Skip to main content

Advertisement

SpringerLink
Log in

The −237C→T promoter polymorphism of the SLC11A1 gene is associated with a protective effect in relation to inflammatory bowel disease in the South African population

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

The purpose of this study was to assess the likelihood that variation in the promoter region of the solute carrier family 11 member 1 gene (SLC11A1) contributes to inflammatory bowel disease (IBD) susceptibility in the South African population. The study cohort included 102 IBD patients, 47 with Crohn's disease (CD) and 55 with ulcerative colitis, and 192 population-matched controls. Mutation analysis revealed two novel alleles for the 5′-(GT)n repeat polymorphism, t(gt)5ac(gt)5ac(gt)6ggcaga(g)6 (allele 8) and t(gt)5ac(gt)5ac(gt)8ggcaga(g)6 (allele 9), and one previously documented point mutation −237C→T. A significantly decreased frequency of the −237C→T promoter polymorphism was observed in the patient group with IBD (p<0.001) and CD (p<0.0006) compared with the population-matched control group. These findings may be related to previous in vitro studies, which demonstrated that the point mutation at nucleotide position −237 represents a functional polymorphism that affects regulation of the upstream 5′-(GT)n repeat polymorphism differentially upon iron loading. Our findings raise the possibility that iron dysregulation mediated by allelic effects of SLC11A1 may contribute to IBD susceptibility.

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

Abbreviations

CARD15 :

caspase recruitment domain-containing protein 15 gene

CD:

Crohn's disease

HEX-SSCP:

heteroduplex single-strand conformation polymorphism

IBD:

inflammatory bowel disease

PAA:

polyacrylamide

PCR:

polymerase chain reaction

RFLP:

restriction fragment length polymorphism

SLC11A1 :

solute carrier family 11 member 1 gene

UC:

ulcerative colitis

References

  1. Sanderson I (1986) Chronic inflammatory bowel disease. Clin Gastroenterol 15:71–87

    PubMed  CAS  Google Scholar 

  2. Griffiths A (1995) Inflammatory bowel disease. Adolesc Med 6:351–368

    PubMed  Google Scholar 

  3. Snook J, de Silva H, Jewell D (1989) The association of autoimmune disorders with inflammatory bowel disease. Q J Med 72:835–840

    PubMed  CAS  Google Scholar 

  4. Yang H, Rotter J (1993) The genetics of inflammatory bowel disease. In: Targan S, Shanahan F (eds) Inflammatory bowel disease: from bench to bedside. Williams and Wilkins, Baltimore, p 32

    Google Scholar 

  5. Sartor R (1995) Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn's disease. Gastroenterol Clin North Am 24:475–507

    PubMed  CAS  Google Scholar 

  6. Shanahan F (1995) Progress in the pathogenesis of ulcerative colitis. In: Tytgat G, Bartelsman J, Van Deventer S (eds) Inflammatory bowel disease. Kluwer, Dordrecht, pp 32–39

    Google Scholar 

  7. Targan S (1995) Definition of the pathogenesis of Crohn's disease: evolution of a hypothetical model. In: Tytgat G, Bartelsman J, Van Deventer S (eds) Inflammatory bowel disease. Kluwer, Dordrecht, pp 40–47

    Google Scholar 

  8. Satsangi J, Jewell D, Rosenberg W, Bell J (1994) Genetics of inflammatory bowel disease. Gut 35:696–700

    Article  PubMed  CAS  Google Scholar 

  9. Satsangi J, Jewell D, Bell J (1997) The genetics of inflammatory bowel disease. Gut 40:572–574

    PubMed  CAS  Google Scholar 

  10. Hugot J, Chamaillard M, Zouali H, Lesage S, Cezard J, Belaiche J, Almer S, Tysk C, O'Morain C, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel J-F, Sahbatou M, Thomas G (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411:599–603

    Article  PubMed  CAS  Google Scholar 

  11. Ogura Y, Bonen D, Inohara N, Nicolae D, Chen F, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr R, Achkar J, Brant S, Bayless T, Kirschner B, Hanauer S, Nunez G, Cho J (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411:603–606

    Article  PubMed  CAS  Google Scholar 

  12. Hampe J, Cuthbert C, Croucher P, Mirza M, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson A, Bridger S, Van Deventer S, Forbes A, Nikolaus S, Lennard-Jones J, Foelsch U, Krawczak M, Lewis C, Schreiber S, Mathew C (2001) Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 357:1925–1928

    Article  PubMed  CAS  Google Scholar 

  13. Lesage S, Zouali H, Cezard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O'Morain C, Gassull M, Binder V, Finkel Y, Modigliani R, Gower-Rousseau C, Macry J, Merlin F, Chamaillard M, Jannot AS, Thomas G, Hugot JP, EPWG-IBD Group, EPIMAD Group, GETAID Group (2002) CARD15/NOD2 mutational analysis and genotype–phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 70:845–857

