Epidemiologic and genetic insights into open-angle glaucoma

288 Pages·2012·20.93 MB·English

boekje_def BW2_GECORRIGEERD 21-1-2012.pdf
Epidemiologic and genetic insights
into open-angle glaucoma
Wishal D. Ramdas
boekje_def BW2_GECORRIGEERD 21-1-2012.pdf
A
cknowledgements
The studies presented in this thesis were conducted at the department of Epidemiology, Erasmus Medical Center,
Rotterdam, the Netherlands.
This work was supported by the Erasmus Medical Center, Erasmus University Rotterdam, Stichting Lijf en Leven,
Krimpen aan de Lek; MD Fonds, Utrecht; Rotterdamse Vereniging Blindenbelangen, Rotterdam; Stichting Oogfonds
Nederland, Utrecht; Blindenpenning, Amsterdam; Blindenhulp, The Hague; OOG, The Hague; Algemene Nederlandse
Vereniging ter Voorkoming van Blindheid (ANVVB), Doorn; Landelijke Stichting voor Blinden en Slechtzienden (LSBS),
Utrecht; Swart van Essen, Rotterdam; Stichting Winckel-Sweep, Utrecht; Prof. Dr. Henkes Stichting, Rotterdam; The
Rotterdam Eye Hospital Research Foundation (Stichting Wetenschappelijk Onderzoek Het Oogziekenhuis [SWOO] Prof.
Dr. H.J. Flieringa, Rotterdam); Netherlands Organization for the Health Research and Development (ZonMw; grant
2200.0035); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science;
the Ministry for Health, Welfare and Sports; the European Commission (DG XII); the Municipality of Rotterdam. The
generation and management of genome-wide association studies (GWAS) genotype data for the Rotterdam Study is
supported by the Netherlands Organization 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 Organization for Scientific Research (NWO)/Netherlands Consortium for Healthy
Aging (NCHA) project nr. 050-060-810. The genetic study in the Erasmus Rucphen (ERF) Study was supported by the
Center for Medical Systems Biology (CMSB) of NGI. Laméris Ootech BV, Nieuwegein; Medical Workshop, de Meern;
Topcon Europe BV, Capelle aan de IJssel, all in the Netherlands, and Heidelberg Engineering, Dossenheim, Germany.
The publication of this thesis was financially supported by:
Blindenhulp
Novartis Pharma B.V.
Alcon Nederland
Bausch+Lomb
Prof. Dr. Henkes stichting
Ergra low-vision
Heidelberg Engineering GmbH
Christelijke Stichting tot Praktisch Hulpbetoon aan Visueel Gehandicapten van alle Gezindten
Landelijke Stichting voor Blinden en Slechtzienden
Rotterdamse Stichting Blindenbelangen
Koninklijke Visio
Lay-out by: W.D. Ramdas
Cover design: Photo and scan are from the left eye of Mrs. W.L. Ramdas-Ramlal;
DNA-image Credit/Source: Genome Management Information System, Oak Ridge National
Laboratory, USA; edited by W.D. Ramdas
Printed by: Optima Grafische Communicatie
ISBN: 978-94-6169-145-3
© 2011 W.D. Ramdas
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 appropriate, of the publisher of the publications.
