Biological Insights from Integrative Genetic, Epigenetic and Microbial analysis of Inflammatory Bowel Disease Öffentlichkeit
Somineni, Hari (Summer 2019)
Published
Abstract
Inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract, that are therapeutically or surgically manageable but not curable. The pathogenesis of inflammatory bowel disease is hypothesized to involve complex interactions between genetic, immunologic and environmental factors, including the microbiota, that remain largely undescribed. Although some of these pathological components, including common variants and the microbiome, were extensively studied in isolation, the lack of translation of these associations into biological insights has been a roadblock to understanding disease biology and for subsequent targeted prevention and therapy. During the course of this study, we first aimed: i) to facilitate new locus discovery of common and rare variants in a population that remains understudied; ii) to define DNA methylation signatures that might play a causal role in the development of Crohn’s disease; iii) to provide a state-of-the art review on the current understanding of the role of the gut microbiota in disease pathogenesis, diagnosis, and therapeutic management; and iv) to gain preliminary insights into the spatial and temporal dynamics of the oral microbiota in the pathogenesis and diagnosis of inflammatory bowel disease, and its relation to inflammation. Second, whenever possible, we performed integrative analyses of some of these pathogenetic datasets to facilitate biological insights into the underpinnings of inflammatory bowel disease, and propose that future studies could use this conceptual framework for integrating genetic, epigenetic and transcriptomic or microbial data. Lastly, based on the knowledge gained over the course of this study, and acknowledging the current gaps in our understanding, we provide a futuristic perspective on how to gain deeper biological insights in order to systematically tackle some of the over-arching objectives that have crystallized in the past decade.
Table of Contents
Chapter 1: Overview and Current Understanding of Inflammatory Bowel Disease 1
Introduction 2
Clinical and epidemiological overview of inflammatory bowel disease 2
Genetics of inflammatory bowel disease 2
Environmental component of inflammatory bowel disease 3
Epigenetics of inflammatory bowel disease 4
The microbiome of inflammatory bowel disease 5
Integration of distinct data types in inflammatory bowel disease 6
Overview of current study 7
References 9
Chapter 2: Whole-Genome Sequencing of African Americans Identifies Novel Rare Variants Associated with Inflammatory Bowel Disease 12
Abstract 13
Introduction 13
Methods 14
Results 18
Discussion 23
References 41
Chapter 3: Blood-derived DNA Methylation Signatures of Crohn’s Disease and Severity of Intestinal Inflammation 43
Abstract 44
Introduction 45
Methods 46
Results 54
Discussion 62
References 87
Chapter 4: The Microbiome in Patients with Inflammatory Diseases 90
Abstract 91
Introduction 91
What is currently known from inflammatory bowel disease microbiome research in humans 93
Causal potential of the gut microbiome in human inflammatory bowel disease 95
Dysbiosis in diagnosing inflammatory bowel disease 96
Targeting of dysbiosis for therapy 98
Probiotics 98
Prebiotics 101
Synbiotics 102
Other microbiome-based therapeutic interventions for the management of inflammatory bowel disease 104
Do IBD patients benefit from butyrate replacement? 104
Do IBD patients benefit from sulfate-reduction? 105
Do IBD patients benefit from fecal microbiota transplantation? 106
Discussion 107
Future directions 108
Need for large, well-designed prospective trials 108
Mendelian randomization to identify causal associations. 109
Role of the gut microbiome in disease course. 109
References 114
Chapter 5: Site- and Taxa-specific Disease-Associated Oral Microbial Structures Distinguish Patients with Inflammatory Bowel Disease 120
Abstract 121
Introduction 122
Methods 123
Results 127
Discussion 133
References 156
Chapter 6: Lessons learnt and Recommendations for Future Studies 159
Need for large, case-control cohorts of non-European ancestry 160
Leveraging the genetic heterogeneity across populations to understand widening ethnic disparities in IBD 160
Un-interpreted genetic signals, and trans-ethnic summary statistic fine-mapping analysis of causal variants in IBD 161
DNA methylation data as a functional tool to identify critical variants in IBD risk loci 162
Integrative epigenetic and transcriptomic analysis of genetic associations to gain molecular insights into GWAS signals 163
Quantifying the impact of environmental exposures on the epigenome and establishing the causal potential of exposure-associated DNA methylation in IBD 164
Genetics of microbiome and its integration with the epigenome and transcriptome to gain causal and molecular insights 165
References 166
About this Dissertation
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Primary PDF
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Biological Insights from Integrative Genetic, Epigenetic and Microbial analysis of Inflammatory Bowel Disease () | 2019-05-30 11:51:57 -0400 |
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Supplemental Files
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Chapter 5 - Supplementary Tables 5-1A to 5-1F (Supplementary Tables 5-1A to 5-1F) | 2019-05-30 11:52:01 -0400 |
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