    Article  PubMed  CAS  Google Scholar 

  14. Van Heel DA, McGovern DP, Cardon LR, Dechairo BM, Lench NJ, Carey AH, Jewell DP (2002) Fine mapping of the IBD1 locus did not identify Crohn disease-associated NOD2 variants: implications for complex disease genetics. Am J Med Genet 111:253–259

    Article  PubMed  Google Scholar 

  15. Podolsky DK (2002) The current future understanding of inflammatory bowel disease. Best Pract Res Clin Gastroenterol 16:933–943

    Article  PubMed  Google Scholar 

  16. Hofmeister A, Neibergs H, Pokorny R, Galandiuk S (1997) The natural resistance-associated macrophage gene is associated with Crohn's disease. Surgery 122:173–179

    Article  PubMed  CAS  Google Scholar 

  17. Kojima Y, Kinouchi Y, Takahashi S, Negoro K, Hiwatashi N, Shimosegawa T (2001) Inflammatory bowel disease is associated with a novel promoter polymorphism of natural resistance-associated macrophage protein 1 (NRAMP1) gene. Tissue Antigens 58:379–384

    Article  PubMed  CAS  Google Scholar 

  18. Blackwell JM, Searle S, Goswami T, Miller EN (2000) Understanding the multiple functions of Nramp1. Microbes Infect 2:317–321

    Article  PubMed  CAS  Google Scholar 

  19. Weber J, Werre JM, Julius HW, Marx JJ (1988) Decreased iron absorption in patients with active rheumatoid arthritis, with and without iron deficiency. Ann Rheum Dis 47:404–409

    Article  PubMed  CAS  Google Scholar 

  20. Nielsen OJ, Andersen LS, Hansen NE, Hansen TM (1994) Serum transferrin receptor levels in anaemic patients with rheumatoid arthritis. Scand J Clin Lab Invest 54:75–82

    Article  PubMed  CAS  Google Scholar 

  21. Shaw M, Clayton D, Atkinson SE, Williams H, Miller N, Sibthorpe D, Blackwell JM (1996) Linkage of rheumatoid arthritis to the candidate gene NRAMP1 on 2q35. J Med Genet 33:672–677

    PubMed  CAS  Google Scholar 

  22. Sanjeevi CB, Miller EN, Dabadghao P, Rumba I, Shtauvere A, Denisova A, Clayton D, Blackwell JM (2000) Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis. Arthritis Rheum 43:1397–1404

    Article  PubMed  CAS  Google Scholar 

  23. Singal DP, Li J, Zhu Y, Zhang G (2000) NRAMP1 gene polymorphisms in patients with rheumatoid arthritis. Tissue Antigens 55:44–47

    Article  PubMed  CAS  Google Scholar 

  24. Yang YS, Kim SJ, Kim JW, Koh EM (2000) NRAMP1 gene polymorphisms in patients with rheumatoid arthritis in Koreans. J Korean Med Sci 15:83–87

    PubMed  CAS  Google Scholar 

  25. Cazzola M, Ponchio L, de Benedetti F, Ravelli A, Rosti V, Beguin Y, Invernizzi R, Barosi G, Martini A (1996) Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis. Blood 87:4824–4830

    PubMed  CAS  Google Scholar 

  26. Oldenburg B, Koningsberger JC, van Berge Henegouwen GP, van Asbeck BS, Marx JJM (2001) Iron and inflammatory bowel disease. Aliment Pharmacol Ther 15:429–438

    Article  PubMed  CAS  Google Scholar 

  27. Searle S, Blackwell JM (1999) Evidence for a functional repeat polymorphism in the promoter of the human NRAMP1 gene that correlates with autoimmune versus infectious disease susceptibility. J Med Genet 36:295–299

    PubMed  CAS  Google Scholar 

  28. Zaahl MG, Robson KJH, Warnich L, Kotze MJ (2004) Expression of the SLC11A1 (NRAMP1) 5′-(GT)n repeat: opposite effect in the presence of −237C→T. Blood Cell Mol Diseases 33:45–50

    Article  CAS  Google Scholar 

  29. Heikenen J, Werlin S, Brown C, Balint J (1999) Presenting symptoms and diagnostic lag in children with inflammatory bowel disease. Inflamm Bowel Dis 5:158–160

    PubMed  CAS  Google Scholar 

  30. Loubser O, Marais AD, Kotze MJ, Godenir N, Thiart R, Scholtz CL, de Villiers JN, Hillermann R, Firth JC, Weich HF, Maritz F, Jones S, van der Westhuyzen DR (1999) Founder mutations in the LDL receptor gene contribute significantly to the familial hypercholesterolemia phenotype in the indigenous South African population of mixed ancestry. Clin Genet 55:340–345

