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Primary Open Angle Glaucoma in the Scottish Population Isolate of Orkney

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Primary Open Angle Glaucoma in the Scottish Population Isolate of Orkney This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: • This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. • A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. • This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. • The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. • When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. QUANTITATIVE TRAITS RELATED TO PRIMARY OPEN ANGLE GLAUCOMA IN THE SCOTTISH POPULATION ISOLATE OF ORKNEY -VIDARSHI KUMUDU KUMARI KARUNARATNE- -PHD- -THE UNIVERSITY OF EDINBURGH- -2011- DECLARATION I declare that I composed this thesis. It is my own work. Where others have played a role, their contributions have been acknowledged accordingly. This work has not been submitted for any other degree or professional qualification. Vidarshi Karunaratne September 2010 ii DEDICATION This work is dedicated to my husband, Denes, and my parents, Ammi and Appachchi iii TABLE OF CONTENTS ACKNOWLEDGEMENTS ix ABSTACT xi LIST OF TABLES AND FIGURES xii ABBREVIATIONS xvi Chapter 1: PRIMARY OPEN ANGLE GLAUCOMA 1 1.1 AN INTRODUCTION TO PRIMARY OPEN ANGLE GLAUCOMA 1 1.2 DEFINITION AND CLASSIFICATION OF GLAUCOMA 7 1.3 EPIDEMIOLOGY OF PRIMARY OPEN ANGLE GLAUCOMA 11 1.3.1 PREVALENCE OF PRIMARY OPEN ANGLE GLAUCOMA 12 1.3.2. INCIDENCE 36 1.3.3 RISK FACTORS FOR PRIMARY OPEN ANGLE GLAUCOMA 38 1.3.3.1 DEMOGRAPHIC RISK FACTORS 40 1.3.3.1.1 AGE 40 1.3.3.1.2 GENDER 43 1.3.3.1.3 ANCESTRY (POPULATION/ETHNICITY/RACE) 45 1.3.3.2 SYSTEMIC DISEASES ASSOCIATED WITH PRIMARY OPEN ANGLE GLAUCOMA 46 1.3.3.3 OCULAR RISK FACTORS ASSOCIATED WITH PRIMARY OPEN ANGLE GLAUCOMA 47 1.3.3.3.1 INTRA-OCULAR PRESSURE 47 1.3.3.3.1.1 GENERATION OF INTRA-OCULAR PRESSURE .47 1.3.3.3.1.2 DISTRIBUTION OF INTRA-OCULAR PRESSURE 49 1.3.3.3.1.3 RELATIONSHIP BETWEEN INTRA-OCULAR PRESSURE AND GLAUCOMA 50 1.3.3.3.1.4 MECHANISMS OF GLAUCOMATOUS OPTIC NEUROPATHY 51 1.3.3.3.1.4.1 THE MECHANICAL THEORY OF GLAUCOMATOUS OPTIC NEUROPATHY 51 1.3.3.3.1.4.2 THE VASCULAR THEORY OF GLAUCOMATOUS OPTIC NEUROPATHY .53 1.3.3.3.1.4.3 THE VASCULAR DYSREGULATION AND GLAUCOMATOUS OPTIC NEUROPATHY 53 1.3.3.3.1.4.4 OXIDATIVE DAMAGE AND IMMUNE FACTORS IN GLAUCOMATOUS OPTIC NEUROPATHY 55 1.3.3.3.1.4.5 NORMAL TENSION GLAUCOMA 56 1.3.3.3.1.4.6 OCULAR HYPERTENSION .62 1.3.3.3.1.4.7 MORE COMPREHENSIVE PARADIGMS OF GLAUCOMATOUS OPTIC NEUROPATHY 63 1.3.3.3.1.4.8 BIOMECHANICAL MODELS OF GLAUCOMATOUS OPTIC NEUROPATHY 64 1.3.3.3.2 CENTRAL CORNEAL THICKNESS 70 1.3.3.3.2.1 THE STRUCTURE OF THE CORNEA 70 1.3.3.3.2.2 CORNEAL THICKNESS AS A RISK FACTOR FOR THE PROGRESSION OF OCULAR HYPERTENSION TO GLAUCOMA 70 1.3.3.3.2.3 CORNEAL THICKNESS