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Is there a future for TNF promoter polymorphisms?

Genes & Immunity volume 5, pages 315–329 (2004)Cite this article

Abstract

The in vitro study of TNF promoter polymorphism (SNP) function was stimulated by the numerous case–control (association) studies of the polymorphisms in relation to human disease and the appearance of several studies claiming to show a functional role for these SNPs provided a further impetus to researchers interested in the role of TNF in their disease of interest. In this review we consider case–control studies, concentrating on the autoimmune and inflammatory diseases rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and asthma, and on infectious diseases including malaria, hepatitis B and C infection, leprosy and sepsis/septic shock. We also review the available evidence on the functional role of the various TNF promoter polymorphisms. In general, case–control studies have produced mixed results, with little consensus in most cases on whether any TNF polymorphisms are actually associated with disease, although results have been more consistent in the case of infectious diseases, particularly malaria. Functional studies have also produced mixed results but recent work suggests that the much studied −308G/A polymorphism is not functional, while the function of other TNF polymorphisms remains controversial. Studies of the TNF region are increasingly using extended haplotypes that can better capture the variation of the MHC region.

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References

  1. Beutler BA . The role of tumor necrosis factor in health and disease. J Rheumatol 1999; 26 (Suppl 57): 16–21.

    Google Scholar 

  2. Keffer J, Probert L, Cazlaris H et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 1991; 10: 4025–4031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rothe J, Lesslauer W, Lotscher H et al. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 1993; 364: 798–802.

    Article  CAS  PubMed  Google Scholar 

  4. Targan SR, Hanauer SB, van Deventer SJ et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med 1997; 337: 1029–1035.

    Article  CAS  PubMed  Google Scholar 

  5. Maini RN, Taylor PC, Paleolog E et al. Anti-tumour necrosis factor specific antibody (infliximab) treatment provides insights into the pathophysiology of rheumatoid arthritis. Ann Rheum Dis 1999; 58 (Suppl 1): I56–I60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Keane J, Gershon S, Wise RP et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345: 1098–1104.

    Article  CAS  PubMed  Google Scholar 

  7. van der Linden MW, Huizinga TW, Stoeken DJ . Determination of tumour necrosis factor-alpha and interleukin-10 production in a whole blood stimulation system: assessment of laboratory error and individual variation. J Immunol Methods 1998; 218: 63–71.

    Article  CAS  PubMed  Google Scholar 

  8. Louis E, Franchimont D, Piron A et al. Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 1998; 113: 401–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Westendorp RG, Langermans JA, Huizinga TW et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997; 349: 170–173.

    Article  CAS  PubMed  Google Scholar 

  10. D'Alfonso S, Richiardi PM . A polymorphic variation in a putative regulation box of the TNFA promoter region. Immunogenetics 1994; 39: 150–154.

    CAS  PubMed  Google Scholar 

  11. Higuchi T, Seki N, Kamizono S et al. Polymorphism of the 5′-flanking region of the human tumor necrosis factor (TNF)-alpha gene in Japanese. Tissue Antigens 1998; 51: 605–612.

    Article  CAS  PubMed  Google Scholar 

  12. Uglialoro AM, Turbay D, Pesavento PA et al. Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-alpha gene promoter. Tissue Antigens 1998; 52: 359–367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Brinkman BM, Giphart MJ, Verhoef A et al. Tumor necrosis factor alpha-308 gene variants in relation to major histocompatibility complex alleles and Felty's syndrome. Hum Immunol 1994; 41: 259–266.

    Article  CAS  PubMed  Google Scholar 

  14. Wilson AG, di Giovine FS, Blakemore AI . Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product. Hum Mol Genet 1992; 1: 353.

    Article  CAS  PubMed  Google Scholar 

  15. Brinkman BM, Kaijzel EL, Huizinga TW et al. Detection of a C-insertion polymorphism within the human tumor necrosis factor alpha (TNFA) gene. Hum Genet 1995; 96: 493.

    Article  CAS  PubMed  Google Scholar 

  16. Hamann A, Mantzoros C, Vidal-Puig A, Flier JS . Genetic variability in the TNF-alpha promoter is not associated with type II diabetes mellitus (NIDDM). Biochem Biophys Res Commun 1995; 211: 833–839.

    Article  CAS  PubMed  Google Scholar 

  17. Jongeneel CV . Transcriptional regulation of the tumor necrosis factor alpha gene. Immunobiology 1995; 193: 210–216.

    Article  CAS  PubMed  Google Scholar 

  18. Pauli U . Control of tumor necrosis factor gene expression. Crit Rev Eukaryot Gene Exp 1994; 4: 323–344.

    Article  CAS  Google Scholar 

  19. Caput D, Beutler B, Hartog K et al. Identification of a common nucleotide sequence in the 3′-untranslated region of mRNA molecules specifying inflammatory mediators. Proc Natl Acad Sci USA 1986; 83: 1670–1674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Grell M, Douni E, Wajant H et al. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 1995; 83: 793–802.

