Skip to main content

Advertisement

SpringerLink
Log in

Advances in the genetics of inflammatory bowel disease

  • Published:
Current Gastroenterology Reports Aims and scope Submit manuscript

Abstract

Research efforts in the inflammatory bowel diseases have been uniquely successful in identifying genetic linkage regions likely containing susceptibility genes for Crohn’s disease and ulcerative colitis. In two of these regions, definitive gene associations have been established, namely for the NOD2/ CARD 15 gene on chromosome 16 (IBD1) and the OCTN1/ SLC22A4-OCT/SLC22A5 genes on chromosome 5q (IBD5), both conferring increased risk for developing Crohn’s disease. Recently, significant gene associations have been reported for additional genes, including DLG5, MDR1, and TLR4 as well. The NOD2/CARD15 gene mutations are associated with ileal disease location and a modestly earlier age of onset compared with NOD2/CARD15 wild-type Crohn’s disease patients. Future progress in the genetics of inflammatory bowel disease will likely involve systematic phenotyping, including the incorporation of clinical subtypes and novel biomarkers. The ultimate goal of genetic research in inflammatory bowel disease is to identify the earliest biologic pathways that are altered, resulting in disease pathogenesis. Identification of these key pathways will potentially highlight novel therapeutic targets.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Tysk C, Lindberg E, Jarnerot G, et al.: 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 1988, 29:990–996.

    PubMed  CAS  Google Scholar 

  2. Thompson NP, Driscoll R, Pounder RE, et al.: Genetics versus environment in inflammatory bowel disease: results of a British twin study. BMJ 1996, 312:95–96.

    PubMed  CAS  Google Scholar 

  3. Subhani J MS, Ounder RE, Wakefield AJ: Concordance rates of twins and siblings in inflammatory bowel disease. Gut 1998, 42(Suppl 1):A40.

    Google Scholar 

  4. Orholm M, Binder V, Sorensen TI, et al.: Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol 2000, 35:1075–1081.

    Article  PubMed  CAS  Google Scholar 

  5. Online Mendelian Inheritance in Man. http:// www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

  6. Hugot JP, Laurent-Puig P, Gower-Rousseau C, et al.: Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature 1996, 379:821–823.

    Article  PubMed  CAS  Google Scholar 

  7. Satsangi J, Parkes M, Louis E, et al.: Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet 1996, 14:199–202.

    Article  PubMed  CAS  Google Scholar 

  8. Cho JH, Nicolae DL, Gold LH, et al.: Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1. Proc Natl Acad Sci U S A 1998, 95:7502–7507.

    Article  PubMed  CAS  Google Scholar 

  9. Hampe J, Shaw SH, Saiz R, et al.: Linkage of inflammatory bowel disease to human chromosome 6p. Am J Hum Genet 1999, 65:1647–1655.

    Article  PubMed  CAS  Google Scholar 

  10. Rioux JD, Silverberg MS, Daly MJ, et al.: Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet 2000, 66:1863–1870.

    Article  PubMed  CAS  Google Scholar 

  11. Duerr RH, Barmada MM, Zhang L, et al.: High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q11-12. Am J Hum Genet 2000, 66:1857–1862.

    Article  PubMed  CAS  Google Scholar 

  12. Ma Y, Ohmen JD, Li Z, Bentley et al.: A genome-wide search identifies potential new susceptibility loci for Crohn’s disease. Inflamm Bowel Dis 1999, 5:271–278.

    Article  PubMed  CAS  Google Scholar 

  13. Hugot JP, Chamaillard M, Zouali H, et al.: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001, 411:599–603. Initial report of the association of NOD2/CARD15 variants with Crohn’s disease.

    Article  PubMed  CAS  Google Scholar 

  14. Ogura Y, Bonen DK, Inohara N, et al.: A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001, 411:603–606. Initial report of the association of NOD2/CARD15 variants with Crohn’s disease and demonstration that the Crohn’s disease mutations are associated with a decreased capacity to activate NFкB.

    Article  PubMed  CAS  Google Scholar 

  15. Hampe J, Cuthbert A, Croucher PJ, et al.: Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 2001, 357:1925–1928.

    Article  PubMed  CAS  Google Scholar 

  16. Rioux JD, Daly MJ, Silverberg MS, et al.: Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001, 29:223–228.

    Article  PubMed  CAS  Google Scholar 

  17. Peltekova VD, Wintle RF, Rubin LA, et al.: Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat Genet 2004, 36:471–475. Characterization of functional variants within the OCTN1/SLC22A4 and OCTN2/SLC22A5 genes that likely account for the Crohn’s disease association observed in the 5q31 region.

    Article  PubMed  CAS  Google Scholar 

  18. van Heel DA, Fisher SA, Kirby A, et al.: Inflammatory bowel disease susceptibility loci defined by genome scan metaanalysis of 1952 affected relative pairs. Hum Mol Genet 2004, 13:763–770.