AS A RISK FACTOR FOR THE PRESENCE OF GLAUCOMA 71 1.3.3.3.2.4 CORNEAL THICKNESS IN OCULAR HYPERTENSION AND GLAUCOMA 72 1.3.3.3.2.4.1 CORNEAL THICKNESS IN APPLANATION TONOMETRY 73 1.3.3.3.2.4.2 CORNEAL THICKNESS AS A SUSCEPTIBILITY FACTOR .75 1.3.3.3.3 CUP TO DISC RATIO 80 1.3.3.3.4 MYOPIA 81 1.3.3.3.5 OTHER OCULAR FACTORS 82 1.3.3.4 ENVIRONMENTAL RISK FACTORS FOR PRIMARY OPEN ANGLE GLAUCOMA 83 1.3.3.5 FAMILY HISTORY / GENETICS AS A RISK FACTOR FOR PRIMARY OPEN ANGLE GLAUCOMA 83 1.4 DIAGNOSIS 89 1.5 MANAGEMENT 91 1.6 PROGNOSIS 92 1.7 THE FUTURE OF GLAUCOMA MANAGEMENT 92 1.8 SUMMARY 93 v Chapter 2: AIMS AND OBJECTIVES 95 2.1 AIMS AND OBJECTIVES 95 2.2 RESEARCH QUESTIONS 98 Chapter 3: ESTABILISHING THE ORCADES EYE PROJECT 103 3.1 OVERVIEW 103 3.2 DEFINING THE PHENOTYPE 103 3.3 STUDY POPULATION 109 3.3.1 CHOICE OF POPULATION 109 3.3.2 THE SCOTTISH POPULATION ISOLATE OF ORKNEY 116 3.3.2.1 A BRIEF HISTORY OF ORKNEY 118 3.3.2.1.1 PRE-HISTORIC ORKNEY 120 3.3.2.1.2 ORKNEY AND THE NORSE 126 3.3.2.1.3 ORKNEY UNDER SCOTTISH RULE 127 3.3.2.1.4 ORKNEY TODAY 129 3.4 THE ORCADES STUDY 132 3.4.1 OVERVIEW OF THE ORCADES STUDY 132 3.4.2 FUNDING 133 3.4.3 ETHICAL APPROVAL 134 3.4.4 PREMISES 134 3.4.5 EQUIPMENT 140 3.4.6 SUBJECTS 141 3.4.7 GENOYTPING 144 Chapter 4: DATA COLLECTION, MANAGEMENT AND ANALYSIS 145 4.1 DATA COLLECTION 145 vi 4.1.1 MEASUREMENT OF VISUAL ACUITY (VA) 148 4.1.2 MEASUREMENT OF REFRACTIVE ERROR 151 4.1.3 MEASUREMENT OF AXIAL LENGTH, ANTERIOR CHAMBER DEPTH, CORNEAL CURVATURE AND WHITE-ON-WHITE 157 4.1.4 GENERAL OCULAR EXAMINATION, MEASUREMENT OF INTRAOCULAR PRESSURE 167 4.1.5 EVALUATION OF THE OPTIC NERVE HEAD 168 4.1.5.1 IMAGE ACQUISITION 171 4.1.5.2 ANALYSIS OF THE OPTIC NERVE HEAD STRUCTURE USING THE HEIDELBERG RETINAL TOMOGRAPH III 175 4.1.6 MEASUREMENT OF CENTRAL CORNEAL THICKNESS 183 4.1.7 VOLUNTEER FEEDBACK 184 4.1.8 DATA COLLECTION INSTRUMENTS 185 4.2 DATA STORAGE 186 4.3 DATA ANALYSIS 192 4.3.1 INTER-OBSERVER VARIATION 192 4.3.3 MULTIVARIABLE ANALYSIS 193 4.4 SUMMARY 197 Chapter 5: RESULTS - OVERALL CHARACTERISTICS OF STUDY SAMPLE 198 5.1 OVERVIEW 198 5.2 INTER-OBSERVER VARIABILITY 209 5.3 DISCUSSION 210 Chapter 6: RESULTS - CENTRAL CORNEAL THICKNESS AND CORNEAL DIAMETER IN THE SCOTTISH POPULATION ISOLATE OF ORKNEY 216 6.1 RESULTS 216 vii 6.2 DISCUSSION 220 Chapter 7: RESULTS - INTRAOCULAR PRESSURE IN THE SCOTTISH POPULATION ISOLATE OF ORKNEY 238 7.1 RESULTS 238 7.2 DISCUSSION 241 Chapter 8: RESULTS - OPTIC NERVE PARAMETERS IN THE SCOTTISH POPULATION ISOLATE OF ORKNEY 253 8.1 RESULTS 253 8.2 DISCUSSION 259 Chapter 9: DISCUSSION 270 Chapter 10: FURTHER WORK 281 APPENDIXES 284 REFERENCES 297 viii ACKNOWLEDGEMENTS I would like to thank the University of Edinburgh, the Medical Research Council Human Genetics Unit, Edinburgh, the Chief Scientist Office of the Scottish Executive, the National Health Service (Scotland), the