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Microsatellite Scanning of the Immunogenome for Associations with Graft-Versus-Host Disease Following Haematopoietic Stem Cell Transplantation

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Microsatellite Scanning of the Immunogenome for Associations with Graft-Versus-Host Disease Following Haematopoietic Stem Cell Transplantation 1 Microsatellite scanning of the Immunogenome for Associations with Graft-versus-Host Disease following Haematopoietic Stem Cell Transplantation A thesis submitted to the University of Newcastle in accordance with the requirements for the degree of Doctor of Philosophy (PhD) Christian Harkensee Institute for Cellular Medicine, University of Newcastle July 2012 2 Candidate’s Declaration I, Christian Harkensee, hereby certify that this thesis has been written by me, that it is the record of work carried out by me (unless stated otherwise) and that it has not been submitted in any previous application for a higher degree. Newcastle, July 2012 Christian Harkensee 3 Dedicated to the memory of Akira Sasaki Without whom this work would never have been undertaken. 4 Acknowledgements I am greatly indebted to the patients and donors who volunteered for this work, and the staff members of the transplantation centers, donor centers, and the Japan Marrow Donor Program (JMDP) Office for their generous cooperation, in particular Dr Yasuo Morishima. I am thankful for the generous aid this project has received from a range of donors. This work was supported by the Research on Allergic Disease and Immunology (Health and Labor Science Research Grant H20-014, H23- 010), the Ministry of Health, Labor, and Welfare of Japan, through JMDP. I was supported during this research by a Short-term Post-doctoral Fellowship from the Japan Society for Promotion of Science (JSPS) – thanks to Polly Watson from the London Office for helping to make this happen. This was followed by an International Fellowship from the Kay Kendall Leukaemia Fund UK (KKLF) (grants No 291,297), which has been exceedingly supportive of helping to steer this work through very difficult economical times (special thanks to Liz Storer). The Great Britain Sasakawa Foundation (GBSF) contributed to the laboratory costs of the exploratory study with a Butterfield Award, and the Daiwa Anglo-Japanese Foundation funded the custom design of microsatellite markers with a Small Grant. My special thanks go to my colleagues and the laboratory staff at the Division of Molecular Life Sciences at Tokai University for their kind support: Professor Hidetoshi Inoko, Dr Akira Oka and Dr Makoto Onizuka for their contributions to the design of the study and the laboratory procedures, and Dr Hirofumi Nakaoka for advice on statistics. Mr Hideki 5 Hayashi, my teacher in the laboratory and companion during endless weeks of pipetting, for all his technical advice; Ms Yamaguchi, Ms Matsushita and Ms Higuchi for assisting in the genotyping work, and Ms Oda and Ms Takahashi for helping with the local administrative work. I am most grateful to my supervisors in Newcastle, Dr Pete Middleton and Dr Andy Gennery, for all their constructive feedback and discussions; and Heather McGrath, who fought through my funding administration. The work described in this thesis is exclusively my own, unless stated otherwise. Finally, this work could not have been done without the support of my family, my wife Ena and my children Aila and Kai. The time should have been yours… 6 Publications The work described in this thesis has been published in part. Peer-reviewed journal publications HARKENSEE, C., OKA, A., ONIZUKA, M., MIDDLETON, P. G., INOKO, H., HIRAYASU, K., KASHIWASE, K., YABE, T., NAKAOKA, H., GENNERY, A. R., ANDO, K. & MORISHIMA, Y. (2012) Single nucleotide polymorphisms and outcome risk in unrelated mismatched Haematopoietic Stem Cell Transplantation: An exploration study. Blood 2012 Jun 28;119(26):6365- 6372. Epub 2012 May 14 . Conference abstracts HARKENSEE, C., OKA, A., MIDDLETON, P. G., ONIZUKA, M., GENNERY, A. R., INOKO, H. & MORISHIMA, Y. (2010) A systematic scanning of the immunogenome with microsatellite markers in a Japanese HSCT population reveals multiple genetic risk loci for graft-versus-host disease. European Bone Marrow Transplantation (EBMT). Vienna, Austria. (oral presentation). HARKENSEE, C., OKA, A., MIDDLETON, P. G., ONIZUKA, M., GENNERY, A. R., INOKO, H., ANDO, O., MORISHIMA, Y. (2012) Microsatellite scanning of the Immunogenome for associations with Haematopoietic Stem Cell Transplantation outcomes. 26th European Immunogenetics and Histocompatibility Conference (EFI) / 23rd British Society of Histocompatibility and Immunogenetics Conference, Liverpool, UK (poster). HARKENSEE, C., OKA, A., INOKO, H., MORISHIMA, Y. (2012) TNF-1031 single nucleotide polymorphism: An independent predictor of severe graft- versus-host disease? 26th European Immunogenetics and Histocompatibility Conference (EFI) / 23rd British Society of Histocompatibility and Immunogenetics Conference, Liverpool, UK (poster). 