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  • Review Article
  • Published:

The genetics and immunopathogenesis of inflammatory bowel disease

Nature Reviews Immunology volume 8, pages 458–466 (2008)Cite this article

Key Points

  • The central challenge of the intestinal immune system is balancing the need to respond to pathogens while co-existing with commensal bacteria and food antigens. Data from genome-wide association (GWA) studies support the concept that dysregulation of the normally controlled immune responses to commensal gut bacteria in a genetically susceptible individual drives the development of inflammatory bowel disease.

  • GWA studies provide a broad view of the relative contributions of various genomic loci to common human diseases and involve genotyping a large number of single-nucleotide polymorphisms (SNPs) that sample human genetic variation throughout the genome.

  • Crohn's disease, but not ulcerative colitis, is associated with functional polymorphisms in the NOD2 (nucleotide-binding oligomerization domain protein 2), ATG16L1 (autophagy related 16-like protein 1) and IRGM (immunity-related GTPase family, M) gene regions. These genes have been implicated in the innate immune system and intracellular processing of bacterial components.

  • Crohn's disease-associated polymorphisms in NOD2 are associated with a decreased ability of the NOD2 protein to appropriately sense bacterial peptidoglycan and activate nuclear factor-κB and mitogen-activated protein kinase pathways. Further studies assessing the altered function of ATG16L1 and IRGM polymorphisms associated with Crohn's disease will be important in establishing the extent to which Crohn's disease occurs as a result of a primary defect in bacterial sensing by the innate immune system.

  • Consistent with previous epidemiological observations, several genes are associated with both Crohn's disease and ulcerative colitis, notably IL23R (encoding interleukin-13 receptor), IL12B (encoding the p40 subunit for IL-12 and IL-23) and STAT3 (encoding signal transducer and activator of transcription 3), all of which are involved in IL-23R signalling. The homeodomain-containing transcription factor NKX2-3 (NK2 transcription factor related, locus 3), which is involved in lymphocyte development, differentiation and organization, is also associated with both Crohn's disease and ulcerative colitis.

  • Within the IL23R gene region, there are multiple independent signals showing association with inflammatory bowel disease and similar patterns of association have been observed in psoriasis and ankylosing spondylitis. The contributions of the IL23R region polymorphisms to intestinal inflammation are complex, reflecting contributions from both the innate and adaptive immune systems.

Abstract

Genome-wide association studies efficiently and powerfully assay common genetic variation. The application of these studies to Crohn's disease has provided insight into the immunopathogenesis of this disease, implicating a role for genes of the innate and adaptive immune systems. In this Review, I discuss our current understanding of the genetics and immunopathogenesis of Crohn's disease and ulcerative colitis. Crohn's disease, but not ulcerative colitis, is associated with genetic variation in NOD2 and an autophagy gene, ATG16L1, both of which affect the intracellular processing of bacterial components. By contrast, variation in the gene encoding the interleukin-23 (IL-23) receptor subunit, as well as in the IL12B, STAT3 and NKX2-3 gene regions, is associated with both Crohn's disease and ulcerative colitis. Comparative analyses of gene associations between these two inflammatory bowel diseases reveal common and unique mechanisms of their immunopathogenesis.

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Figure 1: Key features of the intestinal immune system.
Figure 2: Variation in multiple genes in the IL-23R pathway is associated with Crohn's disease.

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Acknowledgements

The support of NIDDK (U01 DK62429, U01 DK62422, R01 DK072373), the Burroughs Wellcome Foundation, CCFA, Broad Medical Research Foundation and the CTSA are gratefully acknowledged.

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  1. Inflammatory Bowel Disease Center, Section of Digestive Diseases, Yale University, 333 Cedar Street, LMP 1080, New Haven, 06520, Connecticut, USA

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Glossary

Arthalgias

Pain in the joints that may or may not be associated with inflammatory changes.

Gut lamina propria

The layer of mucosal tissue directly under the mucosal epithelial-cell surface of the gastrointestinal tract, in which effector immune cells for mucosal immunity reside.

Goblet cells

Mucus-producing cells found in the epithelial-cell lining of the intestine and lungs.

Crypts

Tubular invaginations of the intestinal epithelium. At the base of the crypts, there are Paneth cells, which produce bactericidal defensins, and stem cells, which continuously divide and are the source of all intestinal epithelial cells.

Defensins

A family of proteins exhibiting bactericidal properties. They are secreted by immune cells (particularly neutrophils), intestinal Paneth cells and epithelial cells.

Single-nucleotide polymorphisms

(SNPs). Bi-allelic (typically) base-pair substitutions, which are the most common forms of genetic polymorphism.

HapMap

A catalogue of common genetic variants that occur in humans. It describes what these variants are, where they occur in our DNA, and how they are distributed among people within populations and among populations in different parts of the world.

Minor allele frequency

The allelic frequency of the less common of the two alleles. Most single base-pair substitutions have only two alleles (bi-allelic).

Causal variant

A genetic polymorphism that directly exerts an effect on protein function and/or expression that is believed to underlie the observed statistical association.

Concordance

The occurrence of the same trait in both members of a pair of twins. Concordance might occur for diseases as well as for behaviours, such as smoking.

Autophagy

Any process involving degradative delivery of a portion of the cytoplasm to the lysosome that does not involve direct transport through the endocytic or vacuolar protein sorting pathways.

Meta-analysis

A statistical approach that combines results from multiple related studies to define a composite effect. When applied to genome-wide association studies, increased power to identify more modest association effects accrue.

Odds ratio

A measurement of association that is commonly used in case-control studies. It is defined as the odds of exposure to the susceptible genetic variant in individuals with disease compared with that in controls. If the odds ratio is significantly greater than one, then the genetic variant is associated with the disease.

Compound heterozygous

Two distinct, recessive alleles that combine to exert effects similar to a homozygous recessive mutation state.

Hygiene hypothesis

The theory that the lack of early childhood exposure to infectious agents, symbiotic microorganisms (for example, changes in gut microflora) and parasites increases susceptibility to allergic and autoimmune diseases by modulating immune system development.

Haplotype block

A chromosomal region in which groups of alleles at different genetic loci are inherited together more often than expected by chance.

Linkage disequilibrium

The non-random association of alleles from two independent loci, owing to their close physical proximity and a lack of recombination between them.

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Cho, J. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol 8, 458–466 (2008). https://doi.org/10.1038/nri2340

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