Skip to main content

Advertisement

Log in

Update on the genetics of inflammatory bowel disease

  • Published:
Current Gastroenterology Reports Aims and scope Submit manuscript

Abstract

Crohn’s disease and ulcerative colitis are related genetic disorders. Epidemiologic studies suggest that both disorders are caused by a complex interplay of genetic and environmental factors. Genetic linkage studies identify the general chromosomal locations of disease susceptibility genes, and a number of genetic linkages have been reported in inflammatory bowel disease (IBD). Most notable among these linkage regions has been the linkage in the pericentromeric region of chromosome 16, IBD1, among families multiply affected with Crohn’s disease. Recent studies have established that at least three coding region variants in the Nod2 gene are responsible for the linkage findings here, and Nod2 therefore represents the first definitively established gene contributing to the pathogenesis of IBD. The implications of these findings for advancing our understanding of Crohn’s disease are discussed.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Loftus EV, Silverstein MD, Sandborn WJ, et al.: Crohn’s disease in Olmsted County, Minnesota, 1940–1993: incidence, prevalence and survival. Gastroenterology 1998, 114:1161–1168.

    Article  PubMed  Google Scholar 

  2. Kurata JH, Kantor-Fish S, Frankl H, et al.: Crohn’s disease among ethnic groups in a large health maintenance organization. Gastroenterology 1992, 102:1940–1948.

    PubMed  CAS  Google Scholar 

  3. Thomas GAO, Millar-Jones D, Rhodes J, Roberst GM, et al.: Incidence of Crohn’s disease in Cardiff over 60 years: 1986–1990: an update. Eur J Gastroenterol Hepatol 1995, 7:401–405.

    PubMed  CAS  Google Scholar 

  4. Munkholm P, Langholz E, Nielsen OH, et al.: Incidence and prevalence of Crohn’s disease in the county of Copenhage. 1962–1987: a sixfold increase in incidence. Scand J Gastroenterol 1992, 27:609–614.

    PubMed  CAS  Google Scholar 

  5. Langholz E, Munkholm P, Nielsen OH, et al.: Incidence and prevalence of ulcerative colitis in Copenhagen couty from 1962–1987. Scand J Gastroenterol 1991, 26:1247–1256.

    PubMed  CAS  Google Scholar 

  6. Roth MP, Petersen GM, McElree C, et al.: Familial empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews. Gastroenterology 1989, 96:1016–1020.

    PubMed  CAS  Google Scholar 

  7. Yang H, McElree C, Roth M-P, et al.: Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut 1993, 34:517–524.

    PubMed  CAS  Google Scholar 

  8. Ogunbi SO, Ransom JA, Sullivan K, et al.: Inflammatory bowel disease in African-American children living in Georgia. J Pediatr 1998, 133:103–107.

    Article  PubMed  CAS  Google Scholar 

  9. Monsen U, Bernell O, Johannson C, Hellers G: Prevalence of inflammatory bowel disease among relatives of patients with Crohn’s disease. Scand J Gastroenterol 1991, 26:302–306.

    PubMed  CAS  Google Scholar 

  10. Russel MG, Pastoor CJ, Janssen, KM, et al.: Familial aggregation of inflammatory bowel disease: a population-based study in South Limburg, the Netherlands. The South Limburg IBD Study Group. Scand J Gastroenterol 1997,223(Suppl):88–91.

    CAS  Google Scholar 

  11. Farmer RG, Michener WM, Mortimer EA: Studies of family history among patients with inflammatory bowel disease. Clin Gastroenterol 1980, 9:271–278.

    PubMed  CAS  Google Scholar 

  12. Binder V: Genetic epidemiology in inflammatory bowel disease. Dig Dis 1998, 16:351–355.

    Article  PubMed  CAS  Google Scholar 

  13. Orholm M, Munkholm P, Langholz E, et al.: Familial occurrence of inflammatory bowel disease. N Engl J Med 1991, 324:84–88.

    Article  PubMed  CAS  Google Scholar 

  14. Peeters M, Nevens H, Baert F, et al.: Familial aggregation in Crohn’s disease: increased age-adjusted risk and concordance in clinical characteristics. Gastroenterology 1998, 111:597–603.

    Article  Google Scholar 

  15. Satsangi J, Rosenberg WMC, Jewell DP: The prevalence of inflammatory bowel disease in relatives of patients with Crohn’s disease. Eur J Gastroenterol Hepatol 1994, 6:413–416.

    Google Scholar 

  16. Tysk C, Linkberg E, Jarnerot G, Floderus-Myrhed B: 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 

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

    PubMed  CAS  Google Scholar 

  18. Subhani J, Montgomery SM, Ounder RE, Wakefield AJ: Concordance rates of twins and siblings in inflammatory bowel disease [abstract]. Gut 1998, 42(suppl 1):A40.

    Google Scholar 

  19. Laharie D, Debeugny S, Peeters M, et al.: Inflammatory bowel disease in spouses and their offspring. Gastroenterology 2001, 120:816–819.

    Article  PubMed  CAS  Google Scholar 

  20. Bennett RA, Rubin PH, Present DH: Frequency of inflammatory bowel disease in offspring of couples both presenting with inflammatory bowel disease. Gastroenterology 1991, 100:1638–1643.

    PubMed  CAS  Google Scholar 

  21. 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 

  22. 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 

  23. Cho JH, Nicolae DL, Gold LH, et al.: Identification of 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 

  24. Hampe J, Schreiber S, Shaw SH, et al.: A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort. Am J Hum Genet 1999, 64:808–816.

    Article  PubMed  CAS  Google Scholar 

  25. Ma Y, Ohmen JD, Li Z, 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 

  26. 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 

  27. Rioux JD, Silverberg MS, Daly MJ, et al.: 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 

  28. The IBD International Genetic Consortium: Crohn’s disease maps to a locus on chromosome 16: results from the IBD International Genetic Consortium. Am J Hum Genet 2001, 68:1165–1171. This large international effort definitively established the significance of linkage at IBD1.

    Article  Google Scholar 

  29. Parkes M, Barmada MM, Satsangi J, et al: The IBD2 locus shows linkage heterogeneity between ulcerative colitis and Crohn disease. Am J Human Genet 2000, 67:1605–1610.

    Article  CAS  Google Scholar 

  30. Lesage S, Zouali H, Colombel JF, et al.: Genetic analyses of chromosome 12 loci in Crohn’s disease. Gut 2000, 47:787–791.

    Article  PubMed  CAS  Google Scholar 

  31. Paavola P, Helio T, Kiuru M, et al.: Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21. Eur J Hum Genet 2001, 9:328–334.

    Article  PubMed  CAS  Google Scholar 

  32. Hampe J, Lynch NJ, Daniels S, et al.: Fine mapping of the chromosome 3p susceptibility locus in inflammatory bowel disease. Gut 2001, 48:191–197.

    Article  PubMed  CAS  Google Scholar 

  33. Vermeire S, Satsangi J, Peeters M, et al.: Evidence for inflammatory bowel disease of a susceptibility locus on the X chromosome. Gastroenterology 2001, 120:834–840.

    Article  PubMed  CAS  Google Scholar 

  34. 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. Frameshift variant in Nod2 deletes the tenth LRR and decreases responsiveness to bacterial LPS.

    Article  PubMed  CAS  Google Scholar 

  35. 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. Association through cloning of regional variants predominating with the LRR region within Nod2 associated with Crohn’s Disease.

    Article  PubMed  CAS  Google Scholar 

  36. 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 

  37. Inohara N, Ogura Y, Chen, FF, et al.: Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem 2001, 276:2551–2554.

    Article  PubMed  CAS  Google Scholar 

  38. Moore KW, de Waal Malefyt R, Coffman RL, O‘Garra A: Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001, 19:683–765.

    Article  PubMed  CAS  Google Scholar 

  39. Holtzman NA, Marteau TM: Will genetics revolutionize medicine? N Engl J Med 2000, 343:141–144.

    Article  PubMed  CAS  Google Scholar 

  40. 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 

  41. Brant SR, Panhuysen CI, Bailey-Wilson JE, et al.: Linkage heterogeneity of the IBD1 locus in Crohn’s disease pedigrees by disease onset and severity. Gastroenterology 2000, 119:483–490.

    Article  Google Scholar 

  42. Kontoyiannis D, Pasparakis M, Pizarro TT, et al.: Impaired on/ off regulartion of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 1999, 10:387–398. Establish that altered TNF expression is capable of producing an ileitis picture.

    Article  PubMed  CAS  Google Scholar 

  43. Spurkland A, Saarinene S, Boberg KM, et al.: HLA class II haplotypes in primary sclerosing cholangitis in patients from five European populations. Tissue Antigens 1999, 53:459–469.

    Article  PubMed  CAS  Google Scholar 

  44. Satsangi J, Chapman RW, Haldar N, et al.: A functional polymorphism of the stromelysin gene (mmp-3) influences susceptibility to primary sclerosing cholangitis. Gastroenterology 2001, 121:124–130.

    Article  PubMed  CAS  Google Scholar 

  45. Hedenfalk I, Duggan D, Chen Y, et al.: Gene-expression profiles in hereditary breast cancer. N Engl J Med 2001, 344:539–548. Heritable mutationsin BRCA1 and BRCA2 influence the gene sexpression profile of cancer.

    Article  PubMed  CAS  Google Scholar 

  46. Golub TR, Slonim DK, Tamayo P, et al.: Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 1999, 286:531–537.

    Article  PubMed  CAS  Google Scholar 

  47. Lawrance IC, Fiocchi C, Chakravarti S: Ulcerative colitis and Crohn’s disease: distinctive gene expression profiles and novel susceptibility candidate genes. Hum Mol Genet 2001, 10:445–456.

    Article  PubMed  CAS  Google Scholar 

  48. Dieckgraefe BK, Stenson WF, Korzenik JR, et al.: Analysis of mucosal gene expression in inflammatory bowel disease parallel oligonucleotide arrays. Physiol Genomics 2000, 4:1–11.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cho, J.H. Update on the genetics of inflammatory bowel disease. Curr Gastroenterol Rep 3, 458–463 (2001). https://doi.org/10.1007/s11894-001-0065-9

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11894-001-0065-9

Keywords

Navigation