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Hereditary Haemochromatosis and the C282Y Genotype

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Hereditary Haemochromatosis and the C282Y Genotype Hereditary Haemochromatosis and The C282Y Genotype: Implications in Diagnosis and Disease CONCHITA MARIA KUEK, BSc This thesis is presented for the Degree of Master of Science in the Department of Pathology at the University of Western Australia October 2003 Declaration The work detailed in this thesis was performed solely by the candidate unless otherwise stated. This thesis was submitted for the degree of Master of Science at the University of Western Australia and has not been submitted elsewhere for any other degree. All work involved in this thesis was carried out between November 1998 and May 2001 Conchita Kuek TABLE OF CONTENTS Table of Contents i Aknowledgements v Summary vi Abbreviations x index of figures xii index of tables xiii Publications xv PAPERS........................................................................................................................ XV POSTERS...................................................................................................................... XV Chapter 1 Literature Review 2 1.1 INTRODUCTION...................................................................................................2 1.2 IRON ABSORPTION .............................................................................................4 1.3 IRON TRANSPORTERS .........................................................................................8 1.4 IRON AND TRANSFERRIN ..................................................................................13 1.5 THE HFE PROTEIN ...........................................................................................13 1.6 HAEMOCHROMATOSIS GENE MUTATIONS........................................................20 1.7 DIAGNOSIS OF GENETIC HAEMOCHROMATOSIS................................................23 1.7.1 Phenotyping ............................................................................................23 1.7.2 Liver Biopsy............................................................................................24 1.7.3 Diagnosis and Treatment of HH .............................................................24 1.7.4 Gender Differences in HH ......................................................................25 1.7.5 Mutations in the HFE Gene ....................................................................26 1.8 OTHER GENES AND MUTATIONS ASSOCIATED WITH HAEMOCHROMATOSIS ....30 1.8.1 The S65C Mutation.................................................................................30 1.8.2 The C282S Mutation...............................................................................31 1.8.3 The I105T and the G93R Mutations .......................................................32 1.8.4 The C282Y Mutation and False Positives...............................................32 1.9 HAEMOCHROMATOSIS AND TYPE II DIABETES.................................................33 1.10 IRON AND CORONARY HEART DISEASE............................................................35 1.10.1 Iron and LDL Oxidation in Atherogenesis .............................................37 1.10.2 The LDL-Oxidation Hypothesis .............................................................37 1.10.3 Mechanisms behind Cell-Mediated LDL Oxidation...............................41 i 1.11 CARDIOVASCULAR DISEASE AND C282Y HETEROZYGOSITY...........................43 1.12 SUMMARY ........................................................................................................45 Chapter 2 Materials and Methods 50 2.1 GENOTYPING....................................................................................................50 2.1.1 DNA Extraction [129].............................................................................50 2.1.2 Mutation Detection..................................................................................53 2.1.3 C282Y Rsa 1 PCR and Digest ................................................................53 2.1.4 C282Y Mutagenically Separated PCR....................................................57 2.1.5 H63D Mbo1 digest and PCR ..................................................................60 2.1.6 S65C Hinf 1 digest and PCR...................................................................63 2.2 SEQUENCING ....................................................................................................65 2.2.1 Sequencing Primers.................................................................................65 2.3 PHENOTYPING ..................................................................................................66 2.3.1 Iron Studies .............................................................................................66 2.4 CAROTID ULTRASOUND ...................................................................................69 Chapter 3 Haemochromatosis: Genotype vs. Phenotype 71 3.1 INTRODUCTION.................................................................................................71 3.2 AIMS ................................................................................................................73 3.3 STUDY GROUP..................................................................................................73 3.4 RESULTS ..........................................................................................................75 3.5 DISCUSSION .....................................................................................................77 Chapter 4 Diabetic Study 82 4.1 INTRODUCTION.................................................................................................82 4.1.1 Haemochromatosis and Type 2 Diabetes................................................83 4.2 AIMS ................................................................................................................83 4.3 STUDY GROUP..................................................................................................84 4.3.1 Diabetic Population.................................................................................84 4.3.2 Busselton Population...............................................................................84 4.4 RESULTS ..........................................................................................................85 ii 4.5 STATISTICAL ANALYSIS ...................................................................................85 4.5.1 C282Y Hardy-Weinberg Equilibrium.....................................................86 4.5.2 Diabetic Population vs. Control Population............................................87 4.5.3 Sub-grouping of Type 1 and Type 2 Diabetics vs. Control Population..89 4.5.4 Ethnicity and Diabetes ............................................................................90 4.5.5 C282Y Homozygotes Identified in the Diabetic Population...................92 4.6 DISCUSSION .....................................................................................................94 Chapter 5 C282Y Heterozygosity, Coronary Heart Disease and Early Mortality 98 5.1 INTRODUCTION.................................................................................................98 5.1.1 Iron and Coronary Heart Disease............................................................98 5.1.2 C282Y Heterozygosity and Coronary Heart Disease............................100 5.2 AIMS ..............................................................................................................101 5.3 CUDAS POPULATION ....................................................................................102 5.3.1 STUDY GROUP............................................................................................102 5.3.1.1 CUDAS Population...............................................................................102 5.3.1.2 Busselton Population.............................................................................102 5.3.2 RESULTS ....................................................................................................103 5.3.3 STATISTICAL ANALYSIS .............................................................................103 5.3.3.1 C282Y Hardy-Weinberg Equilibrium.......................................................103 5.3.4 C282Y STATUS AND CARDIOVASCULAR RISK FACTORS............................105 5.3.4.1 C282Y Genotype and Ferritin...................................................................106 5.3.4.2 C282Y Genotype and Plaque Formation ..................................................107 5.3.4.3 C282Y Genotype and Intima Media Thickness........................................110 5.4 CUPID POPULATION......................................................................................110 5.4.1 STUDY POPULATION...................................................................................110 5.4.1.1 CUPID Population ................................................................................110 5.4.2 RESULTS ....................................................................................................111 5.4.3 STATISTICAL ANALYSIS ............................................................................111 5.4.3.1 C282Y Hardy-Weinberg Equilibrium.......................................................111 5.4.4 HAEMOCHROMATOSIS AND CORONARY HEART DISEASE...........................113 5.5 CAIFOS POPULATION...................................................................................114 5.5.1 STUDY POPULATION..................................................................................114 5.5.1.1 CAIFOS Population ..................................................................................114
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