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Epidemiologic and genetic insights into open-angle glaucoma
Epidemiologische en genetische inzichten in open-kamerhoek glaucoom
Proefschrift
ter verkrijging van de graad van doctor aan de
Erasmus Universiteit Rotterdam
op gezag van de
rector magnificus
Prof.dr. H.G. Schmidt
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
woensdag 9 november 2011 om 15:30 uur
Wishal Djainath Ramdas
geboren te Dorsten, Duitsland
boekje_def BW2_GECORRIGEERD 21-1-2012.pdf
P
romotiecommissie
Promotoren: Prof.dr. J.R. Vingerling
Prof.dr.ir. C.M. van Duijn
Overige leden: Prof.dr. C.J. Hammond
Prof.dr. P.T.V.M. de Jong
Prof.dr. H.G. Lemij
Copromotor: Dr. N.M. Jansonius
boekje_def BW2_GECORRIGEERD 21-1-2012.pdf
MEINEN ELTERN IN DANKBARKEIT GEWIDMET
(DR. O.W. RAMDAS “DAS CHORIONCARCINOM INTRA GRAVIDITATEM INTAKTAM” 1980)
boekje_def BW2_GECORRIGEERD 21-1-2012.pdf
c
ontents
Chapter 1 General introduction 7
Chapter 2 Normative values of the optic nerve head 15
2.1 Heidelberg Retina Tomograph (HRT3) in population-based epidemiology: normative 17
values and criteria for glaucomatous optic neuropathy
2.2 Defining glaucomatous optic neuropathy from a continuous measure of optic nerve 39
damage - the optimal cut-off point for risk-factor analysis in population-based
epidemiology
Chapter 3 Incidence and risk factors for open-angle glaucoma 49
3.1 Incidence of glaucomatous visual field loss: a ten-year follow-up from the Rotterdam 51
Study
3.2 Ocular perfusion pressure and the incidence of glaucoma: real effect or artifact? - The 69
Rotterdam Study
3.3 Lifestyle and risk of developing open-angle glaucoma - The Rotterdam Study 85
3.4 Nutrition and risk of open-angle glaucoma - The Rotterdam Study 99
Chapter 4 Genetics of glaucoma-related traits 113
4.1 A genome-wide association study of optic disc parameters 115
4.2 Genome-wide association studies in Asians confirm the involvement of ATOH7 and 137
TGFBR3, and further identify CARD10 as a novel locus influencing optic disc area
4.3 Common genetic determinants of intraocular pressure and primary open-angle glaucoma 157
4.4 Genetic architecture of open-angle glaucoma and related determinants 187
Chapter 5 Implications of genetic findings in open-angle glaucoma 203
5.1 Common genetic variants associated with open-angle glaucoma 205
5.2 Clinical implications of old and new genes for open-angle glaucoma 221
Chapter 6 General discussion 241
Chapter 7 Samenvatting 263
Dankwoord 269
About the author 275
PhD Portfolio 277
Articles included in this thesis 281
List of publications 283
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Chapter 1
Introduction
boekje_def BW2_GECORRIGEERD 21-1-2012.pdf
Chapter 1
i
ntroduction
The eye is a very complex organ with a remarkable architecture (Figure 1). It is responsible
for one of the main senses of the human being, in that every living person can observe the
world through his/her eyes: “a mirror of life”. Loosing this sense, and thus loss of sight, leads
to a significant reduction in quality of life.1 Therefore it is crucial to prevent or cure the eye from
sight-threatening disorders.
In the past centuries several sight-threatening disorders have been described. One
of the major eye disorders affecting the visual performance is glaucoma. A few centuries
ago the general thought was that glaucoma was a disease of the lens. The word glaucoma
means “opacity of the crystalline lens”. Because a greenish color was observed in eyes with
glaucoma, the phenomenon has also been known as green cataract. However, extraction of
the deep sea-green colored lens in glaucomatous eyes did not result in restoration of vision,
but showed that the lens was often clear rather than opacified. Later on, when the difference
between glaucoma and cataract was discovered, the term glaucoma was used for several
eye disorders other than cataract. Nowadays we still do not exactly know what glaucoma is,
but we know that the optic nerve head is primarily affected instead of the lens.2 Nevertheless,
this does not indicate that the historical findings were all wrong. The greenish color of the
pupil has been ascribed to corneal haze and the presence of blood pigments in some forms of
glaucoma.3 Even today, in German the phrase “grüne Star” means glaucoma.
Glaucoma, forms and facts
A multitude of eye disorders have been referred to as forms of glaucoma. All forms have
in common morphologic changes at the optic nerve head (glaucomatous optic neuropathy;
GON) and corresponding functional changes in the visual field (glaucomatous visual field
loss; GVFL). The visual field is defined as all central and peripheral objects located in the
field of vision that we observe when fixating on a certain object. In glaucoma the peripheral
visual field is generally first affected. Eventually, the central visual field becomes also affected
resulting in complete blindness. Glaucoma has been nicknamed the ”silent thief of sight”,
because the periphery of the visual field is lost unnoticedly while the visual acuity remains
relatively normal until the disease is quite advanced. The damaged visual field cannot be
recovered once it is lost.
In this process the pressure within the eye (intraocular pressure; IOP) plays an
unequivocal role. The anterior segment of the eye contains aqueous humor, which is produced
by the ciliary body. From here aqueous humor flows through the pupil, the anterior chamber,
and drains through the uveoscleral route or, more important, through the trabecular meshwork
located in the angle formed by the iris and cornea (Figure 1). The IOP-level is determined by
the aqueous secretion and the rate of outflow.
