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Analysis of Haemochromatosis Mutations in the North West Population

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Analysis of Haemochromatosis Mutations in the North West Population Analysis of Haemochromatosis Mutations in the North West Population Lydia Kirk, B.Sc. (Hons) This thesis is submitted in accordance with the academic requirements for the Degree of Master of Science From Research carried out at the School of Science, Institute of Technology, Sligo. Research conducted under the supervision of Dr. Jeremy Bird (Institute of Technology, Sligo) & Dr. John Williams (Sligo General Hospital) Submitted to the Higher Education and Training Awards Council June 2006 ACKNOWLEDGEMENTS Acknowledgments I wish to express my sincere thanks to the following people for their involvement in and contributions towards the work contained in this thesis: First and foremost, I would like to thank Dr. John Williams (Pathology Manager, Sligo General Hospital), my Co-Supervisor, an excellent mentor in both research and life, If I can be one quarter the person you are, I would consider myself truly successful. Your dedication to and enthusiasm towards research, has been inspirational. I would also like to thank my other Co-Supervisor, Dr. Jeremy Bird (I.T. Sligo) equally, for his support, guidance and patience throughout the course of the project. Sincere thanks to Dr. Wilma Lourens, Consultant Diabetologist & Dr. Donal Murray, Consultant Physician of Sligo General Hospital, for permitting recruitment of individuals within their clinics. Thanks also to: The Research & Education Foundation of Sligo General Hospital, without whose financial assistance the project would not have been completed. In particular, to Mette Jensen & Dr. Seamus Healy. Dr. Samad & Dr. Ramadan (Registrars, Sligo General Hospital), for sample collection. Nurses & staff of Diabetic Clinic, for their patience during the recruitment period. Study Volunteers, for their time and willingness to participate. Sally Browne (Sligo General Hospital) for her much valued editorial skills and invaluable contributions. Dr. Enda Gibney (I.T. Sligo), for his 'contributions'. Margaret Mullett (Irish Haemochromatosis Association) for information and assistance. Technical staff of I.T. Sligo. Dr. Sharon Barrett, Centre for Liver Disease, Mater Misericordiae Hospital, Dublin 7; for supplying positive controls for S65C mutation analysis and for conducting confirmatory genotyping for the S65C mutation. A special thanks to Mrs. Liz Wall (Biochemistry, Sligo General Hospital) for all her help. Friends: Ericka, Pamela, Percy, Maria, Shauna, Michelle and Azura (my MSc support system). And last but not least, I wish to thank my family for their unfaltering support, love and financial assistance throughout the years. DECLARATION Declaration This thesis has not previously been submitted to this, or any other college. With acknowledged exception, it is entirely my own work. Lydia Kirk ABSTRACT _______________________Abstract ________________________________ Background: Hereditary haemochromatosis is a heritable disorder caused by an inborn error in the metabolism of iron. It results in over absorption of iron by the body, which can manifest clinically as fatigue, arthritis, diabetes and cardiovascular problems. The highest prevalence for the genetic mutations that cause hereditary haemochromatosis can be found in the Irish population. Individuals with diabetes may also have haemochromatosis (and vice versa), due to the bi-directional relationship between iron metabolism and glucose metabolism. Objectives: To determine the incidence of the three haemochromatosis mutations C282Y, H63D & S65C, in a population from the North West of Ireland and to investigate whether there is an increased frequency of these three mutations in a diabetic population from the same region. Method: DNA was extracted from 500 whole blood samples (250 diabetic samples and 250 ‘control’ samples) using a Wizard™ kit. PCR was conducted utilising specific primers for each mutation and in accordance with a set protocol. Following amplification, PCR product was subjected to restriction endonuclease digestion, where different restriction enzymes (Rsa I, Nde II & Hinf I) were employed to determine the HFE genotype status of samples. Results: The incidence of C282Y homozygosity (1/83) and C282Y heterozygosity (1/6) in the ‘control’ group was similar to those reported for the general Irish population (1/83 and 1/5, respectively). Incidences of H63D homozygotes and H63D heterozygotes or ‘carriers’ in the diabetic population were greater than that of the ‘control’ population. A significant finding of this study was that of an incidence of 1/32 S65C carriers in the control population. This is, to our knowledge, the highest incidence of the genotype reported to date in the general Irish population. Statistical analysis showed that there was no significant differences between the HFE genotype frequencies in the Diabetic and Control Populations. Conclusion: Results of the study concord with published