The genetics of inflammatory bowel disease

Abstract

Recent epidemiological, clinical and molecular studies have provided strong evidence that inherited predisposition is important in the pathogenesis of chronic inflammatory bowel diseases. The model most consistent with the epidemiological data suggests that Crohn’s disease and ulcerative colitis are related polygenic diseases, sharing some but not all susceptibility genes. Investigators throughout the world have applied the complementary techniques of genome‐wide scanning and candidate gene analysis. Four areas of linkage have been widely replicated on chromosomes 16 (IBD1), 12 (IBD2), 6 (IBD3—the HLA region), and most recently on chromosome 14. Fine mapping of these regions is underway. Of the ‘positional’ candidate genes, most attention has centred on the genes of the major histocompatibility complex. Genes within this region may determine disease susceptibility, behaviour, complications and response to therapy. Hope continues that studies of inflammatory bowel disease genetics will provide fresh insight into disease pathogenesis and soon deliver clinical applications.

Deficiency in Expression of the Signaling Protein Sin/Efs Leads to T-Lymphocyte Activation and Mucosal Inflammation

“…Similar to our Sin-deficient animals, the histopathology of mucosal inflammation in the SAMP/Yit mice is characterized by chronic inflammation, villus infiltration by CD3 ϩ T cells, crypt enlargement, and changes in epithelial cell architecture (25). Interestingly, recent human linkage studies have identified a particular region on chromosome 14, q11.2-12, which correlates with Crohn's disease development and is designated as the inflammatory bowel disease 4 (IBD4) locus (1,12,22,24,44,45). The sin/efs genomic locus also localizes in region 14q11.2-12 in close proximity to the IBD4 locus, raising the possibility that Sin plays a role in the development of a Crohn's disease-related enteropathy.…”

Human keratin 8 mutations that disturb filament assembly observed in inflammatory bowel disease patients

“…The most prominent characteristic of these disorders is a dysregulated or escalated inflammatory response, which is probably triggered by excessive entry of foreign antigens into the connective tissue underlying the intestinal epithelium, and leading to inflammation and tissue breakdown. Some candidate molecules involved in this inflammatory response arm of the disease have been implicated by genetics (de la Concha et al, 2000) and recently one gene has been identified convincingly as CARD15/NOD2 (Hugot et al, 2001;Lesage et al, 2002;Ogura et al, 2001), mutated in 50% of patients in some populations with Crohn disease in the ileum (Ahmad et al, 2001). The inflammatory aspect of the disease is, however, augmented, or possibly preceded (Irvine and Marshall, 2000), by increased permeability in the intestinal epithelium.…”

The genetic jigsaw of inflammatory bowel disease

“…[7][8][9] These data supplement a number of studies carried out in Europe and the United States which show a high prevalence of familial inflammatory bowel disease in relatives of patients with Crohn's disease and ulcerative colitis. 10 The study by Tysk et al of the Swedish registry of twin births 7 catalysed the epidemiological, clinical, and subsequently molecular genetic studies into inflammatory bowel disease genetics, which have taken place since its publication in 1988. The data reported by the Swedish group have been closely replicated by the investigators in Great Britain 9 and Denmark.…”