Molecular Genetics of Crohn Disease

Jesús K Yamamoto‐Furusho, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico

Published online: March 2009

DOI: 10.1002/9780470015902.a0021483

Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, racial and ethnic differences in disease prevalence. Genome-wide linkage studies pointed towards more than 10 chromosomal regions and fine-mapping of these regions led to the identification of a number of genes, including CARD15 (NOD2, nucleotide oligomerization domain 2), Drosophila long disc homologue 5 gene (DLG5), OCTN1 and 2, TLR4 and CARD4 (NOD1). New genes have identified such as IL23R, immunity-related GTPase family M (IRGM), prostaglandin receptors E-serie 4 (PTGER4) and ATG16L1 for Crohn disease and ulcerative colitis. Genetic factors may influence in the clinical course of IBD patients and their likelihood of responding to certain therapies. Great progress in the understanding of the molecular genetics of IBD has been made over the last 10 years and newer genes are discovering to understand the IBD pathophysiology and to have implications for clinical practice.

Key concepts

  • Genetic factors play a significant role in determining inflammatory bowel disease susceptibility.
  • Characterization of the IBD1 locus on chromosome 16 led to the discovery of the NOD2/CARD15 gene as the first susceptibility gene in Crohn disease.
  • Genome-wide linkage studies pointed towards more than 10 chromosomal regions.
  • Genetic factors may influence in the clinical course of IBD patients and their likelihood of responding to certain therapies.

