Inflammatory Bowel Disease, Genetics of

Charles W Lees, University of Edinburgh, Edinburgh, UK
Gwo‐Tzer Ho, University of Edinburgh, Edinburgh, UK
Jack Satsangi, University of Edinburgh, Edinburgh, UK

Published online: September 2007

DOI: 10.1002/9780470015902.a0020220

Genetic studies of the chronic inflammatory bowel diseases, Crohn disease (CD) and ulcerative colitis (UC), represent a paradigm for complex disease genetics having seen several notable breakthroughs. Indeed, the discovery of NOD2/CARD15 as a CD susceptibility gene in 2001 was the first in a complex genetic disorder. In this review, we detail the genetic epidemiology in inflammatory bowel disease, genome-wide linkage and association studies, and candidate genes highlighting the insights they have provided into disease pathogenesis and therapeutics.

Keywords: inflammatory bowel disease; Crohn disease; ulcerative colitis; CARD15; IL-23R; ATG16L1

Figure 1. Model of pathogenesis of inflammatory bowel disease. UC, ulcerative colitis; IBD, inflammatory bowel disease; CD, Crohn disease. UC and CD can be thought of as overlapping syndromes sharing some phenotypes, and additionally sharing some genetic and environmental susceptibility and modifying stimuli. However, some phenotypic features and environmental/genetic factors are specific to one or other disorder.
Figure 2. Map of susceptibility loci.
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 References
    Achkar JP, Dassopoulos T, Silverberg MS et al. (2006) Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus. American Journal of Gastroenterology 101(3): 572–580.
    Ahmad T, Armuzzi A, Bunce M et al. (2002) The molecular classification of the clinical manifestations of Crohn's disease. Gastroenterology 122(4): 854–866.
    van Bodegraven AA, Curley CR, Hunt KA et al. (2006) Genetic variation in Myosin IXB is associated with ulcerative colitis. Gastroenterology 131(6): 1768–1774.
    Cavanaugh J (2001) International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. American Journal of Human Genetics 68(5): 1165–1171.
    Daly MJ, Rioux JD, Schaffner SF et al. (2001) High-resolution haplotype structure in the human genome. Nature Genetics 29(2): 229–232.
    Duerr RH, Taylor KD, Brant SR et al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314(5804): 1461–1463.
    Fellermann K, Stange DE, Schaeffeler E et al. (2006) A chromosome 8 gene-cluster polymorphism with low human -defensin 2 gene copy number predisposes to Crohn disease of the colon. American Journal of Human Genetics 79(3): 439–448.
    Hampe J, Cuthbert A, Croucher PJ et al. (2001) Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 357(9272): 1925–1928.
    Hampe J, Franke A, Rosenstiel P et al. (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genetics 39(2): 207–211.
    Hampe J, Schreiber S, Shaw SH et al. (1999) A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort. American Journal of Human Genetics 64(3): 808–816.
    van Heel DA, Fisher SA, Kirby A et al. (2004) Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs. Human Molecular Genetics 13(7): 763–770.
    van Heel DA, Ghosh S, Butler M et al. (2005) Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. Lancet 365(9473): 1794–1796.
    Ho GT, Soranzo N, Nimmo ER et al. (2006) ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis: discrimination of critical variants using a gene-wide haplotype tagging approach. Human Molecular Genetics 15(5): 797–805.
    Hue S, Ahern P, Buonocore S et al. (2006) Interleukin-23 drives innate and T cell-mediated intestinal inflammation. Journal of Experimental Medicine 203(11): 2473–2483.
    Hugot JP, Chamaillard M, Zouali H et al. (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411(6837): 599–603.
    Hugot JP, Laurent-Puig P, Gower-Rousseau C et al. (1996) Mapping of a susceptibility locus for Crohn's disease on chromosome 16. Nature 379(6568): 821–823.
    Kobayashi KS, Chamaillard M, Ogura Y et al. (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307(5710): 731–734.
    Kullberg MC, Jankovic D, Feng CG et al. (2006) IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. Journal of Experimental Medicine 203(11): 2485–2494.
    Langmann T, Moehle C, Mauerer R et al. (2004) Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes. Gastroenterology 127(1): 26–40.
    Maeda S, Hsu LC, Liu H et al. (2005) Nod2 mutation in Crohn's disease potentiates NF-B activity and IL-1 processing. Science 307(5710): 734–738.
    Noble CL, Nimmo ER, Drummond H et al. (2005) The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn's disease. Gastroenterology 129(6): 1854–1864.
    Ogura Y, Bonen DK, Inohara N et al. (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411(6837): 603–606.
    Parkes M, Barmada MM, Satsangi J et al. (2000) The IBD2 locus shows linkage heterogeneity between ulcerative colitis and Crohn disease. American Journal of Human Genetics 67(6): 1605–1610.
    Peltekova VD, Wintle RF, Rubin LA et al. (2004) Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nature Genetics 36(5): 471–475.
    Reinhard C and Rioux JD (2006) Role of the IBD5 susceptibility locus in the inflammatory bowel diseases. Inflammatory Bowel Diseases 12(3): 227–238.
    Rioux JD, Daly MJ, Silverberg MS et al. (2001) Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nature Genetics 29(2): 223–228.
    Rioux JD, Silverberg MS, Daly MJ et al. (2000) Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. American Journal of Human Genetics 66(6): 1863–1870.
    Sartor RB (2006) Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis. Nature Clinical Practice Gastroenterology and Hepatology 3(7): 390–407.
    Satsangi J, Parkes M, Louis E et al. (1996a) Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nature Genetics 14(2): 199–202.
    Satsangi J, Welsh KI, Bunce M et al. (1996b) Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet 347(9010): 1212–1217.
    Stokkers PC, Reitsma PH, Tytgat GN and van Deventer SJ et al. (1999) HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis. Gut 45(3): 395–401.
    Tysk C, Lindberg E, Jarnerot G et al. (1988) Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 29(7): 990–996.
    Wehkamp J, Salzman NH, Porter E et al. (2005) Reduced paneth cell -defensins in ileal Crohn's disease. Proceedings of the National Academy of Sciences of the USA 102(50): 18129–18134.
    Yamazaki K, McGovern D, Ragoussis J et al. (2005) Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease. Human Molecular Genetics 14(22): 3499–3506.

Related Sub-Topics:

Cytokines | Inflammation | Major Histocompatibility Complex | Molecular Genetics of Common and Complex Disease | Linkage Analysis | Gene Mapping by Disease Association
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Article Title: Inflammatory Bowel Disease, Genetics of
 
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Lees, Charles W, Ho, Gwo‐Tzer, and Satsangi, Jack(Sep 2007) Inflammatory Bowel Disease, Genetics of. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020220]