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Vol. 66, No. 2, 2002
Issue release date: 2002
Digestion 2002;66:121–126

Candidate Genes Colocalized to Linkage Regions in Inflammatory Bowel Disease

Martin K. · Radlmayr M. · Borchers R. · Heinzlmann M. · Folwaczny C.
aMedizinische Klinik und bMedizinische Poliklinik und Chirurgische Klinik der Universität, Standort Innenstadt, Ludwig-Maximilians Universität München, Deutschland

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Background and Aims: The genes encoding for tumor necrosis factor-α (TNF-α), epidermal growth factor receptor (EGFR) and the vitamin D receptor (VDR) are colocalized to inflammatory bowel disease-associated linkage regions on chromosomes 6, 7 and 12. An association study of these gene polymorphisms with ulcerative colitis or Crohn’s disease and a stratification according to disease phenotypes was performed in order to identify gentically homogenous subgroups. Patients and Methods: 119 healthy, unrelated controls, 95 patients with Crohn’s disease and 93 patients with ulcerative colitis were genotyped for the (G to A) –308 TNF-α promoter polymorphism on chromosome 6, the codon 497 EGFR polymorphism on chromosome 7 and the TaqI polymorphism of the VDR gene on chromosome 12. After genotyping, patients were stratified according to the respective disease phenotype. Results: A disequilibrium in the distribution of the VDR genotypes was found in patients with ulcerative colitis compared to controls (p = 0.024). In fistulizing and fibrostenotic Crohn’s disease the ‘TT’ genotype was significantly reduced compared with other phenotypes (p = 0.006), whereas the ‘tt’ genotype was found more frequently (p = 0.04). The frequency of the WT allele of the EGFR gene was significantly higher in ulcerative colitis (p = 0.04) than in controls. Further significant differences, concerning the associations of the different polymorphisms and disease susceptibility or clinical phenotypes, were not observed. Conclusions: Regardless of the disease phenotype, the associations between the polymorphisms and inflammatory bowel disease investigated herein are modest, even after stratification for the disease phenotypes. Hence, these polymorphisms are unlikely to confer the reported linkage between inflammatory bowel disease and chromosomes 6, 7 and 12.

