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Crohn disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD), are idiopathic, lifelong, chronic inflammatory conditions of the gastrointestinal (GI) tract, which typically manifest during late childhood or young adulthood. The physical and psychological burden of these chronic, relapsing diseases and their devastating effects may be considerable. CD and UC are grouped together in view of their many similarities in epidemiologic, genetic, immunologic, and clinical features. Diagnostic approaches are similar, but treatment approaches and prognoses differ.


IBD was recognized as a disease entity during the early 20th century, and the pathogenesis has been linked to a combination of genetic, environmental, and microbial factors. IBD is a disease of chronic gut inflammation. The most widely accepted theory of pathogenesis is that, in genetically susceptible individuals, an environmental trigger promotes a chronic, dysregulated immune response. The environmental trigger may be an infectious agent such as a commensal organism of the normal gut flora or possibly a ubiquitous environmental agent. Following activation of the response, it appears that the mechanisms that attenuate the response may be defective in some individuals with IBD. It is likely that IBD has several different, as yet unnamed, subtypes. These subtypes would each have different genetic and environmental triggers, but they all present with similar symptoms and signs.

CD is heritable, with specific genes associated with an increased risk of IBD. The comparative risk for CD in first-degree relatives is increased by up to 35 times, but the comparative risk for those of first-degree relatives of UC patients is approximately 3 times. Family history of IBD is present in less than 15% of patients with UC. Sibling-pair-based genome-wide linkage analyses showed a non–major histocompatibility complex (MHC) association at the NOD2 gene on chromosome 16. This NOD2 gene, further renamed caspase recruitment domain-containing protein 15 (CARD15), is only found in whites, indicating that genetic susceptibility may be related to populations. More recently, the application of genome-wide association scanning (GWAS) has identified about 200 confirmed loci to date. Notable findings are that of IL23R susceptibility, indicating involvement of the interleukin (IL)-12–IL-23 pathway and 2 separate autophagy genes, ATG16L1 and IRGM, that increase the CD risk, strongly implicating involvement of an innate immune mechanism for sequestration and control of intracellular bacteria in the pathogenic process.

Several genetic susceptibility loci for UC have been also identified, and most are in common with CD susceptibility. Loci common to both UC and CD include IL23R, IL12B, HLA, NKX2-3, MST1, CCNY, PTPN2, HERC2, STAT3, and 3p21.31. However, ECM1, IL10, IL26, and ARP2C are associated with UC but not CD. Identification of susceptibility haplotypes, causal variant(s) within these haplotypes, and functional consequences will be essential to unraveling the pathogenesis of IBD. By understanding the functional consequences of disease-associated alleles, new therapies ...

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