    Article  PubMed  CAS  Google Scholar 

  19. Ogura Y, Inohara N, Benito A, et al.: Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 2001, 276:4812–4818.

    Article  PubMed  CAS  Google Scholar 

  20. Lala S, Ogura Y, Osborne C, et al.: Crohn’s disease and the NOD2 gene: a role for paneth cells. Gastroenterology 2003, 125:47–57.

    Article  PubMed  CAS  Google Scholar 

  21. Lesage S, Zouali H, Cezard JP, et al.: CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 2002, 70:845–857.

    Article  PubMed  CAS  Google Scholar 

  22. Mathew CG, Lewis CM: Genetics of inflammatory bowel disease: progress and prospects. Hum Mol Genet 2004, 13 Spec No 1:R161–168.

    Article  PubMed  CAS  Google Scholar 

  23. Bonen DK, Ogura Y, Nicolae DL, et al.: Crohn’s diseaseassociated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan. Gastroenterology 2003, 124:140–146.

    Article  PubMed  CAS  Google Scholar 

  24. Sugimura K, Taylor KD, Lin YC, et al.: A novel NOD2/CARD15 haplotype conferring risk for Crohn disease in Ashkenazi Jews. Am J Hum Genet 2003, 72:509–518.

    Article  PubMed  CAS  Google Scholar 

  25. Inoue N, Tamura K, Kinouchi Y, et al.: Lack of common NOD2 variants in Japanese patients with Crohn’s disease. Gastroenterology 2002, 123:86–91.

    Article  PubMed  CAS  Google Scholar 

  26. Bonen DK, Nicolae DL, Moran T, et al.: Racial differences in NOD2 variation: characterization of NOD2 in African-Americans with Crohn’s disease [abstract]. Gastroenterology 2002, 122 (Suppl):A-29.

    Google Scholar 

  27. Weiss B, Shamir R, Bujanover Y, et al.: NOD2/CARD15 mutation analysis and genotype-phenotype correlation in Jewish pediatric patients compared with adults with Crohn’s disease. J Pediatr 2004, 145:208–212.

    Article  PubMed  CAS  Google Scholar 

  28. Ahmad T, Armuzzi A, Bunce M, et al.: The molecular classification of the clinical manifestations of Crohn’s disease. Gastroenterology 2002, 122:854–866.

    Article  PubMed  CAS  Google Scholar 

  29. Vermeire S, Louis E, Rutgeerts P, et al.: NOD2/CARD15 does not influence response to infliximab in Crohn’s disease. Gastroenterology 2002, 123:106–111.

    Article  PubMed  CAS  Google Scholar 

  30. Ferreiros-Vidal I, Barros F, Pablos JL, et al.: CARD15/NOD2 analysis in rheumatoid arthritis susceptibility. Rheumatology (Oxford) 2003, 42:1380–1382.

    Article  CAS  Google Scholar 

  31. Ferreiros-Vidal I, Garcia-Meijide J, et al.: The three most common CARD15 mutations associated with Crohn’s disease and the chromosome 16 susceptibility locus for systemic lupus erythematosus. Rheumatology (Oxford) 2003, 42:570–574.

    Article  CAS  Google Scholar 

  32. Nair RP, Stuart P, Ogura Y, et al.: Lack of association between NOD2 3020InsC frameshift mutation and psoriasis. J Invest Dermatol 2001, 117:1671–1672.

    Article  PubMed  CAS  Google Scholar 

  33. Rahman P, Bartlett S, Siannis F, et al.: CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. Am J Hum Genet 2003, 73:677–681.

    Article  PubMed  CAS  Google Scholar 

  34. Giardina E, Novelli G, Costanzo A, et al.: Psoriatic arthritis and CARD15 gene polymorphisms: no evidence for association in the Italian population. J Invest Dermatol 2004, 122:1106–1107.

    Article  PubMed  CAS  Google Scholar 

  35. Peeters H, Vander Cruyssen B, Laukens D, et al.: Radiological sacroiliitis, a hallmark of spondylitis, is linked with CARD15 gene polymorphisms in patients with Crohn’s disease. Ann Rheum Dis 2004, 63:1131–1134.

    Article  PubMed  CAS  Google Scholar 

  36. Inohara N, Ogura Y, Fontalba A, et al.: Host recognition of bacterial muramyl dipeptide mediated through NOD2: implications for Crohn’s disease. J Biol Chem 2003, 278:5509–5512.

    Article  PubMed  CAS  Google Scholar 

  37. Girardin SE, Boneca IG, Viala J, et al.: Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 2003, 278:8869–8872.

    Article  PubMed  CAS  Google Scholar 

  38. Korzenik JR, Dieckgraefe BK: Is Crohn’s disease an immunodeficiency? A hypothesis suggesting possible early events in the pathogenesis of Crohn’s disease. Dig Dis Sci 2000, 45:1121–1129.

