Genetics of inflammatory bowel diseases

Abstract

The inflammatory bowel diseases (IBD), Crohn disease and ulcerative colitis, are immune-mediated disorders resulting in chronic, relapsing inflammation of the gastrointestinal tract. While no specific etiology has been defined, the complex nature of IBD supports the notion that its origin is likely multi-factorial. Current theory suggests that in genetically predisposed individuals, environmental factors and maladaptive immune responses to gastrointestinal flora generate a dysregulated inflammatory cascade creating mucosal injury. Over the last decade, considerable interest and research has focused on the genetic aspect of IBD. The identification of linkage between Crohn disease and the pericentromeric region of chromosome 16 (IBD1) by Hugot in 1996, spawned a series of genome scans and linkage analyses in search of susceptibility and phenotypic modifier genes [1]. In 2001, the discovery that specific polymorphisms in the CARD15/NOD2 gene at the IBD1 locus were associated with Crohn disease engendered a new era of genotype-phenotype investigations [2, 3]. The advent of genome-wide association studies has resulted in the successful identification of new, well-replicated disease associations. The heterogeneity of IBD phenotypes suggests that it is a polygenic disorder in which susceptibility loci act in epistasis with other disease-modifying genes and the environment to produce disease. The field of IBD genetics is of special interest to pediatric gastroenterologists for both practical and investigational reasons. From a clinical practice standpoint, pediatric gastroenterologists are often faced with questions from concerned parents regarding the risk of IBD among current or future siblings, as well as the eventual offspring of the affected child. Understanding genetic associations of IBD can provide patients and their families with useful information that may help them cope with the disease. Furthermore, as our knowledge of genotype-phenotype associations grows, it is anticipated that genotyping at the onset of disease may enable physicians to predict disease course and tailor medical therapies specific for each patient. In terms of advancing the field of gastroenterology through research, studies of pediatric IBD genetics are of significance because children have been exposed to fewer environmental confounders of disease than their adult counterparts. Examining the disease of young individuals could provide us with keys to unlock intrinsic genetic mechanisms in IBD that may not otherwise be detected in adult studies. This may be of special importance in individuals with very early onset IBD (< 5 years), whose disease course and phenotypes are the most discordant with those of adult-onset IBD. © 2008 Springer Science+Business Media, LLC. All rights reserved.