Reviews in basic and clinical gastroenterologyThe Genetics of Inflammatory Bowel Disease
Section snippets
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,
References (138)
- et al.
Cdcs1, a major colitogenic locus in mice, regulates innate and adaptive immune response to enteric bacterial antigens
Gastroenterology
(2005) - et al.
Identification of a quantitative trait locus for ileitis in a spontaneous mouse model of Crohn’s disease: SAMP1/YitFc
Gastroenterology
(2003) - et al.
Linkage to peroxisome proliferator-activated receptor-gamma in SAMP1/YitFc mice and in human Crohn’s disease
Gastroenterology
(2005) - et al.
Lack of common NOD2 variants in Japanese patients with Crohn’s disease
Gastroenterology
(2002) International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16
Am J Hum Genet
(2001)- et al.
Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection
J Biol Chem
(2003) - et al.
Host recognition of bacterial muramyl dipeptide mediated through NOD2Implications for Crohn’s disease
J Biol Chem
(2003) - et al.
Crohn’s disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan
Gastroenterology
(2003) - et al.
CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease
Am J Hum Genet
(2002) - et al.
Induction of Nod2 in myelomonocytic and intestinal epithelial cells via nuclear factor-kappa B activation
J Biol Chem
(2002)
The genetics of inflammatory bowel disease
Gastroenterology
Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis
Immunity
CARD15/NOD2 functions as an anti-bacterial factor in human intestinal epithelial cells
Gastroenterology
Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB
J Biol Chem
A role for Erbin in the regulation of Nod2-dependent NF-kappaB signaling
J Biol Chem
Centaurin beta1 down-regulates nucleotide-binding oligomerization domains 1- and 2-dependent NF-kappaB activation
J Biol Chem
GRIM-19 interacts with nucleotide oligomerization domain 2 and serves as downstream effector of anti-bacterial function in intestinal epithelial cells
J Biol Chem
Reciprocal cross-talk between Nod2 and TAK1 signaling pathways
J Biol Chem
The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn’s disease
Gastroenterology
IBD5 is a general risk factor for inflammatory bowel disease: replication of association with Crohn disease and identification of a novel association with ulcerative colitis
Am J Hum Genet
Association of organic cation transporter risk haplotype with perianal penetrating Crohn’s disease but not with susceptibility to IBD
Gastroenterology
A risk haplotype in the Solute Carrier Family 22A4/22A5 gene cluster influences phenotypic expression of Crohn’s disease
Gastroenterology
HLA class II haplotype associations with inflammatory bowel disease in Jewish (Ashkenazi) and non-Jewish caucasian populations
Hum Immunol
Interleukin-10-deficient mice develop chronic enterocolitis
Cell
Genetic variation in myosin IXB is associated with ulcerative colitis
Gastroenterology
IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease
Gastroenterology
Association of variants of the interleukin-23 receptor gene with susceptibility to pediatric Crohn’s disease
Clin Gastroenterol Hepatol
A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes
Am J Hum Genet
Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice
Gastroenterology
Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota
Immunol Rev
Mechanisms of disease: the hygiene hypothesis revisited
Nat Clin Pract Gastroenterol Hepatol
Defects in mucosal immunity leading to ulcerative colitis
Immunol Rev
A major quantitative trait locus on chromosome 3 controls colitis severity in IL-10-deficient mice
Proc Natl Acad Sci U S A
Initial sequencing and analysis of the human genome
Nature
Finishing the euchromatic sequence of the human genome
Nature
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease
Nature
A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease
Nature
Haplotype structure and association to Crohn’s disease of CARD15 mutations in two ethnically divergent populations
Eur J Hum Genet
Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn’s disease
J Hum Genet
Comparative phenotypic and CARD15 mutational analysis among African American, Hispanic, and White children with Crohn’s disease
Inflamm Bowel Dis
Discovering genotypes underlying human phenotypes: past successes for Mendelian disease, future approaches for complex disease
Nat Genet
The ENCODE (ENCyclopedia Of DNA Elements) Project
Science
Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
Nature
Mapping determinants of human gene expression by regional and genome-wide association
Nature
The International HapMap Project
Nature
Evaluating and improving power in whole-genome association studies using fixed marker sets
Nat Genet
Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease
Nat Genet
Genetic dissection of complex traits
Science
HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis
Gut
Mapping of a susceptibility locus for Crohn’s disease on chromosome 16
Nature
Cited by (145)
siRNA-based identification of IBD-related targets in human monocyte-derived dendritic cells
2021, Journal of Immunological MethodsCitation Excerpt :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.
An Update on Inflammatory Bowel Disease
2017, Primary Care - Clinics in Office PracticeCitation Excerpt :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
Gnotobiotics and Inflammatory Bowel Disease
2017, GnotobioticsMultiomics-empowered Deep Phenotyping of Ulcerative Colitis Identifies Biomarker Signatures Reporting Functional Remission States
2023, Journal of Crohn's and Colitis
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.).