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Open-Angle Glaucoma: from Epidemiology to Molecular Aspects and Anatomical Features

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Open-Angle Glaucoma: from Epidemiology to Molecular Aspects and Anatomical Features Open-angle glaucoma: from epidemiology to molecular aspects and anatomical features Hendrika Springelkamp Acknowledgements: The research described in this thesis was supported by the NWO Graduate Programme 2010 BOO (022.002.023). The Rotterdam Study and ERF were supported by the Netherlands Organisation of Scientific Research (NWO; 91111025); Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands; Netherlands Organization for Health Research and Development (ZonMw); UitZicht; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); the municipality of Rotterdam; the Netherlands Genomics Initiative/NWO; Center for Medical Systems Biology of NGI; Stichting Lijf en Leven; Stichting Oogfonds Nederland; Landelijke Stichting voor Blinden en Slechtzienden; Prof. Dr. Henkes Stichting; Algemene Nederlandse Vereniging ter Voorkoming van Blind- heid; MD Fonds; Glaucoomfonds; Medical Workshop; Heidelberg Engineering; Topcon Europe BV. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The publication of this thesis was financially supported by: Glaucoomfonds, Prof.Dr. Henkes Stichting, Landelijke Stichting voor Blinden en Slecht- zienden, Erasmus MC (Department of Epidemiology), Allergan BV, Bayer B.V., Théa Pharma Cover & lay-out: Jessy Wijgerde Printing: Ridderprint BV ISBN: 9789491462252 © 2016 H. Springelkamp All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without permission of the author, or, when appro- priate, of the publisher of the publications. OPEN-ANGLE GLAUCOMA: FROM EPIDEMIOLOGY TO MOLECULAR ASPECTS AND ANATOMICAL FEATURES Open kamerhoek glaucoom: van epidemiologie naar moleculaire aspecten en anatomische kenmerken Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.A.P. Pols en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 13 januari 2016 om 15.30 uur door Hendrika Springelkamp geboren te Apeldoorn PROMOTIECOMMISSIE Promotoren: Prof.dr.ir. C.M. van Duijn Prof.dr. N.M. Jansonius Prof.dr. C.C.W. Klaver Overige leden: Prof.dr. R.M.W. Hofstra Prof.dr. P.J. Foster Prof.dr. L.R. Pasquale Voor mijn ouders TABLE OF CONTENTS Part 1 Introduction 9 1.1 General introduction 11 1.2 The genetics of primary open-angle glaucoma 17 Part 2 The role of optical coherence tomography in glaucoma 27 2.1 Optimizing the information yield of 3-D OCT in glaucoma 29 2.2 Population-based evaluation of retinal nerve fiber layer, retinal ganglion 47 cell layer, and inner plexiform layer as a diagnostic tool for glaucoma Part 3 Risk factors for intraocular pressure and glaucoma 69 3.1 Incidence of glaucomatous visual field loss after two decades of follow-up: 71 the Rotterdam Study 3.2 Relationship between sleep apnea and open-angle glaucoma: 85 a population-based cohort study 3.3 Associations with intraocular pressure across Europe: The European Eye 99 Epidemiology (E3) Consortium Part 4 Genetics of intraocular pressure and optic nerve head measurements 123 4.1 Genome-wide analysis of multi-ancestry cohorts identifies new loci 125 influencing intraocular pressure and susceptibility to glaucoma 4.2 Meta-analysis of genome-wide association studies identifies novel loci that 139 influence cupping and the glaucomatous process 4.3 Meta-analysis of genome-wide association studies identifies novel loci 153 associated with optic disc morphology 4.4 ARHGEF12 influences the risk of glaucoma by increasing intraocular 171 pressure 4.5 New insights into genetics of primary open-angle glaucoma based on 189 meta-analyses of intraocular pressure and optic disc characteristics Part 5 Functional consequences of genetic variants 245 5.1 Exome sequencing and functional analyses suggest SIX6 is a gene involved 247 in an altered proliferation-differentiation balance early in life and optic nerve degeneration at old age Part 6 General discussion 271 Part 7 289 Samenvatting 290 Summary 293 Acknowledgements – Dankwoord 296 PhD Portfolio 300 List of publications 302 About the author 305 part 1 introduction chapter 1.1 General introduction 12 | Chapter 1.1 Glaucoma The eye helps us to create vision by gathering, focusing and transmitting light to the brain. Light first passes through the cornea, which refracts the light; then through the pupil, which controls the amount of incoming light; and through the lens, which subsequently focuses the light onto the retina. Photoreceptor cells in the retina convert the light into electric signals. These signals are transferred along the optic nerve and subsequent visual pathways to the brain where they are processed so that we can form an image of the outside world. Each optic nerve contains approximately 1 million nerve fibers. Glaucoma