International Journal of Colorectal Disease

, Volume 22, Issue 9, pp 1021–1025 | Cite as

Lack of association of the 3′-UTR polymorphism in the NFKBIA gene with Crohn’s disease in an Israeli cohort

  • E. Leshinsky-SilverEmail author
  • A. Karban
  • S. Cohen
  • M. Fridlander
  • O. Davidowich
  • G. Kimmel
  • R. Shamir
  • A. Levine
Original Article



Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract associated with dysregulation of the immune response. It is caused by a combination of environmental and genetic factors. Patients with CD have a TH1-type inflammatory response characterized by nuclear factor kappa B (NFκB) activation. Mutations in the bacterial pattern recognition receptors NOD2/CARD15 and Toll-like receptor 4 (TLR4) genes, which lead to activation of NFκB under normal circumstances, have been associated with increased susceptibility for CD. NFκB plays a critical role in the immune response and is down-regulated by NFκB inhibitor α (NFKBIA). NFKBIA was found to be a susceptibility gene for German CD patients lacking NOD2/CARD15 mutations.

Materials and methods

A cohort of 231 Israeli CD patients previously genotyped for the single nucleotide polymorphisms (SNPs) in the CARD15, TLR4 susceptibility genes for CD, was analyzed for the 3′-untranslated region (UTR) SNP of the NFKBIA gene in comparison to 100 healthy ethnically matched controls. We evaluated the contribution of the 3′-UTR SNP in NFKBIA in patients with or without other SNPs in CARD15 to age of onset, disease location, and disease behavior (Vienna classification).


We did not identify a significant difference in allele and genotype frequencies between either groups or an effect on phenotype. No interactions were found between NFKBIA and any NOD2.


The contribution of population diversity to susceptibility genes for CD plays an important role in disease-associated variants and is important for better understanding of the pathologic mechanisms of the polymorphism.