literature in terms of C282Y homozygosity and C282Y heterozygosity in the general Irish population. An increased frequency of the H63D mutation in diabetic individuals was also found but was not statistically significant. The biochemical effect of the H63D mutation is still unknown. The significance of such a high incidence of S65C carriers in the ‘control’ population warrants further investigation. TABLE OF CONTENTS TABLE OF CONTENTS Title Page i Acknowledgements ii Declaration iii Abstract iv Table of Contents V List of Figures ix List of Tables xiii List of Appendices XV 1.0 Literature Review 1.1 Introduction 1 1.2 Haemochromatosis: A Historical Review 1 1.3 Types of Haemochromatosis 3 1.3.1 Type 1 / Hereditary Haemochromatosis 3 1.3.2 Type 2 / Juvenile Haemochromatosis 3 1.3.3 Type 3 / Transferrin Receptor-Related Hereditary Haemochromatosis 3 1.3.4 Type 4 ! Ferroportin-Related Iron Overload 4 1.3.5 Type 5 Haemochromatosis 4 1.4 Genetics of Haemochromatosis 4 1.4.1 Molecular Basis of Haemochromatosis 4 1.4.2 Origins, Population Genetics, Gene Frequency & Prevalence 7 1.4.3 Phenotype vs. Genotype 9 1.4.4 C282Y Homozygosity 10 1.4.5 C282Y Heterozygosity 11 1.4.6 C282Y/H63D Compound Heterozygosity 12 1.4.7 H63D Mutations 12 v 1.4.8 S65C Mutations 13 1.5 Penetrance 13 1.6 Iron Metabolism in Haemochromatosis 14 1.7 Diagnostic Techniques for Iron Overload 17 1.8 Screening 23 1.9 Therapy 26 1.9.1 Phlebotomy 26 1.9.2 Chelation Therapy 27 1.10 Social & Ethical Issues 28 1.11 Relationship to other disorders 28 1.12 Summary of Mutational Incidence (Worldwide) 30 1.13 Diabetes: A brief History & Classification 38 1.14 Genetics of Diabetes 40 1.14.1 Genetics of Type I Diabetes 41 1.14.2 Genetics of Type II Diabetes 42 1.15 Summary of Incidence (Worldwide) 43 1.16 Haemochromatosis & Diabetes 43 1.17 Information on Incidence of Haemochromatosis & Diabetes in Ireland 51 1.18 Research Question I Objectives of the Study 52 2.0 Materials & Methods 2.1 Materials 53 2.2 Study Design 58 2.3 Ethics 58 2.4 Research Subject Recruitment 58 2.5 Blood I Serum Samples 59 2.6 TBE Buffer Preparation 59 2.7 Agarose Gel Preparation 60 2.8 Molecular Weight Marker Preparation 60 2.9 Primer Stock Solution & Working Solution Preparation 61 vi 2.10 DNA Purification 62 2.11 PCR 67 2.11.1 Optimisation of PCR 67 2.11.2 Optimisation of PCR in terms of MgCh concentration 68 2.11.3 Optimisation of PCR in terms of Pnmer annealing Temperature 70 2.11.4 Optimisation of PCR in terms of Primer concentration 73 2.11.5 Optimisation of PCR in terms of Template DNA Concentration 75 2.12 Restriction Endonuclease Digestion 78 2.13 Agarose Gel Electrophoresis 81 2.14 Gel Analysis & Documentation 82 2.15 Biochemistry Analysis 83 2.16 Risk Assessment 87 2.17 Statistics I Data Analysis 88 2.18 Flow Diagram of Analysis for Present Study 89 3.0 Results 3.1 DNA Purification from Whole Blood 90 3.2 Genetic Analysis 91 3.2.1 Optimisation of PCR 91 3.2.2 Optimisation of PCR in terms of MgCk concentration 91 3.2.3 Optimisation of PCR in terms of Primer annealing Temperature 92 3.2.4 Optimisation of PCR in terms of Template DNA Concentration 93 3.2.5 PCR Master Mix versus ReadyMix™ 94 3.2.6 Restriction Endonuclease Digestion / Mutational Analysis 95 3.3 Biochemistry Analysis 115 Vll 4.0 Discussion 4.1 Sample Collection 118 4.2 DNA Purification from Whole Blood 119 4.3 PCR Optimisation 121 4.4 Restriction Endonuclease Digestion 122 4.5 Quality Control (pre- and post- PCR) 124 4.6 Genetic Analysis 126 4.6.1 C282Y Mutations 127 4.6.2 H63D Mutations 129 4.6,3 S65C Mutations 130 4.6.4 Compound Heterozygotes 132 4.6.5 Haemochromatosis Allele Frequencies 133 4.6.6 Recommendations of Practice Guidelines for the Diagnosis of Haemochromatosis by Genetic Testing: Clinical Implications 135 4.7 Biochemistry Analysis 136 4.8 Haemochromatosis & Diabetes 142 5.0 Conclusions 5.1 Conclusion 146 6.0 References 6.1 References 148 Appendices List Of Figures Figure 1.0 Examples of HFE genotypes in families with haemochromatosis. Figure 1.1 Estimated haemochromatosis frequency in Europe and the Mediterranean littoral. Figure 1.2 Hepatic micrograph showing iron accumulation in liver cells (Haemochromatosis) using Peris stain. Figure 1.3 The T ransferrin Cycle. Figure 1.4 Polymerase Chain Reaction Figure 1.5 Exon 2 of the HFE gene and location of the H63D and S65C mutations. Figure 1.6 Chemical structure of agarose. Figure 1.7 ASLD (American Association for the Study of Liver Diseases) algorithm for the evaluation of hereditary haemochromatosis. Figure 1.8 Iron Chelators. Figure 1.9 Incidence of C282Y homozygosity and C282Y/H63D compound heterozygosity in clinically diagnosed proband populations. Figure 1.10 Incidence of C282Y homozygosity and C282Y/H63D compound heterozygosity in general populations. Figure 1.11 Incidence of H63D homozygosity, C282Y heterozygosity and H63D heterozygosity in clinically diagnosed proband populations. Figure 1.12 Incidence of H63D homozygosity in general populations. Figure 1.13 Incidence of C282Y heterozygosity in general populations.
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