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Molecular Signatures of the Pathogenesis ISBN-10: 90-9021312-0 ISBN-13: 978-90-9021312-5

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Molecular Signatures of the Pathogenesis ISBN-10: 90-9021312-0 ISBN-13: 978-90-9021312-5 GENOMICS OF COELIAC DISEASE Molecular Signatures of the Pathogenesis ISBN-10: 90-9021312-0 ISBN-13: 978-90-9021312-5 Cover, layout and print: Budde Grafimedia bv, Nieuwegein The work presented in this thesis was performed at the DBG - Department of Medical Genetics of the University Medical Center Utrecht, and financially supported by the Dutch Digestive Disease Foundation (MLDS) grants WS 00-13 and WS 97-44, the Netherlands Organization for Medical and Health Research (NWO) grants 902-22-094 and 912-02-028, and by the Celiac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government (BSIK03009). The publication of this thesis was facilitated by a financial contribution from the Department of Medical Genetics and generous donations from the Dutch Digestive Disease Foundation (MLDS); the Section of Experimental Gastroenterology (SGE) of the Netherlands Society of Gastroenterology (NVGE); the JE Juriaanse Stichting; and the Dr Ir JHJ van der Laar Stichting. GENOMICS OF COELIAC DISEASE Molecular Signatures of the Pathogenesis GENOMICS VAN COELIAKIE Moleculaire Kenmerken van de Pathogenese (met een inleiding en samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. W.H. Gispen, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op dinsdag 28 november 2006 des middags te 2.30 uur door Mari Cornelis Wapenaar geboren op 14 juli 1958 te Vlaardingen Promotor: Prof. dr. C. Wijmenga Eén koorengraan, wie zal ‘t verstaan? behelst tienduizend schooven: gelooft gij niet als ‘t geen gij ziet, hoe zult gij dit gelooven? Guido Gezelle (1830 - 1899) You cannot depend on your eyes when your imagination is out of focus Mark Twain (1835 – 1910) Ter nagedachtenis aan mijn ouders In loving memory of Lisa: still so much to accomplish so much to live for so much to love CONTENTS PREFACE 9 SECTION I: INTRODUCTION Chapter 1: A combined genetics and genomics approach to unravelling 15 molecular pathways in coeliac disease Chapter 2: Erfelijke factoren bij coeliakie (in Dutch with English summary) 35 SECTION II: HIGH-THROUGHPUT GENE EXPRESSION ANALYSIS Chapter 3: Gene expression mosaicism precedes duodenal tissue patchiness 45 in coeliac disease Chapter 4: A microarray screen for novel candidate genes in coeliac disease 63 pathogenesis Chapter 5: Arrested enterocyte differentiation in coeliac disease causes 73 clinical pleiotropism and IBD-like detoxification impairment SECTION III: MOLECULAR PATHWAY ANALYSIS Chapter 6: A transcriptome of the tight junction gene network in the normal 97 and coeliac disease-affected duodenal mucosa Chapter 7: Association of tight junction genes UMCU23 and UMCU29 with 119 gluten sensitive enteropathy and inflammatory bowel disease implies a common barrier defect SECTION IV: CANDIDATE GENE AND GENE FAMILY STUDIES Chapter 8: The interferon gamma gene in coeliac disease: augmented 133 expression correlates with tissue damage but no evidence for genetic susceptibility Chapter 9: IFNG association with coeliac disease in the Dutch population 143 Chapter 10: The SPINK gene family and coeliac disease susceptibility 153 GENERAL Discussion 171 SUMMARY 189 SAMENVATTING 195 PUBLICATIONS 201 ACKNOWLEDGEMENTS 207 CURRICULUM VITAE 213 COLOR ILLUSTRATIONS 217 PREFACE Preface 11 Preface Definition “Coeliac disease; a malabsorption syndrome precipitated by ingestion of gluten-containing foods and marked by diarrhea with bulky, frothy, fatty fetid stools, abdominal distention, weight loss, asthenia, deficiency of vitamins B, D, and K, and electrolyte depletion” (from 24th Edition of Dorland’s Pocket Medical Dictionary, DM Anderson, WB Saunders Comp, Philadelphia). When I started this research six years ago, one of my first encounters with coeliac disease was this rather graphic description that, admittedly, features a certain poetic beauty. Aim The aim of this thesis was to gain insight into the pathogenesis of coeliac disease by means of a genomics approach. More explicitly, we carried out integrated genetic analysis and gene expression studies to identify, and gain better understanding of the genes and mechanisms behind the pathology and etiology of coeliac disease. Outline In the introductory chapters 1 and 2 (in Dutch with English summary), coeliac disease is presented as a gluten-intolerance and complex genetic disorder. Information is provided on the currently identified susceptibility genes and loci. Genetic strategies for the identification of new at-risk genes are discussed, and include sib-pair linkage analysis and genetic association. Gene expression studies are discussed as a tool