Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria

Abstract

Genetic variation in cytokine promoter regions is postulated to influence susceptibility to infection, but the molecular mechanisms by which such polymorphisms might affect gene regulation are unknown. Through systematic DNA footprinting of the TNF (encoding tumour necrosis factor, TNF) promoter region, we have identified a single nucleotide polymorphism (SNP) that causes the helix-turn-helix transcription factor OCT-1 to bind to a novel region of complex protein-DNA interactions and alters gene expression in human monocytes. The OCT-1-binding genotype, found in approximately 5% of Africans, is associated with fourfold increased susceptibility to cerebral malaria in large case-control studies of West African and East African populations, after correction for other known TNF polymorphisms and linked HLA alleles.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Protein-DNA interactions in the region of the TNF-376 polymorphism.
Figure 2: Competition EMSA investigating binding at sites α and β.
Figure 3: Ultraviolet-crosslinking experiments investigating protein complexes binding at site α.
Figure 4: Binding of OCT-1 in the presence of the adenine substitution at nt –376.
Figure 5: G→A substitution at nt –376 may induce DNA bending.

References

  1. Wilson, A.G. et al. An allelic polymorphism within the human tumor factor α promoter region is strongly associated with HLA A1, B8 and DR3 alleles. J. Exp. Med. 177, 557–560 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. D'Alfonso, S. & Richiardi, P.M. A polymorphic variation in a putative regulation box of the TNFA promoter region. Immunogenetics 39, 150–154 ( 1994).

    CAS  PubMed  Google Scholar 

  3. Hamann, A., Mantzoros, C., Vidal-Puig, A. & Flier, J.S. Genetic variability in the TNF-α promoter is not associated with type II diabetes mellitus (NIDDM). Biochem. Biophys. Res. Commun. 211, 833–839 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. McGuire, W., Hill, A.V.S., Allsopp, C.E.M., Greenwood, B.M. & Kwiatkowski, D. Variation in the TNF-α promoter region associated with susceptibility to cerebral malaria. Nature 371, 508–511 ( 1994).

    Article  CAS  PubMed  Google Scholar 

  5. Cabrera, M. et al. Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. J. Exp. Med. 182, 1259–1264 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Nadel, S., Newport, M.J., Booy, R. & Levin, M. Variation in the tumor necrosis factor-α gene promoter region may be associated with death from meningococcal disease. J. Infect. Dis. 174 , 878–880 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Roy, S. et al. Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy. J. Infect. Dis. 176, 530–532 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Conway, D.J. et al. Scarring trachoma is associated with polymorphism in the tumor necrosis factor α (TNF-α) gene promoter and with elevated TNF-α levels in tear fluid. Infect. Immun. 65, 1003–1006 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Moffatt, M.F. & Cookson, W.O.C.M. Tumour necrosis factor haplotypes and asthma. Hum. Mol. Genet. 6, 551– 554 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Wilson, A.G., Symons, J.A., McDowell, T.L., McDevitt, H.O. & Duff, G.W. Effects of a polymorphism in the human tumor necrosis factor α promoter on transcriptional activation. Proc. Natl Acad. Sci. USA 94, 3195– 3199 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brinkman, B.M.N., Zuijdgeest, D., Kaigzel, E.L., Breedveld, F.C. & Verweij, C.L. Relevance of the tumor necrosis factor α-308 promoter polymorphism in TNF α gene regulation. J. Inflamm. 46, 32–41 ( 1996).

    CAS  Google Scholar 

  12. Ziegler-Heitbrock, H.W.L. et al. Establishment of a human cell line (MonoMac 6) with characteristics of mature monocytes. Int. J. Cancer 41, 456–461 (1988).

    Article  CAS  PubMed  Google Scholar 

  13. Fletcher, C., Heintz, N. & Roeder, R.G. Purification and characterization of OTF-1, a transcription factor regulating cell cycle expression of a human histone H2b gene. Cell 51, 773–781 ( 1987).

    Article  CAS  PubMed  Google Scholar 

  14. Herr, W. & Cleary, M.A. The POU domain: versatility in transcriptional regulation by a flexible two-in-one DNA-binding domain. Genes Dev. 9, 1679–1693 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Clark, I.A. Cell-mediated immunity in protection and pathology of malaria. Parasitol. Today 3, 300–305 (1987).

    Article  CAS  PubMed  Google Scholar 

  16. Kwiatkowski, D. Malarial toxins and the regulation of parasite density. Parasitol. Today 11, 206–212 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  17. Grau, G.E. et al. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science 237, 1210–1212 (1987).

    Article  CAS  PubMed  Google Scholar 

  18. Grau, G.E. et al. Tumor necrosis factor and disease severity in children with falciparum malaria. N. Engl. J. Med. 320, 1586–1591 (1989).