International Glaucoma Association and the people and institutions of Orkney for supporting and sponsoring this project. Without the support of these organizations and people, the Orcades Eye Project and this PhD thesis would not have been possible. I would also like to thank my supervisors Alan Wright, Brian Fleck and Harry Campbell. Also Nick Hastie, Jim Wilson, Veronique Vitart, Chris Franklin, Ruth McQuillan, Gordon Murray, Niall Anderson, the staff of the Orcades Project, the University of Edinburgh and of the MRC Human Genetics Project, and Tunde Peto and Edward White of Moorfields Eye Hospital. Alan initially allowed me to start this project and introduced me to the world of quantitative genetics and without his support and faith in an unknown but enthusiastic senior house officer, the Orcades Eye Project would have never come to fruition. A thank you to Harry for allowing me to work at Public Health Sciences, and register my PhD there, and to Nick Hastie for allowing me to work at the MRC. Thank you to Brian, for agreeing to be my clinical supervisor. Jim Wilson, the head of the Orcades Study – thank you to Jim and his team for allowing this project to proceed and join the rest of the Orcades Study. Veronique Vitart, a guru in quantitative and population genetics, has been a source of information and guidance in quantitative and population genetics. Veronique was one of the few people ix allowed access to genetic information from the Orcades Study and kindly performed a number of analyses as detailed in Chapter 4. Thank you Tunde and Ed for your friendship, support and for training me so well. Thanks Chris and Ruth for also being a great sources of information and support. Niall Anderson, despite having little to do with the project, kindly answered my numerous questions on regression analysis, principle components analysis and other questions of a statistical nature. Thanks Niall. I was really impressed by your generosity of time and spirit. Thank you to Gordon Murray for his enthusiasm and encouragement with the PhD. Also thanks to Narinder, Safraz, Petros, Dave, Colin, Naz, Valerie and others of the third floor, both members and non-members of the erstwhile Third Floor Philosopher’s Club for your friendship and support. Last, but those who really come first, my family and friends. Thank you for your patience, love, and support whilst I disappeared from your lives for the last 3 years to pursue this project. Thank you for still being there when I emerged. Ammi and Appachchi, I owe you everything. Sam, Jon, Meranda, Veena, Sharon, Sushila and the wonderful LFC, thank you. And finally Denes. Thank you for everything. Words can not express how grateful I am for everything you have done and the support you have shown. I look forward to spending the rest of my life with you.
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