    Article  PubMed  CAS  Google Scholar 

  31. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  PubMed  CAS  Google Scholar 

  32. Kotze MJ, de Villiers JNP, Rooney RN, Grobbelaar JJ, Mansvelt EPG, Bouwens CS, Carr J, Stander I, du Plessis L (2001) Analysis of the NRAMP1 gene implicated in iron transport: association with multiple sclerosis and age effects. Blood Cells Mol Diseases 27:44–53

    Article  CAS  Google Scholar 

  33. Kotze MJ, Theart L, Callis M, Peeters AV, Thiart R, Langenhoven E (1995) Nonradioactive multiplex PCR screening strategy for the simultaneous detection of multiple low-density lipoprotein receptor gene mutations. PCR Methods Appl 4:352–356

    PubMed  CAS  Google Scholar 

  34. Graham AM, Dollinger MM, Howie SEM, Harrison DJ (2000) Identification of novel alleles at a polymorphic microsatellite repeat region in the human NRAMP1 gene promoter: analysis of allele frequencies in primary biliary cirrhosis. J Med Genet 37:150–152

    Article  PubMed  CAS  Google Scholar 

  35. Lewis LA, Victor TC, Helden EG, Blackwell JM, da Silva-Tatley F, Tullett S, Ehlers M, Beyers N, Donald PR, van Helden PD (1996) Identification of C to T mutation at position −236 bp in the human NRAMP1 gene promoter. Immunogenetics 44:309–311

    Article  PubMed  CAS  Google Scholar 

  36. Stokkers P, de Heer K, Leegwater A, Reitsma P, Tytgat G, van Deventer S (1999) Inflammatory bowel disease and the genes for the natural resistance-associated macrophage protein 1 and the interferon-γ receptor 1. Int J Colorectal Dis 14:13–17

    Article  PubMed  CAS  Google Scholar 

  37. Ruuls SR, Sedgwick JD (1999) Unlinking tumor necrosis factor biology from the major histocompatibility complex: lessons from human genetics and animal models. Am J Hum Genet 65:294–301

    Article  PubMed  CAS  Google Scholar 

  38. Koss K, Satsangi J, Fanning GC, Welsh KI, Jewell DP (2000) Cytokine (TNF-alpha, LT-alpha, and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies. Genes Immun 1:185–190

    Article  PubMed  CAS  Google Scholar 

  39. Sashio H, Tamura K, Ito R, Yamamoto Y, Bamba H, Kosaka T, Fukui S, Sawada K, Fukuda Y, Tamura K, Satomi M, Shimoyama T, Furuyama J (2002) Polymorphisms of the TNF gene and the TNF receptor superfamily member 1B gene are associated with susceptibility to ulcerative colitis and Crohn's disease, respectively. Immunogenetics 53:1020–1027

    Article  PubMed  CAS  Google Scholar 

  40. Van Montfrans C, Peppelenbosch M, te Velde AA, van Deventer S (2002) Inflammatory signal transduction in Crohn's disease and novel therapeutic approaches. Biochem Pharmacol 64:789–795

    Article  PubMed  Google Scholar 

  41. O'Callaghan NJ, Adams KE, Walker EJ, van Heel DA, Cavanaugh JA (2003) Association of TNF-α −857 with IBD in the Australian population. Dig Dis Week M1534:524

    Google Scholar 

Download references

Acknowledgements

The Harry and Doris Crossley Foundation, the South African Medical Research Council and the Universities of Stellenbosch and Cape Town supported this work. T Marks is thanked for DNA extraction.

Author information

Authors and Affiliations

  1. Department of Genetics, University of Stellenbosch, Stellenbosch, South Africa

    Monique G. Zaahl & Louise Warnich

  2. Gastrointestinal Clinic, Groote Schuur Hospital, Cape Town, South Africa

    Trevor A. Winter

  3. Genecare Molecular Genetics, Christiaan Barnard Memorial Hospital, Cape Town, South Africa

    Maritha J. Kotze

Authors
  1. Monique G. Zaahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Trevor A. Winter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Louise Warnich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maritha J. Kotze
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monique G. Zaahl.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zaahl, M.G., Winter, T.A., Warnich, L. et al. The −237C→T promoter polymorphism of the SLC11A1 gene is associated with a protective effect in relation to inflammatory bowel disease in the South African population. Int J Colorectal Dis 21, 402–408 (2006). https://doi.org/10.1007/s00384-005-0019-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-005-0019-z

Keywords

Search

Navigation