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  1. Satsangi J, Parkes M, Louis E, Hahimoto L, Kato N, Welsh K, Terwilliger JD, Lathrop GM, Bell JI, Jewell DP: 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.
  2. Hampe J, Lynch NJ, Daniels S, Bridger S, Macpherson AJS, Stokkers P, Forbes A, Lennard-Jones JE, Mathew CG, Curran ME, Schreiber S: Fine mapping of the chromosome 3p susceptibility locus in inflammatory bowel disease. Gut 2001;48:191–197.
  3. Curran ME, Lau KF, Hampe J, Schreiber S, Bridger S, Macpherson AJ, Cardon LR, Sakul H, Harris TJ, Stokkers P, Van Deventer SJ, Mirza M, Raedler A, Kruis W, Meckler U, Theuer D, Herrmann T, Gionchetti P, Lee J, Mathew C, Lennard-Jones J: Genetic analysis of inflammatory bowel disease in a large European cohort supports linkage to chromosomes 12 and 16. Gastroenterology 1998;115:1066–1071.
  4. Hampe J, Shaw SH, Saiz R, Leysens N, Lantermann A, Mascheretti S, Lynch NJ, Macpherson AJ, Bridger S, van Deventer S, Stokkers P, Morin P, Mirza MM, Forbes A, Lennard-Jones JE, Mathew CG, Curran ME, Schreiber S: Linkage of inflammatory bowel disease to human chromosome 6p. Am J Hum Genet 1999;65:1647–1655.
  5. Hampe J, Schreiber S, Shaw S, Lau KF, Bridger S, Macpherson AJ, Cardon LR, Sakul H, Harris TJ, Buckler A, Hall J, Stokkers P, van Ceventer SJ, Nurnberg P, Mirza MM, Lee JC, Lennard-Jones JE, Mathew CG, Curran ME: 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.
  6. Hugot JP, Laurentpuig P, Gower-Rousseau C, Olson JM, Lee JC, Beaugerie L, Naom I, Dupas JL, Vangossum A, Orholm M, Bonaitipellie C, Weissenbach J, Mathew CG, Lennardjones JE, Cortot A, Colombel JF, Thomas G: Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature 1996;379:821–823.
  7. Brant SR, Fu Y, Fields CT, Baltazar R, Ravenhill G, Pickles MR, Rohal PM, Mann J, Kirschner BS, Jabs EW, Bayless TM, Hanauer SB, Cho JH: American families with Crohn’s disease have strong evidence for linkage to chromosome 16 but not chromosome 12. Gastroenterology 1998;115:1056–1061.
  8. Cho JH, Nicolae DL, Gold LH, Fields CT, LaBuda MC, Rohal PM, Pickles MR, Yin L, FuY, Mann JS, Kirschner VS, Jabs EW, Weber J, Hanauer SB, Bayless TM, Brant SR: Identification of novel susceptibility loci for inflammatory bowel diseases on chromosomes 1p, 3q and 4q: Evidence for epistasis between 1p and IBD1. Proc Natl Acad Sci USA 1998;95:7502–7507.
  9. Cavanaugh JA, Callen DF, Wilson SR, Stanford PM, Sraml ME, Gorska M, Crawford J, Whitmore SA, Shlegel C Foote S, Kohonen-Corish M, Pavli P: Analysis of Australian Crohn’s disease pedigrees refines the localization for susceptibility to inflammatory bowel disease on chromosomes 16. Ann Hum Genet 1998;62:291–298.
  10. Parkes M, Varmada MM, Satsangi J, Weeks DE, Jewell DP, Duerr RH: The IBD2 locus shows linkage heterogeneity between ulcerative colitis and Crohn disease. Am J Hum Genet 2000;67:1605–1610.
  11. Riox JD, Silverberg MS, Daly MJ, Steinhart AH, McLeod RS, Griffiths AM, Green T, Brettin TS, Stone V, Bull SB, Bitton A, Williams CN, Greenberg GT, Cohen Z, Lander ES, Hudson TJ, Siminovitch KA: Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet 2000;66:1863–1870.
  12. Cavanaugh J: International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16. Am J Hum Gent 2001;68:1165–1171.
  13. Paavola P, Helio T, Kiuru M, Halme L, Turunen U, Terwilliger J, Karvonen AL, Julkunen R, Niemela S, Nurmi H, Farkkila M, Kontula K: Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21. Eur J Hum Genet 2001;9:328–334.
  14. Rioux JD, Daly MJ, Green T, Stone V, Lander ES, Hudson TJ, Steinhart AH, Bull S, Cohen Z, Greenberg G, Griffiths A, McLeod R, Silverberg M, Williams CN, Siminovitch KA: Absence of linkage between inflammatory bowel disease and selected loci on chromosomes 3, 7, 12 and 16. Gastroenterology 1998;115:1062–1065.
  15. Vermeire S, Peeters M, Vlietinck R, Parkes M, Satsangi J, Jewell D, Rutgeerts P: Exclusion of linkage of Crohn’s disease to previously reported regions on chromosomes 12, 7 and 3 in the Belgian population indicates genetic heterogeneity. Inflamm Bowel Dis 2000;6:165–170.
  16. Wilson AG, di Giovine FS, Blakemore AIF, Duff GW: Single base change in the human tumor necrosis factor-α gene detectable by NcoI restriction of a PCR product. Hum Mol Genet 1992;1:353.
  17. Bouma G, Crusius JBA, Oudkerk Pool M, Kolkman JJ, von Blomberg BM, Kostnese PJ, Giphart MJ, Schreuder GM, Meuwissen SG, Pena AS: Secretion of tumor necrosis factor-α and lymphotoxin-α in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease. Scand J Immunol 1996;43:456–463.
  18. Grisham MB, Von Ritter C, Smith BF, LaMont TJ, Granger DN: Interaction between oxygen radicals and gastric mucin. Am J Physiol 1987;253:G93–G96.
  19. Reinshagen M, Procaccino F, McRoberts JA, Lakshmanan J, Eysselein VE et al: Up-regulation of EGF-binding sites in rat colitis (abstract). Gastroenterology 1993;104:A642.
  20. Moriai T, Kobrin MS, Korc M: Cloning of a variant epidermal growth factor receptor. Biochem Biophys Res Commun 1993;191:1034–1039.
  21. Duerr RH, Barmada MM, Zhang L, Davis S, Preston RA, Chensny LJ, Brown JL, Ehrlich GD, Weeks DE, Aston CE: Linkage and association between inflammatory bowel disease an a locus on chromosome 12. Am J Hum Genet 1998;63:95–100.
  22. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O’Riordan J, Stanford J: Vitamin D3, γ-interferon and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986;57:159–163.
