Review Article | Published:

Genetics of Crohn disease, an archetypal inflammatory barrier disease


Chronic inflammatory disorders such as Crohn disease, atopic eczema, asthma and psoriasis are triggered by hitherto unknown environmental factors that function on the background of some polygenic susceptibility. Recent technological advances have allowed us to unravel the genetic aetiology of these and other complex diseases. Using Crohn disease as an example, we show how the discovery of susceptibility genes furthers our understanding of the underlying disease mechanisms and how it will, ultimately, give rise to new therapeutic developments. The long-term goal of such endeavours is to develop targeted prophylactic strategies. These will probably target the molecular interaction on the mucosal surface between the products of the genome and the microbial metagenome of a patient.

Key Points

  • The aetiology of Crohn disease, as an archetypal inflammatory barrier disease, involves inherited defects in several genes that maintain the integrity of barrier function.

  • CARD15 was identified as the first disease gene for Crohn disease; the main three variants identified all affect the ligand-binding domain of the NOD2 protein.

  • CARD15 variants confer an almost autosomal-recessive genetic effect that is much stronger than expected for a susceptibility gene in a polygenic condition.

  • Additional disease genes (SLC22A4, SLC22A5 and DLG5) that have small odds ratios have been identified, but their involvement remains to be confirmed in independent samples.

  • The function of variability in susceptibility genes that leads to disease might be understood by studying evolutionary control.

  • Epidemiological trigger factors for inflammatory barrier diseases might interact with genetic susceptibility on the individual level through alterations of the human flora on body surfaces.

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The authors would like to acknowledge support from the FP5 Program of the European Commission, Nationales Genomforschungsnetz, Competence Network for Chronic Inflammatory Bowel Disease, Deutsche Forschungsgemeinschaft and Mucosaimmunologie Gemeinnützige Forschungsgesellschaft mbH. S. Nikolaus, S. Ott and T. Lengauer are gratefully acknowledged for their discussion and helpful comments.

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Correspondence to Stefan Schreiber.

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Genetic loci or chromosomal regions that contribute to variability in complex quantitative traits (such as plant height or body weight). Quantitative traits are typically affected by several genes and by the environment.


The claim that the genetic factors predisposing to, or associated with, a disease of high prevalence should also be frequent in the same population.


Granulomatous relapsing inflammatory disease that mainly affects the lung.


The ratio between the odds of an event occurring in two different groups (for example, exposed and non-exposed).


(TDT). This compares the rates of transmission and non-transmission of a given allele or haplotype from parents with one copy of the allele or haplotype in question to their affected offspring. The TDT is robust against population stratification.


A particular form of confounding in which a genetic variant is associated with a true disease risk factor that varies in frequency between population strata (ethnic, geographical or social).


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


The mixture of two or more genetically distinct populations.


(LD). Deviation of the observed population frequency of haplotypes from the expected under a model of independent segregation. LD is not stable across the genome; that is, areas of high internal LD ('LD blocks') contrast with regions of low LD.


Pathogen-associated molecular pattern receptor — named for a group of proteins with broad specificities, which is often anchored in lipid or glycostructures of pathogens.


Cytokines that induce movement of responsive (immune) cells ('chemotaxis') following the concentration gradient of the mediator.


Secretory cells with a coarsely granular structure found in the basal regions of crypts in the small intestine. The intense expression of bactericidal peptides (cryptdins (murine) or defensins (human), respectively) points to an important role in host defence.


The most abundant type of granular leukocyte.


A class of immunoglobulin protein that is determined by the constant region of the IgH gene that is placed nearest to the joining segments. The isotype can switch during maturation of the B cell.


A mechanism used by many bacterial pathogens and mutualists to detect crucial bacterial cell numbers in host tissues. Cell densities are indicated by the concentration on autoinducers, which regulate the expression of specific genes.


Biofilms result from the growth of microbes on surfaces. Bacteria produce extracellular substances that become part of the glycocalyx and provide contact between microorganisms and to the surface.


Non-pathogenic microorganisms that live on or within the human organism. They derive a benefit without resulting in injury or a benefit to the host.


Living bacteria that result in health benefits after ingestion.


A site of chronic inflammation that is usually triggered by persistent infectious agents or foreign substances. Granulomas are typical for mycobacterial diseases.

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Figure 1: Clustering of linkage regions and disease genes in human inflammatory barrier disease.
Figure 2: Domain architectures of selected CATERPILLER-related gene products from different eukaryotes.
Figure 3: NOD2 function and the intestinal epithelial barrier.
Figure 4: Variation in CATERPILLER genes contributes to gene plasticity and gives rise to various autoimmune diseases.
Figure 5: A mechanism for generating plasticity of barrier gene function: complex regulation of CATERPILLER gene function.