for gaining insight into the pathology and for identifying genes and molecular pathways to aid the genetic analysis. Special emphasis is placed on the new high-throughput screening technologies and their application for gene expression studies is described in section II. In chapter 3 we deal with the issue of heterogeneity in patients’ tissue samples and to what extent this has an impact on gene expression studies. Much to our surprise, we observed that gene expression mosaicism was always present, regardless of whether there was tissue patchiness or not. This led us to propose a model to explain the emergence of tissue patchiness from the existing gene expression mosaicism. Our first genome-wide expression study using cDNA-microarrays is described in chapter 4. In these experiments we compared patients with flat mucosa to controls and identified several dynamic processes, including proliferation and differentiation. The differentiation-stimulating and proliferation-attenuating gene TM4SF4 that emerged in this study also appears in chapters 3 and 5. An alternative strategy, using oligonucleotide-microarrays and patients in various degrees of remission, is described in chapter 5. Here we demonstrated that incomplete differentiation of enterocytes causes the impairment of multiple nutrient-absorption functions of the intestine, which can be related to the diverse clinical features seen in coeliac 11 Preface disease patients. In addition, we observed the loss of intestinal detoxification, a feature that has also been reported for inflammatory bowel disease. In section III we depart from the genome-wide approach and focus on a specific molecular pathway, the tight junction gene network. Epithelial tight junctions seal the luminal environment from the internal circulation and a breach in this barrier could contribute to the pathogenesis of coeliac disease. Chapter 6 is a descriptive study of the transcriptional activity of the genes comprising the tight junction network and how they change under the influence of coeliac disease. The same gene network was investigated in a genetic association study that made use of single nucleotide polymorphisms and linkage disequilibrium maps. This yielded two candidate genes that not only contribute to coeliac disease susceptibility, but also enhance the risk of developing inflammatory bowel disease. Section IV deals with the genomics of candidate genes related to the immune defense. Interferon-gamma (IFNG) is the major pro-inflammatory cytokine that drives the adaptive immune response in coeliac disease and evokes the tissue remodeling that leads to a flat mucosa. In chapter 8 we describe the relationship between IFNG expression and the extent of mucosal remodeling in patients. Two types of genetic analyses, using a microsatellite from the first intron of this gene, failed to reveal any association in Dutch patients. However, by using genetic analysis with single nucleotide polymorphism markers we were able to demonstrate weak association, as described in chapter 9. The SPINK gene family plays an important role in tissue preservation and bacterial containment, and could be considered part of the innate immune system. Particularly the interesting location in the genome of individual members of this gene family led us to decide to perform a genetic association test. However, no association could be observed in Dutch coeliac disease patients, as reported in chapter 10. Finally, in the Discussion, I attempt to unify our findings, and those of other workers, into a model for the pathogenesis of coeliac disease. 12 Preface SECTION I INTRODUCTION 12 Chapter 1 A combined genetics and genomics approach to unravelling molecular pathways in coeliac disease MC Wapenaar and C Wijmenga Novartis Found Symp 2005; 267:113-34 (reproduced with permission from John Wiley & Sons Limited) Chapter I - A combined genetics and genomics approach to CD 17 Chapter I - A combined genetics and genomics approach to CD A combined genetics and genomics approach to unravelling molecular pathways in coeliac disease Martin C. Wapenaar and Cisca Wijmenga1 Complex Genetics Group, Department of Biomedical Genetics, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands Abstract. Coeliac disease (CD) is a complex, in£ammatory disorder of the small intestine induced by gluten. It is common and has a prevalence of *1:200 in Western populations. A major known susceptibility locus for CD is the HLA-DQ locus. However, the genetic contribution of this region is limited to *40%, so non-HLA genes must also be involved in the disease aetiology. Genetic studies have so far identi¢ed multiple loci that may potentially be involved in disease aetiology, although the majority of these loci are expected to point to genes with a
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