Keywords: genetics; IBD; molecular; CD; UC

 References
    Armuzzi A, Ahmad T, Ling KL et al. (2003) Genotype-phenotype analysis of the Crohn's disease susceptibility haplotype on chromosome 5q31. Gut 52: 1133–1139.
    Barrett JC, Hansoul S, Nicolae DL et al. (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature Genetics 40: 955–962.
    Bouma G, Xia B, Crusius JB et al. (1996) Distribution of four polymorphism in the tumour necrosis factor (TNF) genes in patients with inflammatory bowel disease (IBD). Clinical and Experimental Immunology 103: 391–396.
    Brant SR and Shugart YY (2004) Inflammatory bowel disease gene hunting by linkage analysis: rationale, methodology, and present status on the field. Inflammatory Bowel Diseases 10: 300–311.
    Cantor MJ, Nickerson P and Bernstein CN (2005) The role of cytokine gene polymorphisms in determining disease susceptibility and phenotype in inflammatory bowel disease. American Journal of Gastroenterology 100: 1134–1142.
    Cho JH (2008) The genetics and immunopathogenesis of inflammatory bowel disease. Nature Reviews in Immunology 8: 458–466.
    Cucchiara S, Latiano A, Palmeiri O et al. (2007) Polymorphisms of tumor necrosis factor- but not MDR1 influence response to medical therapy in pediatric-onset inflammatory bowel disease. Journal of Pediatrics Gastroenterology Nutrition 44: 171–179.
    De Jager PL, Franchimont D, Waliszewska A et al. (2007) The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. Genes Immunity 8: 387–397.
    Dresner-Pollak R, Ackerman Z, Eliakim R et al. (2004) The Bsml vitamin D receptor gene polymorphism is associated with ulcerative colitis in Jewish Ashkenazi patients. Genetic Testing 8: 417–420.
    Fell JM, Paintin M, Arnaud-Battandier F et al. (2000) Mucosal healing and a fall in mucosal pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric Crohn's disease. Alimentary Pharmacology and Therapeutics 14: 281–289.
    Franchimont D, Vermeire S, El Housni H et al. (2004) Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299Gly polymorphism is associated with Crohn's disease and ulcerative colitis. Gut 53: 987–992.
    Friedrichs F, Brescianini S, Annese V et al. (2006) Evidence of transmission ratio distortion of DLG5 R30Q variant in general and implication of an association with Crohn disease in men. Human Genetics 119: 305–311.
    Henckaerts L, Figueroa C, Vermeire S and Sans M (2008) The role of genetics in inflammatory bowel disease. Current Drug Targets 9: 361–368.
    Ho GT, Nimmo ER, Tenesa A et al. (2005) Gastrointestinal allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis. Gastroenterology 128: 288–296.
    Hugot JP, Chamaillard M, Zouali H et al. (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411: 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: 821–823.
    Klein W, Tromm A, Griga T et al. (2002) A polymorphism in the IL11 gene is associated with ulcerative colitis. Genes and Immunity 3: 494–496.
    Kobayashi KS, Chamaillard M, Ogura Y et al. (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307: 731–734.
    Lee HJ, Choi SC, Lee MH et al. (2005) Increased expression of MIP-3alpha/CCL20 in peripheral blood mononuclear cells from patients with ulcerative colitis and its down-regulation by sulfasalazine and glucocorticoid treatment. Inflammatory Bowel Diseases 11: 1070–1079.
    Leeb SN, Vogl D, Gunckel M et al. (2003) Reduced migration of fibroblasts in inflammatory bowel disease: role of inflammatory mediators and focal adhesion kinase. Gastroenterology 125: 1341–1354.
    Lodes MJ, Cong Y, Elson CO et al. (2004) Bacterial flagellin is a dominant antigen in Crohn disease. Infectious Immunity 113: 1296–1306.
    Louis E, Satsangi J, Roussomoustakaki M et al. (1996) Cytokine gene polymorphism in inflammatory bowel disease. Gut 39: 705–710.
    Ma Y, Ohmen JD, Li Z et al. (1999) A genome-wide search identifies potential new susceptibility loci for Crohn's disease. Inflammatory Bowel Diseases 5: 271–278.
    Mathew CG (2008) New links to the pathogenesis of Crohn disease provided by genome-wide association scans. Nature Reviews in Genetics 9: 9–14.
    McGovern DP, Hysi P, Ahmad T et al. (2005) Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease. Human Molecular Genetics 14: 1245–1250.
    McKaig BC, Hughes K, Tighe PJ and Mahida YR (2002) Differential expression of TGF-beta isoforms by normal and inflammatory bowel disease intestinal myofibroblasts. American Journal of Cell Physiology 282: 172–182.
    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: 1854–1864.
    Ogawa M, Yoshimori T, Suzuki T et al. (2005) Escape of intracellular Shigella from autophagy. Science 307: 727–731.
    Ogura Y, Bonen DK, Inohara N et al. (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411: 603–606.
    Owyang AM, Zaph C, Wilson EH et al. (2006) Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract. Journal of Experimental Medicine 203: 843–849.
    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 60: 1605–1610.
    Parkes M, Barrett JC, Prescott NJ et al. (2007) Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nature Genetics 39: 830–832.
