Gastroenterology

Gastroenterology

Volume 133, Issue 4, October 2007, Pages 1327-1339
Gastroenterology

Reviews in basic and clinical gastroenterology
The Genetics of Inflammatory Bowel Disease

https://doi.org/10.1053/j.gastro.2007.08.032Get rights and content

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Value of Genetic Studies in IBD

The primary goal of genetic studies in IBD is the identification and prioritization of mechanisms contributing to expression of clinical disease. The identification of key pathogenic mechanisms will serve to prioritize development of new therapeutic approaches in IBD. The plethora of murine genetic models of IBD1 (Table 1) shows the broad variety of very different mechanisms by which an IBD-like phenotype can result. The complex and delicate balance required to maintain intestinal homeostasis

Murine Genetic Models Relevant to IBD

An extensive and growing number of animal studies have contributed to establishing the mechanistic bases for our current understanding of IBD pathogenesis. Mouse models with induced or spontaneous mutations in a diversity of genes have established the complex interrelationships that control the lifelong host response to the intestinal microbiota and have identified a number of pathways that can lead to IBD.1 With few exceptions, these models implicate a dysregulated dialogue between the

Naturally Occurring Human Genetic Variation

The comprehensive sequencing and characterization of genetic variation in humans and other species has provided an enormous wealth of biologic information.8 Recent studies estimate the presence of 25,000 genes contained within 3 billion DNA nucleotides.9 Naturally occurring interindividual variations in DNA sequences include large-scale copy number polymorphisms (variations in the number of copies of a given DNA sequence), repetitive sequences of varying length, a variety of insertions and

IBD Genetics Before the GWA Era

Efforts to identify IBD susceptibility alleles before the advent of GWA studies involved focused candidate gene studies combined with fine-mapping efforts in regions of genetic linkage (demonstrations of increased genomic sharing between multiple, close relatives sharing a disease).23 The candidate gene approach resulted in well-replicated associations of IBD with various major histocompatibility complex class II associations.24 The NOD2 association with CD10, 11 was preceded by the

GWA Studies in IBD

Progress from the Human Genome Project and HapMap Project, combined with markedly decreasing genotyping costs, has made possible the performance of adequately powered GWA studies in complex genetic disorders such as IBD. The capacity to detect association to an (untyped) susceptibility variant by genotyping a neighboring marker will be proportionate to the r2 value (measure of linkage disequilibrium, or correlation) between the susceptibility allele and genotyped marker. In European ancestry

Emerging Themes in IBD Genetics and Future Directions

Significant recent progress in the genetics of IBD has fundamentally advanced understanding of disease pathogenesis. A unique feature of the intestinal immune system is its close apposition to high concentrations of luminal bacteria. The initial association of the NOD2 gene clearly established that altered host responses in intracellular bacterial processing contribute to CD pathogenesis. This theme has been advanced with the report of CD associations with the ATG16L1 gene and IRGM gene region,

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      These genetic factors are mainly linked to CD but also in UC immune related genes play an important role. Some of the associated genes, such as IL-23R, IL-12B, STAT3, MHC, NKX2-3 and MST-1, are even shared between these two diseases (Abraham and Cho, 2009; Cho and Weaver, 2007). Patients with IBD are at higher risk to develop other immune related disorders (Bernstein et al., 2005), emphasizing the importance of the immune system in disease onset and the further course.

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      The relative risk of first-degree relatives developing IBD is fivefold or greater.6 Some genes may be common to both diseases, as cases of CD and UC can occur within the same family.7 Earlier disease onset in children of parents (genetic anticipation) occurs in both diseases but the tendency is stronger in UC.8,9

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    Supported by grants R01DK072373, U01 DK62429, and U01 DK062422 and Burroughs Wellcome Translational Research Award (all to J. H. C.), as well as grants U19 AI056542, PO1 DK071167, R24 DK064400, RO1 AI057956, and RO1 AI035783 (all to C. T. W.) and the Crohn’s and Colitis Foundation of America (C. T. W.).

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