    Article  CAS  PubMed  Google Scholar 

  19. Hill, A.V.S. et al. Common West African HLA antigens are associated with protection from severe malaria. Nature 352, 595– 600 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Brinkman, B.M.N., Keet, I.P.M., Miedema, F., Verweij, C.L. & Klein, M.R. Polymorphisms within the human tumor necrosis factor-α promoter region in human immunodeficiency virus type-1 seropositive persons. J. Infect. Dis. 175, 188–190 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Kaushansky, K., Shoemaker, S.G., O'Rork, C.A. & McCarty, J.M. Coordinate regulation of multiple human lymphokine genes by Oct-1 and potentially novel 45 and 43 kDa polypeptides. J. Immunol. 152, 1812–1820 (1994).

    CAS  PubMed  Google Scholar 

  22. Wu, G.D., Lai, E.J., Huang, N. & Wen, X. Oct-1 and CCAAT/enhancer-binding protein (C/EBP) bind to overlapping elements within the interleukin-8 promoter. The role of Oct-1 as a transcriptional repressor. J. Biol. Chem. 272, 2396–2403 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  23. Berendt, A.R., Simmons, D.L., Tansey, J., Newbold, C.I. & Marsh, K. Intercellular adhesion molecule 1 is an endothelial cell adhesion receptor for Plasmodium falciparum. Nature 341, 57–59 (1989).

    Article  CAS  PubMed  Google Scholar 

  24. Newbold, C. et al. Receptor-specific adhesion and clinical disease in Plasmodium falciparum. Am. J. Trop. Med. Hyg. 57, 389 –398 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Fong, C.W., Siddiqui, A.H. & Mark, D.F. Identification and characterisation of a novel repressor site in the human tumor necrosis factor α gene. Nucleic Acids Res. 22, 1108–1114 ( 1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Brinkman, B.M.N. et al. Tumour necrosis factor α gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease. Br. J. Rheumatol. 36, 516–521 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Hohler, T. et al. A TNF-α promoter polymorphism is associated with juvenile onset psoriasis and psoriatic arthritis. J. Invest. Dermatol. 109, 562–565 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Zuckerkandl, E. Neutral and nonneutral mutations: the creative mix—evolution of complexity in gene interaction systems. J. Mol. Evol. 44, S2–S8 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Udalova, I.A., Knight, J.C., Vidal, V., Nedospasov, S.A. & Kwiatkowski, D. Complex NF-κB interactions at the distal tumor necrosis factor promoter region in human monocytes. J. Biol. Chem. 273, 21178–21186 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  30. Schreiber, E., Matthias, P., Muller, M. & Schaffner, W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 17, 6419 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sandaltzopoulos, R. & Becker, P.B. Solid phase DNase I footprinting: quick and versatile. Nucleic Acids Res. 22, 1511–1515 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hansen, S.K. et al. A novel complex between the p65 subunit of NF-κB and c-rel binds to a DNA element involved in phorbol ester induction of the human urokinase gene. EMBO J. 11, 205– 213 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nordeen, S.K. Luciferase reporter gene vectors for analysis of promoters and enhancers. BioTechniques 6, 454–458 (1988).

    CAS  PubMed  Google Scholar 

  34. Udalova, I.A., Turetskaya, R.L., Kuprash, D.V. & Nedospasov, S.A. Two-step activation of human TNF gene transcription in macrophages. Role of NF-κB/Rel family members in LPS activation. Dokl. Acad. Nauk 342, 413–417 ( 1995).

    CAS  Google Scholar 

  35. Stuber, F. et al. -308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter. J. Inflamm. 46, 42–50 (1996).

    CAS  Google Scholar 

  36. Shakhov, A.N., Collart, M.A., Vassalli, P., Nedospasov, S.A. & Jongeneel, C.V. κB-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor α gene in primary macrophages. J. Exp. Med. 171, 35–47 ( 1990).

    Article  CAS  PubMed  Google Scholar 

  37. Snow, R.W. et al. Periodicity and space-time clustering of severe malaria on the coast of Kenya. Trans. R. Soc. Trop. Med. Hyg. 87, 386–390 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Molyneux, M.E., Taylor, T.E., Wirima, J.J. & Borgstein, A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q. J. Med. 71, 441–459 (1989).

    CAS  PubMed  Google Scholar 

  39. Lewontin, R.C. The interaction of selection and linkage. General considerations: heterotic models. Genetics 49, 49– 67 (1964).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank R. Snow, Nick Anstey, S. Bennett and our medical and scientific colleagues in The Gambia and Kenya who made these case-control studies possible; M. Gravenor for assistance with statistical analysis; V. Vidal and J. Frampton for technical advice; D. Roberts for assistance with DNA collection; K. Allsopp for HLA typing; and H. Ackerman for critical comments. Funded by the Medical Research Council (J.K., I.U., B.M.G., D.K.) and the Wellcome Trust (A.V.S.H., N.P., K.M.).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Julian C. Knight or Dominic Kwiatkowski.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Knight, J., Udalova, I., Hill, A. et al. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet 22, 145–150 (1999). https://doi.org/10.1038/9649

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/9649

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing