Skip to main content
SpringerLink
Log in

Genetics of Ulcerative Colitis

  • Chapter
  • First Online:
Molecular Genetics of Inflammatory Bowel Disease

Abstract

While it has been known for several decades that susceptibility to ulcerative colitis (UC), one of the two major forms of inflammatory bowel disease (IBD), is in part inherited, it is only recently that considerable progress has been made in identifying some of the key genetic determinants playing a role in predisposition to disease. The advent of genome-wide association studies (GWAS) has provided geneticists with an extremely powerful tool for the identification of causative genes in complex diseases. To date, 163 IBD risk loci have been identified, and functional insight obtained from genes mapping to these associated regions has highlighted the importance of immune function and gut interaction with bacteria, as well as the maintenance of epithelial barrier in UC pathogenesis. The functional characterization of the remaining genes, as well as the identification of rare causative variants in these associated regions, represents a considerable challenge for the future, but promises to unravel novel biological pathways that may be amenable to exploitation for the design of innovative therapeutic strategies in UC.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. De Dombal FT (1968) Ulcerative colitis: definition, historical background, aetiology, diagnosis, natural history and local complications. Postgrad Med J 44(515):684–692, Epub 1968/09/01

    Article  PubMed  Google Scholar 

  2. Stokkers PC, Reitsma PH, Tytgat GN, van Deventer SJ (1999) HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis. Gut 45(3):395–401, Epub 1999/08/14

    Article  PubMed  CAS  Google Scholar 

  3. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J et al (2001) Initial sequencing and analysis of the human genome. Nature 409(6822):860–921, Epub 2001/03/10

    Article  PubMed  CAS  Google Scholar 

  4. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG et al (2001) The sequence of the human genome. Science 291(5507):1304–1351, Epub 2001/02/22

    Article  PubMed  CAS  Google Scholar 

  5. Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD et al (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43(3):246–252, Epub 2011/02/08

    Article  PubMed  CAS  Google Scholar 

  6. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491(7422):119–124, Epub 2012/11/07

    Article  PubMed  CAS  Google Scholar 

  7. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T et al (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 42(12):1118–1125, Epub 2010/11/26

    Article  PubMed  CAS  Google Scholar 

  8. Amiel JL (1967) Study of the leukocyte phenotypes in Hodgkin’s disease. In: Curtoni ES, Mattiuz PL, Tosi RM (eds) Histocompatibility testing. Munksgaard, Copenhagen, pp 79–81

    Google Scholar 

  9. The_MHC_Consortium (1999) Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium. Nature 401(6756):921–923, Epub 1999/11/30

    Article  Google Scholar 

  10. Robinson J, Waller MJ, Parham P, de Groot N, Bontrop R, Kennedy LJ et al (2003) IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res 31(1):311–314, Epub 2003/01/10

    Article  PubMed  CAS  Google Scholar 

  11. Fernando MM, Stevens CR, Walsh EC, De Jager PL, Goyette P, Plenge RM et al (2008) Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet 4(4):e1000024, Epub 2008/04/26

    Article  PubMed  Google Scholar 

  12. Orchard TR, Dhar A, Simmons JD, Vaughan R, Welsh KI, Jewell DP (2001) MHC class I chain-like gene A (MICA) and its associations with inflammatory bowel disease and peripheral arthropathy. Clin Exp Immunol 126(3):437–440, Epub 2001/12/12

    Article  PubMed  CAS  Google Scholar 

  13. Rioux JD, Goyette P, Vyse TJ, Hammarstrom L, Fernando MM, Green T et al (2009) Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases. Proc Natl Acad Sci U S A 106(44):18680–18685, Epub 2009/10/23

    Article  PubMed  CAS  Google Scholar 

  14. Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ et al (2008) Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease. Nat Genet 40(6):710–712, Epub 2008/04/29

    Article  PubMed  CAS  Google Scholar 

  15. Kugathasan S, Baldassano RN, Bradfield JP, Sleiman PM, Imielinski M, Guthery SL et al (2008) Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet 40(10):1211–1215, Epub 2008/09/02

    Article  PubMed  CAS  Google Scholar 

  16. Ho GT, Moodie FM, Satsangi J (2003) Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant in gastrointestinal disease? Gut 52(5):759–766, Epub 2003/04/15

    Article  PubMed  CAS  Google Scholar 

  17. Panwala CM, Jones JC, Viney JL (1998) A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis. J Immunol 161(10):5733–5744, Epub 1998/11/20

    PubMed  CAS  Google Scholar 

  18. Annese V, Valvano MR, Palmieri O, Latiano A, Bossa F, Andriulli A (2006) Multidrug resistance 1 gene in inflammatory bowel disease: a meta-analysis. World J Gastroenterol 12(23):3636–3644, Epub 2006/06/15

    PubMed  CAS  Google Scholar 

  19. Zintzaras E (2012) Is there evidence to claim or deny association between variants of the multidrug resistance gene (MDR1 or ABCB1) and inflammatory bowel disease? Inflamm Bowel Dis 18(3):562–572, Epub 2011/09/03

    Article  PubMed  Google Scholar 

  20. van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M et al (2007) A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 39(7):827–829, Epub 2007/06/15

    Article  PubMed  Google Scholar 

  21. Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V et al (2007) Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 39(7):857–864, Epub 2007/06/08

    Article  PubMed  CAS  Google Scholar 

  22. Zhernakova A, Alizadeh BZ, Bevova M, van Leeuwen MA, Coenen MJ, Franke B et al (2007) Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases. Am J Hum Genet 81(6):1284–1288, Epub 2007/11/14

    Article  PubMed  CAS  Google Scholar 

  23. Sawalha AH, Kaufman KM, Kelly JA, Adler AJ, Aberle T, Kilpatrick J et al (2008) Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus. Ann Rheum Dis 67(4):458–461, Epub 2007/08/28

    Article  PubMed  CAS  Google Scholar 

  24. Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner J et al (2008) A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet 4(3):e1000041, Epub 2008/03/29

    Article  PubMed  Google Scholar 

  25. Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M et al (2008) IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454(7202):350–352, Epub 2008/05/13

    Article  PubMed  CAS  Google Scholar 

  26. Monteleone G, Monteleone I, Fina D, Vavassori P, Del Vecchio Blanco G, Caruso R et al (2005) Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn’s disease. Gastroenterology 128(3):687–694

    Article  PubMed  CAS  Google Scholar 

  27. Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I (1993) Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75(2):253–261, Epub 1993/10/22

    Article  PubMed  CAS  Google Scholar 

  28. Festen EA, Goyette P, Scott R, Annese V, Zhernakova A, Lian J et al (2009) Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. Gut 58(6):799–804, Epub 2009/02/10

    Article  PubMed  CAS  Google Scholar 

  29. Glas J, Stallhofer J, Ripke S, Wetzke M, Pfennig S, Klein W et al (2009) Novel genetic risk markers for ulcerative colitis in the IL2/IL21 region are in epistasis with IL23R and suggest a common genetic background for ulcerative colitis and celiac disease. Am J Gastroenterol 104(7):1737–1744, Epub 2009/05/21

    Article  PubMed  CAS  Google Scholar 

  30. Marquez A, Orozco G, Martinez A, Palomino-Morales R, Fernandez-Arquero M, Mendoza JL et al (2009) Novel association of the interleukin 2-interleukin 21 region with inflammatory bowel disease. Am J Gastroenterol 104(8):1968–1975, Epub 2009/05/28

    Article  PubMed  CAS  Google Scholar 

  31. Shi J, Zhou L, Zhernakova A, Qian J, Zhu F, Sun G et al (2011) Haplotype-based analysis of ulcerative colitis risk loci identifies both IL2 and IL21 as susceptibility genes in Han Chinese. Inflamm Bowel Dis 17(12):2472–2479, Epub 2011/06/08

