Microbial Ecology in States of Health and Disease Workshop Summary (2014) / Chapter Skim
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A20 From genetics of inflammatory bowel disease towards mechanistic insights--Daniel B. Graham and Ramnik J. Xavier
A20 From genetics of inflammatory bowel disease towards mechanistic insights--Daniel B. Graham and Ramnik J. Xavier
Pages 471-488
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BMJ 342, d35. A20 From genetics of inflammatory bowel disease towards mechanistic insights90 Daniel B
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The observation that some individuals develop IBD at childhood and others during adulthood, suggests distinct environmental contributions to disease initiation versus disease progression. Although the genetic elements predisposing to IBD are present from birth, disease onset occurs later in life, and there is further need to understand how host genetic and epigenetic factors interact with environmental triggers at disease onset and how genetics influence immune regulatory networks that sustain disease.
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. Identifying causal mutations within coding and noncoding regions of these loci has begun to reveal gene function and shed new light on disease mechanisms.
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Such germlineencoded DNA variation can lead to nonsynonymous coding variants that change protein function and/or posttranslational regulation. However, the majority of the SNPs implicated by GWASs represent variation in noncoding regions of the genome.
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Exome sequencing at IBD loci has identified novel coding variants and helped pinpoint specific genes within these loci that are likely to impact disease (Rivas et al., 2011)
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Addressing Genetic Epistasis The diversity of genetic backgrounds in human subjects complicates phenotyping endeavors, but highlights the notion that phenotypes derive from the aggregate effects of multiple genetic factors. Furthermore, IBD genes interact, as highlighted by the discovery of a microtubule-associated serine/threonine-protein kinase 3-regulated transcriptional program that broadly controls expression of inflammatory genes associated with nuclear factor-kappa-B (NFkB)
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Prior pathogen exposure elicits more robust responses to subsequent infection. While memory within the adaptive immune system provides antigen-specific protection upon rechallenge, the innate immune system can be "trained" by prior infection and poised to respond more robustly to a variety of pathogens (Cooper et al., 2009; O'Leary et al., 2006; Quintin et al., 2012; Sun et al., 2009)
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Genetic studies have helped to identify critical biological processes and cell types that regulate intestinal inflammation. Genetic variation that perturbs any stage of immune homeostasis, inflammation, or resolution can result in the inappropriate inflammatory response to commensals that is observed in IBD.
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. TABLE A20-1 Candidate IBD Genes Select IBD genes identified by ImmunoChip (Jostens et al., 2012)
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. Select IBD genes with coding variants identified by exome sequencing (Rivas et al., 2011)
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. Furthermore, expression of IBD genes identified by GWASs highlight the gut epithelium and innate immune mechanisms including barrier function, goblet cell secretion of mucins, and Paneth cell secretion of antimicrobial mediators (Bevins and Salzman, 2011)
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One can posit that candidate IBD genes with unknown function may control key immune functions that drive disease, and that assigning function to these genes will expand our understanding of immunoregulatory mechanisms. To meet the challenge of assigning functions to candidate IBD genes in relevant immune responses, high throughput RNAi screening approaches have been developed.
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These are important distinctions when attempting to infer disease mechanisms or design new therapeutics. By the same token, determining how genetic variation in risk alleles versus protective alleles impacts a cellular response requires mechanistic insight.
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Significant overlap in genes implicated across several autoimmune/autoinflammatory diseases indicates common immunologic mechanisms as well as unique disease-specific pathways that must be tightly regulated to balance host defense against the risk for pathological inflammation. Only with a deeper understanding of the mechanisms driving disease and their underlying genetic components will the goal of interpreting patient genotypes become feasible.
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(2012) Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes.
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(2012) Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease.
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(2012) NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2.
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(2011) Deep resequencing of GWAS loci identifies independent rare variants asso ciated with inflammatory bowel disease.
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