7 Abstract Non-HLA gene polymorphisms contribute to the immune response, leading to complications of haematopoietic stem cell transplantation (HSCT). A systematic approach using 4,321 microsatellite (MS) markers typing for 2,909 immune response genes (‘immunogenome’) on pooled DNA of 922 Japanese donors and recipients of HSCT was used to identify recipient and donor risk loci for graft-versus-host disease (GVHD). Splitting the population into discovery and confirmation cohorts (460/462 pairs), DNA pools were created for a 2-step pooled DNA screening. Fisher’s exact test for 2x2 (each MS allele) and 2xm Chi Square tests were performed, comparing allele frequencies of recipient/donor pools with GVHD grade 0-1 with those of GVHD grade 2-4. The independent, 2-step pooled DNA screening process has effectively reduced false-positive associations. In the final pooled DNA analysis, 17 (recipient) and 31 (donor) MS loci remained associated with risk or protection from GVHD and were further investigated by individual genotyping in the combined cohorts. Ten of these loci were confirmed to have consistent associations with GVHD; of these, two associations remained when applying multiple testing correction and multivariate statistics: D6S0035i (MAPK14, p=0.00035, OR=0.68) and D1S0818i (ELTD1, p=0.000078, OR=1.52). These findings implicate important new immunoregulatory genes with the process of moderate to severe acute GVHD. These data show that genetic susceptibility to GVHD following HSCT is complex and depends on multiple recipient and donor risk loci. Large-scale genomic screening with microsatellites on pooled DNA, here described for the first time in a HSCT population, is a useful method for the systematic evaluation of multigeneic traits. 8 List of Contents Introductory Material Page Title Page 1 Declaration 2 Dedication 3 Acknowledgements 4 Publications 6 Abstract 7 Contents 8 List of Tables 10 List of Figures 12 List of Appendices 13 List of Supplementary Material 14 Chapter 1: Introduction 15 1.1. Haematopoietic Stem Cell Transplantation 16 and Graft-versus-Host Disease 1.2. Pathophysiology and pathobiology of GVHD 21 1.3. The genetics of HSCT 30 1.4. Summary and conclusion, aim of this study 39 1.5. Outline of study plan/brief history of the project 41 Chapter 2: Methodology 43 2.1. Aim and purpose 44 2.2. Objectives 45 2.3. Study question and hypothesis 47 2.4. Overview of Study design 48 2.5. Selection of the study population 53 2.6. Selection of genes and markers 57 2.7. Preparation of DNA 64 2.8. Construction of DNA pools 68 2.9. Procedure of individual sample DNA PCR 79 9 2.10. Procedure of pooled DNA PCR 82 2.11. DNA genotyping 85 2.12. Data retrieval and processing 88 2.13. Data analysis 92 Chapter 3: Exploratory Study 94 3.1. Introduction 95 3.2. Aims, hypotheses, objectives and study design 96 3.3. Materials and methods 98 3.4. Results 104 3.5. Discussion 119 Chapter 4: Results 122 4.1. Pooled DNA PCR and genotyping – 1st and 2nd 123 screening steps 4.2. Individual Genotyping 134 4.3. Further exploration of a susceptibility region by 152 SNP typing 4.4. Genetic susceptibility regions for moderate- 156 severe acute GVHD Chapter 5: Discussion and Conclusion 175 5.1. Strengths and limitations of the methodology 176 5.2. Discussion of results 208 5.3. Future 220 5.4. Conclusions 223 References Appendices Supplementary Material 10 List of Tables Page Chapter 1 Table 1.1. Genes associated with GVHD outcomes 36 Chapter 2 Table 2.1. Gene and marker selection 61 Table 2.2. Specification of degree of LD coverage 61 Table 2.3. Estimation of total gene coverage 62 Table 2.4. Construction of DNA pools 75 Chapter 3 Table 3.1. Selected candidate SNP markers 103 Table 3.2. Results of SNP genotyping on all donor 107 samples Table 3.3. Results of SNP genotyping on all 109 recipient samples Table 3.4. Results of SNP genotyping on HLA 111 matched donor samples Table 3.5. Results of SNP genotyping on HLA 112 matched recipient samples Table 3.6. SNP markers showing an association 113 Table 3.7. Multivariate analysis of IL2-330 genotypes 116 Table 3.8. Multivariate analysis of CTLA-CT60 117 genotypes Table 3.9. Multivariate analysis of TNF-1031 118 genotypes Chapter 4 Table 4.1. Results of pooled donor GVHD analysis 130 Table 4.2. Results of pooled recipient analysis 131 Table 4.3. Overview of individual genotyping 136 11 Table 4.4. Genotyping results of pooled screening 137 Table 4.5. Individual genotyping results 138 Table 4.6. Allele numbers and Odd’s ratio for 139 associated alleles Table 4.7. Associated alleles by HLA matching 142 Table 4.8. Other allele associations by HLA 143 matching Table 4.9. Homozygous genotype associations of 144 associated alleles Table 4.10. Homozygous genotype associations of 145 associated alleles, by HLA matched subgroup Table 4.11. Homozygous genotype associations of 146 other alleles, by HLA matched subgroup Table 4.12. Homozygous genotype associations of 147 other alleles Table 4.13. X-chromosome marker associations 149 Table 4.14. Multivariate analysis of associated alleles 151 Table 4.15. SNP allele and genotype associations at 155 MAPK14 locus Chapter 5 Table 5.1. Advantages and disadvantages of 186 different approaches to gene selection Table 5.2.
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