paper, I will argue that cup/disc ratios alone have poor sensitivity to glaucoma, and a more sophisticated approach is needed to make the earliest diagnosis. Methods: This paper reviews the literature and describes the changes that occur at the optic nerve head and in the peripapillary region as a consequence of glaucomatous optic neuropathy (GON). Results: The concept of 'risk factors' is developed to help screen for glaucoma. Glaucoma suspects require a full clinical investigation (visual field, IOP, assessment of anterior chamber, disc features and nerve fibres) and need to be monitored annually. For future reference, they should have their disc features recorded by instrumental methods o r with photography at an early age. As no single sign provides the perfect diagnostic marker for the disease, clinicians need to examine for a group of signs before making the diagnosis. A clinical logic is developed in this paper to enhance the detection of glaucoma. Conclusion: Adoption of a protocol similar to that detailed in this paper will enhance the early and reliable detection of glaucoma.