    Article  PubMed  Google Scholar 

  32. McGovern DP, Gardet A, Torkvist L, Goyette P, Essers J, Taylor KD et al (2010) Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet 42(4):332–337, Epub 2010/03/17

    Article  PubMed  CAS  Google Scholar 

  33. Franke A, Balschun T, Sina C, Ellinghaus D, Hasler R, Mayr G et al (2010) Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat Genet 42(4):292–294, Epub 2010/03/17

    Article  PubMed  CAS  Google Scholar 

  34. Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V et al (2009) Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet 41(2):216–220, Epub 2009/01/06

    Article  PubMed  CAS  Google Scholar 

  35. Barrett JC, Lee JC, Lees CW, Prescott NJ, Anderson CA, Phillips A et al (2009) Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet 41(12):1330–1334, Epub 2009/11/17

    Article  PubMed  CAS  Google Scholar 

  36. Asano K, Matsushita T, Umeno J, Hosono N, Takahashi A, Kawaguchi T et al (2009) A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet 41(12):1325–1329, Epub 2009/11/17

    Article  PubMed  CAS  Google Scholar 

  37. Franke A, Balschun T, Karlsen TH, Sventoraityte J, Nikolaus S, Mayr G et al (2008) Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet 40(11):1319–1323, Epub 2008/10/07

    Article  PubMed  CAS  Google Scholar 

  38. Imielinski M, Baldassano RN, Griffiths A, Russell RK, Annese V, Dubinsky M et al (2009) Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet 41(12):1335–1340, Epub 2009/11/17

    Google Scholar 

  39. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ et al (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314(5804):1461–1463, Epub 2006/10/28

    Article  PubMed  CAS  Google Scholar 

  40. Power C, Elliott J (2006) Cohort profile: 1958 British birth cohort (National Child Development Study). Int J Epidemiol 35(1):34–41, Epub 2005/09/13

    Article  PubMed  Google Scholar 

  41. Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y et al (2003) Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways. Oncogene 22(21):3307–3318, Epub 2003/05/23

    Article  PubMed  CAS  Google Scholar 

  42. Goyette P, Lefebvre C, Ng A, Brant SR, Cho JH, Duerr RH et al (2008) Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis. Mucosal Immunol 1(2):131–138, Epub 2008/12/17

    Article  PubMed  CAS  Google Scholar 

  43. WTCCC (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145):661–678, Epub 2007/06/08

    Article  Google Scholar 

  44. Franke A, Balschun T, Karlsen TH, Hedderich J, May S, Lu T et al (2008) Replication of signals from recent studies of Crohn’s disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet 40(6):713–715, Epub 2008/04/29

    Article  PubMed  CAS  Google Scholar 

  45. Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ et al (1996) Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature 384(6608):458–460, Epub 1996/12/05

    Article  PubMed  CAS  Google Scholar 

  46. Battle MA, Konopka G, Parviz F, Gaggl AL, Yang C, Sladek FM et al (2006) Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proc Natl Acad Sci U S A 103(22):8419–8424, Epub 2006/05/23

    Article  PubMed  CAS  Google Scholar 

  47. Karayiannakis AJ, Syrigos KN, Efstathiou J, Valizadeh A, Noda M, Playford RJ et al (1998) Expression of catenins and E-cadherin during epithelial restitution in inflammatory bowel disease. J Pathol 185(4):413–418, Epub 1998/11/26

    Article  PubMed  CAS  Google Scholar 

  48. Schmehl K, Florian S, Jacobasch G, Salomon A, Korber J (2000) Deficiency of epithelial basement membrane laminin in ulcerative colitis affected human colonic mucosa. Int J Colorectal Dis 15(1):39–48, Epub 2000/04/15

    Article  PubMed  CAS  Google Scholar 

  49. Anderson CA, Massey DC, Barrett JC, Prescott NJ, Tremelling M, Fisher SA, et al (2009) Investigation of Crohn’s disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology 136(2):523–529. e3. Epub 2008/12/11