    Article  PubMed  CAS  Google Scholar 

  39. Erdman S, Fox JG, Dangler CA, et al.: Typhlocolitis in NFkappa B-deficient mice. J Immunol 2001, 166:1443–1447.

    PubMed  CAS  Google Scholar 

  40. Hisamatsu T, Suzuki M, Reinecker HC, et al.: CARD15/NOD2 functions as an anti-bacterial factor in human intestinal epithelial cells. Gastroenterology 2003, 124:993–1000.

    Article  PubMed  CAS  Google Scholar 

  41. Ogura Y, Lala S, Xin W, Smith E, et al.: Expression of NOD2 in Paneth cells: a possible link to Crohn’s ileitis. Gut 2003, 52:1591–1597.

    Article  PubMed  CAS  Google Scholar 

  42. Ayabe T, Satchell DP, Wilson CL, et al.: Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol 2000, 1:113–118.

    Article  PubMed  CAS  Google Scholar 

  43. Fuss IJ, Neurath M, Boirivant M, et al.: Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease: Crohn’s disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 1996, 157:1261–1270.

    PubMed  CAS  Google Scholar 

  44. Watanabe T, Kitani A, Murray PJ, Strober W: NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 2004, 5:800–808. Establishment that the NOD2 pathway may normally serve to downregulate Th1 responses to TLR2 stimulation.

    Article  PubMed  CAS  Google Scholar 

  45. Armuzzi A, Ahmad T, Ling KL, et al.: Genotype-phenotype analysis of the Crohn’s disease susceptibility haplotype on chromosome 5q31. Gut 2003, 52:1133–1139.

    Article  PubMed  CAS  Google Scholar 

  46. Stokkers PC, Reitsma PH, Tytgat GN, van Deventer SJ: HLA-DR and -DQ phenotypes in inflammatory bowel disease: a metaanalysis. Gut 1999, 45:395–401.

    Article  PubMed  CAS  Google Scholar 

  47. Bonen DK, Cho JH: The genetics of inflammatory bowel disease. Gastroenterology 2003, 124:521–536.

    Article  PubMed  CAS  Google Scholar 

  48. Roussomoustakaki M, Satsangi J, Welsh K, et al.: Genetic markers may predict disease behavior in patients with ulcerative colitis. Gastroenterology 1997, 112:1845–1853.

    Article  PubMed  CAS  Google Scholar 

  49. Newman B, Silverberg MS, Gu X, et al.: CARD15 and HLA DRB1 alleles influence susceptibility and disease localization in Crohn’s disease. Am J Gastroenterol 2004, 99:306–315.

    Article  PubMed  CAS  Google Scholar 

  50. Stoll M, Corneliussen B, Costello CM, et al.: Genetic variation in DLG5 is associated with inflammatory bowel disease. Nat Genet 2004, 36:476–480.

    Article  PubMed  CAS  Google Scholar 

  51. Wakabayashi M, Ito T, Mitsushima M, et al.: Interaction of lp-dlg/ KIAA0583, a membrane-associated guanylate kinase family protein, with vinexin and beta-catenin at sites of cell-cell contact. J Biol Chem 2003, 278:21709–21714.

    Article  PubMed  CAS  Google Scholar 

  52. Panwala CM, Jones JC, Viney JL: A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis. J Immunol 1998, 161:5733–5744.

    PubMed  CAS  Google Scholar 

  53. Brant SR, Panhuysen CI, Nicolae D, et al.: MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet 2003, 73:1282–1292.

    Article  PubMed  CAS  Google Scholar 

  54. Schwab M, Schaeffeler E, Marx C, et al.: Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology 2003, 124:26–33.

    Article  PubMed  CAS  Google Scholar 

  55. Arbour NC, Lorenz E, Schutte BC, et al.: TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000, 25:187–191.

    Article  PubMed  CAS  Google Scholar 

  56. Franchimont D, Vermeire S, El Housni H, et al.: Deficient hostbacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn’s disease and ulcerative colitis. Gut 2004, 53:987–992.

    Article  PubMed  CAS  Google Scholar 

  57. The International HapMap Project. Nature 2003, 426:789–796.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Chicago, 5841 South Maryland Avenue, MC 6084, 60637, Chicago, IL, USA

    Judy H. Cho MD

Authors
  1. Judy H. Cho MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cho, J.H. Advances in the genetics of inflammatory bowel disease. Curr Gastroenterol Rep 6, 467–473 (2004). https://doi.org/10.1007/s11894-004-0068-4

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11894-004-0068-4

Keywords

Search

Navigation