    Peltekova VD, Wintle RF, Rubin LA et al. (2004) Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nature Genetics 36: 471–475.
    Pierik M, Joossens S, Van Oteen K et al. (2006) Toll-like receptor -1, -2 and -6 polymorphisms influence disease extension in inflammatory bowel diseases. Inflammatory Bowel Diseases 12: 1–8.
    Podolsky DK (2002) Inflammatory bowel disease. New England Journal of Medicine 347: 417–429.
    Raelson JV, Little RD, Ruether A et al. (2007) Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci. Proceedings of the National Academy of Sciences of the USA 104: 14747–14752.
    Satsangi J, Morecroft J, Shah NB and Nimmo E (2003) Genetics of inflammatory bowel disease: scientific and clinical implications. Best Practice Research Clinical Gastroenterology 17: 3–18.
    Satsangi J, Parkes M, Louis E et al. (1996) Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nature Genetics 14: 199–202.
    Simmons JD, Mullighan C, Welsh KI and Jewell DP (2000) Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility. Gut 47: 211–214.
    Stokkers PC, Reitsma PH, van Tytgat GN and Deventer SJ (1999) HLA-DR and DQ phenotypes in inflammatory bowel disease: a meta-analysis. Gut 45: 395–401.
    Stoll M, Corneliussen B, Costello CM et al. (2004) Genetic variation in DGL5 is associated with inflammatory bowel disease. Nature Genetics 36: 476–480.
    Takagawa T, Tamura K, Takeda N et al. (2005) Association between IL-18 gene promoter polymorphisms and inflammatory bowel disease in a Japanese population. Inflammatory Bowel Diseases 11: 1038–1043.
    Van Limbergen J, Russell RK, Nimmo ER and Satsangi J (2007) The genetics of inflammatory bowel disease. American Journal of Gastroenterology 102: 2820–2831.
    Vermeire S, Pierik M, Hlavaty T et al. (2005) Association of organic cation transporter risk haplotype with perianal penetrating Crohn's disease but not with susceptibility to IBD. Gastroenterology 129: 1845–1853.
    Vermiere S, Rutgeerts P, Van Steen K et al. (2004) Genome wide scan in Flemish inflammatory bowel disease population: support for the IBD4 locus, population heterogeneity and epistasis. Gut 53: 980–986.
    Yamamoto-Furusho JK, Cantú C, Vargas-Alarcón G et al. (1998) Complotype SC30 is associated with susceptibility to develop ulcerative colitis in Mexicans. Journal of Clinical Gastroenterology 27: 178–179.
    Yamamoto-Furusho JK, Uscanga LF, Vargas-Alarcón G et al. (2004) Polymorphisms in the promoter region of tumour necrosis factor alpha (TNF-) and the HLA-DRB1 locus in mexican mestizo patients with ulcerative colitis. Immunology Letters 95: 31–35.
    Yamamoto-Furusho JK, Uscanga LF, Vargas-Alarcón G et al. (2003) Clinical and genetic heterogeneity in Mexican patients with ulcerative colitis. Human Immunology 64: 119–123.
    Yamamoto-Furusho JK (2003) Inmunogenética de la colitis ulcerosa crónica inespecífica. Revista de Investigación Clinica 55: 705–710.
    Yen D, Cheung J, Scheerens H et al. (2006) IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. Journal of Clinical Investigation 116: 1310–1316.
 Further Reading
    Ahmad T, Marshall SE and Jewell D (2006) Genetics of inflammatory bowel disease: the role of the HLA complex. World Journal of Gastroenterology 12: 3628–3635.
    Annese V, Valvano MR, Palmieri O et al. (2006) Multidrug resistance 1 gene in inflammatory bowel disease: a meta-analysis. World Journal of Gastroenterology 2: 3636–3644.
    Dubinsky MC, Taylor K, Targan SR and Rotter JI (2006) Immunogenetic phenotypes in inflammatory bowel disease. World Journal of Gastroenterology 12: 3645–3650.
    Goyette P, Labbé C, Trinh TT, Xavier RJ and Rioux JD (2007) Molecular pathogenesis of inflammatory bowel disease: genotypes, phenotypes and personalized medicine. Annals of Medicine 39: 177–199.
    Shugart YY, Silverberg MS, Duerr RH et al. (2008) An SNP linkage scan identifies significant Crohn's disease loci on chromosomes 13q13.3 and, in Jewish families, on 1p35.2 and 3q29. Genes Immunity 9: 161–167.
    Vermeire S (2006) Review article: genetic susceptibility and application of genetic testing in clinical management of inflammatory bowel disease. Alimentary Pharmacology and Therapeutics 3: 2–10.
    Weersma RK, van Dullemen HM, van der Steege G et al. (2007) Review article: inflammatory bowel disease and genetics. Alimentary Pharmacology and Therapeutics 2: 57–65.
    Xavier RJ and Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448: 427–434.
    Xavier RJ and Rioux JD (2008) Genome-wide association studies: a new window into immune-mediated diseases. Nature Reviews Immunology 8: 631–643.
    Yamamoto-Furusho JK (2007) Genetic factors associated with the development of inflammatory bowel disease. World Journal of Gastroenterology 13: 5594–5597.

Related Sub-Topics:

Inflammation | Innate Immunity | Molecular Genetics of Common and Complex Disease | Techniques and Tools in Clinical Genetics | Linkage Analysis | Gene Mapping by Disease Association
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Molecular Genetics of Crohn Disease
 
How to Cite close
Yamamoto‐Furusho, Jesús K(Mar 2009) Molecular Genetics of Crohn Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021483]