    Google Scholar 

  50. Huang ZY, Chien P, Indik ZK, Schreiber AD (2011) Human platelet FcgammaRIIA and phagocytes in immune-complex clearance. Mol Immunol 48(4):691–696, Epub 2010/12/21

    Article  PubMed  CAS  Google Scholar 

  51. Wu B, Jin M, Zhang Y, Wei T, Bai Z (2011) Evolution of the IL17 receptor family in chordates: a new subfamily IL17REL. Immunogenetics 63(12):835–845, Epub 2011/07/07

    Article  PubMed  CAS  Google Scholar 

  52. van Heel DA, Udalova IA, De Silva AP, McGovern DP, Kinouchi Y, Hull J et al (2002) Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors. Hum Mol Genet 11(11):1281–1289, Epub 2002/05/23

    Article  PubMed  Google Scholar 

  53. Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I et al (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397(6716):263–266, Epub 1999/02/04

    Article  PubMed  CAS  Google Scholar 

  54. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S et al (2007) Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448(7152):470–473, Epub 2007/07/06

    Article  PubMed  CAS  Google Scholar 

  55. http://www.ibdgenetics.org/

  56. Oshimori N, Li X, Ohsugi M, Yamamoto T (2009) Cep72 regulates the localization of key centrosomal proteins and proper bipolar spindle formation. EMBO J 28(14):2066–2076, Epub 2009/06/19

    Article  PubMed  CAS  Google Scholar 

  57. http://www.ncbi.nlm.nih.gov/

  58. Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of T(H)17 cells. Nature 453(7198):1051–1057

    Article  PubMed  CAS  Google Scholar 

  59. Yang SK, Jung Y, Hong M, Kim H, Ye BD, Lee I et al (2011) No association between TNFSF15 and IL23R with ulcerative colitis in Koreans. J Hum Genet 56(3):200–204, Epub 2011/01/14

    Article  PubMed  CAS  Google Scholar 

  60. Mahurkar S, Banerjee R, Rani VS, Thakur N, Rao GV, Reddy DN et al (2011) Common variants in NOD2 and IL23R are not associated with inflammatory bowel disease in Indians. J Gastroenterol Hepatol 26(4):694–699, Epub 2010/12/16

    Article  PubMed  CAS  Google Scholar 

  61. Yamazaki K et al (2002) Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn’s disease. J Hum Genet 47:469–472

    Article  PubMed  CAS  Google Scholar 

  62. Yamazaki K et al (2007) Association analysis of genetic variants in IL23R, ATG16L1and 5p13.1 loci with Crohn’s disease in Japanese patients. J Hum Genet 52:575–583

    Article  PubMed  CAS  Google Scholar 

  63. Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK et al (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43(11):1066–1073, Epub 2011/10/11

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biosciences and Nutrition, NOVUM, Karolinska Institutet, Hälsovägen 7-9, 14183, Stockholm, Sweden

    Mauro D’Amato Ph.D.

  2. Montreal Heart Institute, Montréal, QC, Canada

    Catherine Labbé M.Sc., Ph.D.

  3. Université de Montréal, Montréal, QC, Canada

    Catherine Labbé M.Sc., Ph.D.

  4. Université de Montréal and the Montreal Heart Institute, Montréal, QC, Canada

    John D. Rioux

Authors
  1. Mauro D’Amato Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catherine Labbé M.Sc., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John D. Rioux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mauro D’Amato Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden

    Mauro D'Amato

  2. Research Center, Montreal Heart Institute, Montreal, Québec, Canada

    John D Rioux

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

D’Amato, M., Labbé, C., Rioux, J.D. (2013). Genetics of Ulcerative Colitis. In: D'Amato, M., Rioux, J. (eds) Molecular Genetics of Inflammatory Bowel Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8256-7_6

Download citation

Publish with us

Policies and ethics

Search

Navigation