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Introduction
Figure 1. The anatomy of eye (left) with a magnification of the area of the ciliary body (right). (from: Fraser S, Manvikar
S; Glaucoma - the pathophysiology and diagnosis; Hospital Pharmacist; July/August 2005; Vol. 12; p251-254; with
permission)
There are two main forms of glaucoma characterized by the depth of the anterior
chamber angle. We call the glaucoma open-angle glaucoma (OAG) if the anterior chamber
angle is open. The reduced outflow is presumed to be caused by an increased resistance
at the level of the trabecular meshwork. If the anterior chamber angle is closed, we call the
glaucoma angle-closure glaucoma (ACG). Glaucoma may also be classified as primary or
secondary. In contrast to the latter, the cause of elevation of the IOP in the former form is not
known. Because the pathophysiology and treatment of the different forms of glaucoma are
so diverse, there is no single definition that adequately encompasses all forms. Primary OAG
is more common in Caucasian persons, whereas primary ACG is more common in Asian
persons.4
The burden of glaucoma is obvious. It is the leading cause of irreversible blindness
worldwide. The number of people suffering from glaucoma is expected to increase.4 It has
become a major healthcare issue in ophthalmology. Nevertheless, the etiology of OAG is
still obscure. After decades of research only a few risk factors have been identified for OAG.
Known risk factors include high age, African descent, elevated IOP, myopia, and a positive
family history of OAG – the latter indicating a genetic background. Currently treatment is
targeted on regulating IOP.5,6 Treatment aims to decrease the progression of damage to
the optic nerve head and thus the progression of GVFL. Despite the current approach of
controlling IOP in OAG, there are also patients with well-controlled IOP, who continue to lose
sight.7 From a pathophysiological point of view, the main factors involved in the OAG course
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Chapter 1
next to elevated IOP are: bloodflow, ischemia, glial cells activation, and apoptosis, leading to
optic nerve head changes (GON). In order to increase our knowledge of this major cause of
blindness, we need to find more environmental and genetic risk factors associated with OAG.
This should give us a better understanding of the underlying pathophysiologic mechanisms of
GON and subsequent GVFL.
In this thesis we focused on primary OAG. We first outlined how to define GON more
precisely, as required for adequate risk-factor analyses in an epidemiological setting. Next, we
evaluated one of the theories implicated in the pathophysiological pathway of IOP and OAG,
and search for other risk factors. Finally, we examined the genetics of OAG with the view to
identify new genes and their impact.
GON in epidemiological settings
Glaucomatous damage due to loss of the retinal nerve fiber layer becomes visible as an
excavation (cupping) at the optic nerve head (optic disc), and is measured by comparing the
diameter or area of cupping with the diameter or area of the whole optic disc. The optic disc
cupping occurs more in vertical direction resulting in a vertical ovalisation of the cup. This
is quantified as the vertical cup-disc ratio (VCDR), a clinical important parameter in OAG
management. Although a single measurement of VCDR is a significant determinant of the risk
of developing OAG,8,9 persons born with a high but stable VCDR are presumably not at risk
for OAG. A considerable variation of VCDR and optic disc area in children without OAG has
been described.10 Irrespective of the VCDR at birth, an increase in VCDR over time suggests
a loss of retinal ganglion cells in excess of the normal age-related decline, a pathological sign
of OAG.
In epidemiological research the presence of GON is often defined as a certain value of
VCDR, also called cut-off. Theoretically the development of GON starts together with GVFL.
However, if GON is based on a certain cut-off point of VCDR persons may be classified wrongly
as having GON. For example, a person born with a high but stable VCDR may be classified
as having GON irrespective of glaucomatous changes at the optic nerve head. Furthermore,
persons with GVFL might be classified as not having GON. The other way around GVFL might
not be detected in persons with GON, due to visual field defects, which are too subtle to be
captured with perimetry. Therefore, albeit some misclassification is evitable, it is important
to find the optimal cut-off point of VCDR in order to get more precise results in risk-factor
analyses.
Evaluating risk factors for OAG
Regarding the most important risk factor for OAG, two main theories exist as to how elevated
IOP may initiate glaucomatous damage. An increase in IOP can result in either mechanical
pressure or ischemia of the optic nerve head (optic disc). Both mechanisms may independently
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