  23. Lemire JM, Archer DC, Beck L, Spiegelberg HL: Immunosuppressive actions of 1,25-dihydroxyvitamin D3: Preferential inhibition of TH1 functions. J Nutr 1995;125:1704S–1708S.
  24. Yu XP, Belllido T, Manolagas SC: Down-regulation of NF-κB protein levels in activated human lymphocytes by 1,25-dihydroxivitamin D3. Proc Natl Acad Sci USA 1995;92:10990–10994.
  25. Verjans GMGM, Brinkman BMN, van Doornik CEM, Kijlstra A, Verweij CL: Polymorphism of tumour necrosis factor-α at position –308 in relation to ankylosing spondylitis. Clin Exp Immunol 1994;97:45–47.
  26. Simmons JD, Mullighen C, Welsh KI, Jewell DP: Vitamin D receptor gene polymorphism: Association with Crohn’s disease susceptibility. Gut 2000;47:211–214.
  27. Vermeire S, Peeters M, Vlietinck R, Parkes M, Satsangi J, Jewell D, Rutgeerts P: Exclusion of linkage of Crohn’s disease to previously reported regions on chromosomes 12, 7 and 3 in the Belgian population indicates genetic heterogeneity. Inflamm Bowel Dis 2000;6:165–170.
  28. Lesage S, Zouli 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.
  29. Murch SH, Lamkin VA, Savage MO, Walker-Smith JA, MacDonald TT: Serum concentrations of tumour necrosis factor-α in childhood chronic inflammatory bowel disease. Gut 1991;32:913–917.
  30. Braegger CP, Nichoos S, Murch SH, Stephens S, MacDonald TT: Tumor necrosis factor-α in stool as a marker of intestinal inflammation. Lancet 1992;339:89–91.
  31. Breese EJ, Michie CA, Nicholls SW, Murch SH, Williams CB, Domizio P, Walker-Smithe JA, MacDonald TT: Tumor necrosis factor-α-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology 1994;106:1455–1466.
  32. Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott RP, Raedler A: Enhanced secretion of tumour necrosis factor-α, IL-6 and IL-1β by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol 1993;94:174–181.
  33. Targan SR, Hanauer SB, Van Deventer SJ, Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor-α for Crohn’s disease. N Engl J Med 1997;337:1029–1035.
  34. Stack WA, Mann SD, Roy AJ, Heath P, Sopwith M, Freeman J, Holmes G, Long R, Forbes A, Kamm MA, Hawkey CJ: Randomised controlled trial of CDP571 antibody to tumour necrosis factor-α in Crohn’s disease. Lancet 1997;349:521–524.
  35. Van Dullemen HM, Deventer SJH, Hommes DW, Bijl HA, Jansen J, Tytgat GNJ, Woody J: Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995;109:129–135.
  36. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW: Effects of a polymorphism in the human tumor necrosis factor-α promoter on transcriptional activation. Proc Natl Acad Sci USA 1997;94:3195–3199.
  37. Braun N, Michel U, Ernst BP, Metzner R, Bitsch A, Rieckmann P: Gene polymorphism at position –308 of the tumor necrosis factor-α in multiple sclerosis and its influence on the regulation of TNF-α production. Neurosci Lett 1996;215:75–78.
  38. Kroeger KM, Carville KS, Abraham LJ: The –308 tumor necrosis factor-α promoter polymorphism effects transcription. Mol Immunol 1997;34:391–399.
  39. Louis E, Satsangi J, Rousssomoustakaki M, Parkes M, Fanning G, Welsh K, Jewell D: Cytokine gene polymorphisms in inflammatory bowel disease. Gut 1996;39:705–710.
  40. Bouma G, Xia B, Crusius JB, Bioque G, Koutroubakis I, Von Blomberg BM, Meuwissen SG, Pena AS: Distribution of four polymorphisms in the tumour necrosis factor genes in patients with inflammatory bowel disease. Clin Exp Immunol 1996;103:391–396.
  41. Procaccino F, Reinshagen M, Hoffmann P, Zeeh JM, Lakshmanan J, McRoberts JA, Patel A, French S, Eysselein VE: Protective effect of epidermal growth factor in an experimental model of colitis in rats. Gastroenterology 1994;107:12–17.
  42. Sarosiek J, Bilski J, Murty VL, Slomiany A, Slomiany BL: Role of salivary epidermal growth factor in the maintenance of physiochemical characteristics of oral and gastric mucus coat. Biochem Biophys Res Commun 1988;152:1421–1427.
  43. Yoshida S, Kasuga S, Hirao Y, Fuwa T, Nakagawa S: Effect of biosynthetic human epidermal growth factor on the synthesis and secretion of mucin glycoprotein from primary culture of rabbit fundal mucosa cells. In Vitro Cell Dev Biol 1987;23:460–464.
  44. Kell SM, Hunter O: Epidermal growth factor stimulates synthesis and secretion of mucus glycoproteins in human gastric mucosa. Clin Sci 1990:452–427.
  45. Moriai T, Kobrin MS, Hope C, Speck L, Korc M: A variant epidermal growth factor receptor exhibits altered type α transforming growth factor binding and transmembrane signaling. Proc Natl Acad Sci USA 1994;91:10217–10221.
  46. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA: Prediction of bone density from vitamin D receptor alleles. Nature 1994;367:284–287.
  47. Ingles SA, Ross RK, Yu MC, Irvine RA, La Pera G, Haile RW, Coetzee GA: Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst 1997;89:166–170.
  48. Bellamy R, Ruwende C, Corrah T, McAdam KP, Thursz M, Whittle HC, Hill AV: Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis 1999;179:721–724.
  49. Roy S, Frodsham A, Saha B, Hazra SK, Mascie-Taylor CG, Hill AV: Association of vitamin D receptor genotype with leprosy type. J Infect Dis 1999;179:187–191.
  50. Hill AV: The immunogenetics of human infectious diseases. Annu Rev Immunol 1998;16:593–617.
  51. Mocharla H, Butch AW, Papas AA, Flick JT, Weinstein RS, De Togni P, Jilka RL, Roberson PK, Parfitt AM, Manolagas SC: Quantification of vitamin D receptor mRNA by competitive polymerase chain reaction in PBMC: Lack of correspondence with common allelic variants. J Bone Miner Res 1997;12:726–723

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