is a disease that affects the optic nerve. An elevated pressure within the eye (intraocular pressure; IOP) is an important risk factor for glaucoma. Intraocular pressure is the result of a balanced process of secretion and drainage of aqueous humor. Aqueous humor is produced by the ciliary body and goes through the pupil and anterior chamber to the trabecular meshwork in the iridocorneal angle, where it leaves the eye (see Figure 1C). The balance between production and outflow determines the IOP. In glaucoma, changes of the optic nerve lead to irreversible visual field loss which may end in blindness. In 2010, 60 million people were estimated to suffer from glaucoma, of which more than 8 million people were blind, making this disease the most important cause of irreversible blindness worldwide1. Glaucoma is categorized in several subtypes, based on the cause of elevated IOP. In open-angle glaucoma (OAG) there is no visible damage or obstruction in the iridocorneal angle, in contrast to angle-closure glaucoma in which a blockage of the trabecular outflow consists. The most common form in Europeans is OAG. This can be further divided into primary open-angle glaucoma, i.e., without a detectable underlying disease, and glaucomas in eyes with other abnormalities. Examples of the latter are the pseudoexfoliation and pigment dispersion syndromes. Imaging OAG is characterized by various features such as thinning of the retinal nerve fiber layer (RNFL) and retinal ganglion cell layer (RGCL). The best-known characteristic is a change of the appearance of the optic nerve head (ONH), also called optic disc. The ONH is visible by ophthalmoscopy. The center of the ONH is called the cup. The nerve fibers are located in the rim, which surrounds the cup. Loss of RNFL and RGCL leads to an enlarged cup, or cupping. This process can be quantified by, amongst others, the vertical cup-disc ratio (VCDR), which is the vertical diameter of the cup compared to the vertical diameter of the total ONH. The ONH can also be examined by imaging. A commonly used device is the Heidelberg Retina Tomograph (HRT)2, a confocal scanning laser ophthalmoscope. A laser light scans the ONH at different depths in a series of sequential scans, allowing the creation of a three-dimensional image of the ONH, which can subsequently be analyzed quantitatively. It can also image the RNFL around the ONH and assess its thickness. Another device, the GDx, is a scanning laser polarimetry3,4. It can also measure the RNFL thickness around the ONH, using the birefringent properties of the RNFL. A lot of studies have been published about the correlation between functional loss (visual field loss) as assessed with perimetry and structural loss as assessed with HRT or GDx, however, this correlation was not very good. New imaging techniques were considered, such as Optical Coherence Tomography (OCT)5,6. This technology is based on low-coherence interferometry of electromagnetic radiation, typically employing the near- infrared part of the spectrum, and the results for OAG diagnosis are promising. Most OAG General introduction | 13 studies on OCT were based on selected patients from the clinic. How well OCT performs in a setting free of selection bias is currently unclear. Epidemiology Although the glaucomatous characteristics of the ONH are well defined, the pathogenesis of OAG is largely unknown. Other risk factors besides an elevated IOP (see above) include a positive family history, myopia or nearsightedness, higher age, and African descent7-9. Another risk factor is a thin central corneal thickness. This causes an underestimation of the actual IOP, but it was also found that it is a risk factor for progression to glaucoma in patients with ocular hypertension independent of IOP10-12. The known risk factors cannot explain OAG in all cases. For example, it has been estimated that up to 50% of OAG patients have a normal IOP13,14. The identification of new risk factors may lead to a better understanding of the disease and eventually the development of new therapies. Genetic epidemiology It has been known for decades that genetic predisposition plays an important role in glaucoma (see Chapter 1.2). In 1993, the first OAG gene (MYOC) was identified by linkage studies15-17. In the next decades, other genes (OPTN, WDR36) were identified using this technique18-20. During the last years, the identification of new glaucoma genes has been accelerated by the introduction of genome-wide association studies (GWAS). In GWAS, millions of single nucleotide polymorphisms (SNPs) are determined across the genome. Subsequently, the association between these SNPs and the disease or outcome of interest is determined. The identified genetic variants or genes (SIX6, ATOH7, CDKN2B) explain less than 5% of the variation in risk of OAG21.
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