Crohn’s Genotype NOD2 CARD15 NFKBIA 


  1. 1.
    Hugot JP, Zouali H, Lesage S, Thomas G (1999) Etiology of the inflammatory bowel diseases. Int J Colorectal Dis 14:2–9PubMedCrossRefGoogle Scholar
  2. 2.
    Fiocchi C (1998) Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115:182–205PubMedCrossRefGoogle Scholar
  3. 3.
    Thompson NP, Driscoll R, Pounder RE, Wakefield AJ (1996) Genetics versus environment in inflammatory bowel disease; results of a British twin study. BMJ 312:95–96PubMedGoogle Scholar
  4. 4.
    Sartor JB (1997) Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases. Am J Gastroenterol 92:5S–11SPubMedGoogle Scholar
  5. 5.
    Newman B, Siminovitch K (2003) Inflammatory bowel disease: Crohn’s disease and the success of the NODern genetics. Clin Invest Med 26:303–312PubMedGoogle Scholar
  6. 6.
    Mathew C, Lewis CM (2004) Genetics of the inflammatory bowel disease: progress and prospects. Hum Mol Genet 13:161–168CrossRefGoogle Scholar
  7. 7.
    Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603PubMedCrossRefGoogle Scholar
  8. 8.
    Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nunez G, Cho JH (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606PubMedCrossRefGoogle Scholar
  9. 9.
    Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ, Bridger S, van Deventer S, Forbes A, Nikolaus S, Lennard-Jones JE, Foelsch UR, Krawczak M, Lewis C, Schreiber S, Mathew CG (2001) Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 357:1925–1928PubMedCrossRefGoogle Scholar
  10. 10.
    Inohara N, Nunez G (2001) The NOD: a signaling module that regulates apoptosis and host defense against pathogens. Oncogene 20:6473–6481PubMedCrossRefGoogle Scholar
  11. 11.
    Aderem A, Ulevitch RJ (2000) Toll-like receptors in the induction of the innate immune response. Nature 406:782–787PubMedCrossRefGoogle Scholar
  12. 12.
    Cario E, Podolsky DK (2000) Differential alternation in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun 68:7010PubMedCrossRefGoogle Scholar
  13. 13.
    Franchimont D, Vermeire S, El Housni H, Pierik M, Van Steen K, Gustot T, Quertinmont E, Abramowicz M, Van Gossum A, Deviere J, Rutgeerts P (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 53:987–992PubMedCrossRefGoogle Scholar
  14. 14.
    Levine A, Karban A, Eliakim R, Shaoul R, Reif S, Pacht A, Wardi J, Yakir B, Leshinsky-Silver E (2005) A polymorphism in the TNF-α promotor gene is associated with pediatric onset and colonic location of Crohn’s disease. Am J Gastroenterol 100:407–413PubMedCrossRefGoogle Scholar
  15. 15.
    Levine A, Raanan A, Wine E, Weiss B, Karban A, Shaoul R, Eliakim R, Reif S, Pacht A, Yakir B, Friedlander M, Kaniel Y, Leshinsky-Silver E (2005) TNF promotor polymorphism and modulation of growth retardation and disease severity in pediatric Crohn’s disease. Am J Gastroenterol 100:1–7CrossRefGoogle Scholar
  16. 16.
    Schreiber S, Nikolaus S, Hampe J (1998) Activation of nuclear factor kappa B inflammatory bowel disease. Gut 42:477–484PubMedCrossRefGoogle Scholar
  17. 17.
    Rogler G, Brand K, Vogl D, Page S, Hofmeister R, Andus T, Knuechel R, Baeuerle PA, Scholmerich J, Gross V (1998) Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 15:357–369CrossRefGoogle Scholar
  18. 18.
    Neurath MF, Fuss I, Schurmann G, Pettersson S, Arnold K, Muller-Lobeck H, Strober W, Herfarth C, Buschenfelde KH (1998) Cytokine gene transcription by NF-kappa B family members in patients with inflammatory bowel disease. Ann NY Acad Sci 859:149–159PubMedCrossRefGoogle Scholar
  19. 19.
    Neurath MF, Pettersson S (1997) Predominant role of NF-kappa B p65 in the pathogenesis of chronic intestinal inflammation. Immunobiology 198:91–98PubMedGoogle Scholar
  20. 20.
    Miterski B, Bohringer S, Klein W, Sindern E, Haupts M, Schimrigk S, Epplen JT (2002) Inhibitors in the NFkappaB cascade comprise prime candidate genes predisposing to multiple sclerosis, especially in selected combinations. Genes Immun 3:211–219PubMedCrossRefGoogle Scholar
  21. 21.
    Duerr RH, Barmada MM, Zhang L, Pfutzer R, Weeks DE (2000) High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q11-12. Am J Hum Genet 66:1857–1862PubMedCrossRefGoogle Scholar
  22. 22.
    Klein W, Tromm A, Folwaczny C, Hagedorn M, Duerig N, Epplen JT, Wolff H, Schmiegel WH, Griga T (2004) A polymorphism of the NFKBIA gene is associated with Crohn’s disease patients lacking a predisposing allele of the CARD15 gene. Int J Colorectal Dis 19:153–156PubMedCrossRefGoogle Scholar
  23. 23.
    Glavac D, Ravnik-Glavac M, O’Brien SJ, Dean M (1994) Polymorphisms in the 3′ untranslated region of the I kappa B/MAD-3 (NFKBI) gene located on chromosome 14. Hum Genet 93:694–696PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang K, Deng M, Chen T, Waterman MS, Sun F (2002) A dynamic programming algorithm for haplotype block partitioning. Proc Natl Acad Sci USA 99:7335–7339PubMedCrossRefGoogle Scholar
  25. 25.
    Kimmel G, Shamir R (2005) GERBIL: genotype resolution and block identification using likelihood. Proc Natl Acad Sci USA 102:158–162PubMedCrossRefGoogle Scholar
  26. 26.
    Wine E, Reif S, Leshinsky-Silver E, Weiss B, Shaoul RR, Shamir R, Wasserman D, Lerner A, Boaz M, LevineA (2004) Pediatric Crohn’s disease and growth retardation: the role of genotype, phenotype, and disease severity. Pediatrics 114:1281–1286PubMedCrossRefGoogle Scholar
  27. 27.
    Leshinsky-Silver E, Karban A, Buzhakor E, Yakir B, Eliakim R, Reif S, Shaul R, Boaz M, Lev D, Levine A (2005) Is age of onset of Crohn’s disease governed by mutations in NOD2/CARD15 and Toll-like receptor 4? Evaluation of a pediatric cohort. Pediatr Res 58:499–504PubMedCrossRefGoogle Scholar
  28. 28.
    Conne B, Stutz A, Vassalli JD (2000) The 3′-untranslated region of messenger RNA: a molecular hotspot for pathology? Nat Med 6:637–641PubMedCrossRefGoogle Scholar
  29. 29.
    Inoue N, Tamura K, Kinouchi Y, Fukuda Y, Takahashi S, Ogura Y, Inohara N, Nunez G, Kishi Y, Koike Y, Shimosegawa T, Shimoyama T, Hibi T (2002) Lack of common NOD2 variants in Japanese patients with Crohn’s disease. Gastroenterology 123:86–91PubMedCrossRefGoogle Scholar
  30. 30.
    Yamazaki K, Takazoe M, Tanaka T, Kazumori T, Nakamura Y (2002) Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn’s disease. J Hum Genet 47:469–472PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • E. Leshinsky-Silver
    • 1
    Email author
  • A. Karban
    • 2
  • S. Cohen
    • 1
  • M. Fridlander
    • 3
  • O. Davidowich
    • 4
  • G. Kimmel
    • 4
  • R. Shamir
    • 4
  • A. Levine
    • 5
  1. 1.Molecular Genetics LabE Wolfson Medical CenterHolonIsrael
  2. 2.Division of GastroenterologyRambam Medical Center HaifaHaifaIsrael
  3. 3.Danyel BiotechRehovotIsrael
  4. 4.School of Computer ScienceTel Aviv UniversityTel AvivIsrael
  5. 5.Pediatric Gastroenterology Unit, Wolfson Medical Center, Sackler School of MedicineTel Aviv UniversityTel AvivIsrael

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