    Article  CAS  PubMed  Google Scholar 

  21. Mohan MJ, Seaton T, Mitchell J et al. The tumor necrosis factor-alpha converting enzyme (TACE): a unique metalloproteinase with highly defined substrate selectivity. Biochemistry 2002; 41: 9462–9469.

    Article  CAS  PubMed  Google Scholar 

  22. Aderka D . The potential biological and clinical significance of the soluble tumor necrosis factor receptors. Cytokine Growth Factor Rev 1996; 7: 231–240.

    Article  CAS  PubMed  Google Scholar 

  23. Cytokine Gene Polymorphisms in Human Disease##2002. http://www.pam.bris.ac.uk/pathandmicro/services/GAI/cytokine4.htm.

  24. Wilson AG, de Vries N, van de Putte LB . A tumour necrosis factor alpha polymorphism is not associated with rheumatoid arthritis. Ann Rheum Dis 1995; 54: 601–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vinasco J, Beraun Y, Nieto A et al. Polymorphism at the TNF loci in rheumatoid arthritis. Tissue Antigens 1997; 49: 74–78.

    Article  CAS  PubMed  Google Scholar 

  26. Martinez A, Fernandez-Arquero M, Pascual-Salcedo D et al. Primary association of tumor necrosis factor-region genetic markers with susceptibility to rheumatoid arthritis. Arthritis Rheum 2000; 43: 1366–1370.

    Article  CAS  PubMed  Google Scholar 

  27. Shibue T, Tsuchiya N, Komata T et al. Tumor necrosis factor alpha 5′-flanking region, tumor necrosis factor receptor II, and HLA-DRB1 polymorphisms in Japanese patients with rheumatoid arthritis. Arthritis Rheum 2000; 43: 753–757.

    Article  CAS  PubMed  Google Scholar 

  28. Seki N, Kamizono S, Yamada A et al. Polymorphisms in the 5′-flanking region of tumor necrosis factor-alpha gene in patients with rheumatoid arthritis. Tissue Antigens 1999; 54: 194–197.

    Article  CAS  PubMed  Google Scholar 

  29. Danis VA, Millington M, Hyland V et al. Increased frequency of the uncommon allele of a tumour necrosis factor alpha gene polymorphism in rheumatoid arthritis and systemic lupus erythematosus. Dis Markers 1995; 12: 127–133.

    Article  CAS  PubMed  Google Scholar 

  30. Yen JH, Chen CJ, Tsai WC et al. Tumor necrosis factor promoter polymorphisms in patients with rheumatoid arthritis in Taiwan. J Rheumatol 2001; 28: 1788–1792.

    CAS  PubMed  Google Scholar 

  31. Cvetkovic JT, Wallberg-Jonsson S, Stegmayr B . Susceptibility for and clinical manifestations of rheumatoid arthritis are associated with polymorphisms of the TNF-alpha, IL-1beta, and IL-1Ra genes. J Rheumatol 2002; 29: 212–219.

    CAS  PubMed  Google Scholar 

  32. Brinkman BM, Huizinga TW, Kurban SS et al. Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease? Br J Rheumatol 1997; 36: 516–521.

    Article  CAS  PubMed  Google Scholar 

  33. van Krugten MV, Huizinga TW, Kaijzel EL et al. Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis. Genes Immun 1999; 1: 91–96.

    Article  CAS  PubMed  Google Scholar 

  34. Fabris M, Di PE, D'Elia A et al. Tumor necrosis factor-alpha gene polymorphism in severe and mild-moderate rheumatoid arthritis. J Rheumatol 2002; 29: 29–33.

    CAS  PubMed  Google Scholar 

  35. Hajeer AH, Dababneh A, Makki RF et al. Different gene loci within the HLA-DR and TNF regions are independently associated with susceptibility and severity in Spanish rheumatoid arthritis patients. Tissue Antigens 2000; 55: 319–325.

    Article  CAS  PubMed  Google Scholar 

  36. Mattey DL, Hassell AB, Dawes PT et al. Independent association of rheumatoid factor and the HLA-DRB1 shared epitope with radiographic outcome in rheumatoid arthritis. Arthritis Rheum 2001; 44: 1529–1533.

    Article  CAS  PubMed  Google Scholar 

  37. Mu H, Chen JJ, Jiang Y et al. Tumor necrosis factor a microsatellite polymorphism is associated with rheumatoid arthritis severity through an interaction with the HLA-DRB1 shared epitope. Arthritis Rheum 1999; 42: 438–442.

    Article  CAS  PubMed  Google Scholar 

  38. Field M, Gallagher G, Eskdale J et al. Tumor necrosis factor locus polymorphisms in rheumatoid arthritis. Tissue Antigens 1997; 50: 303–307.

    Article  CAS  PubMed  Google Scholar 

  39. Udalova IA, Richardson A, Ackerman H . Association of accelerated erosive rheumatoid arthritis with a polymorphism that alters NF-kappaB binding to the TNF promoter region. Rheumatology 2002; 41: 830–831.

    Article  CAS  PubMed  Google Scholar 

  40. Zeggini E, Thomson W, Kwiatkowski D et al. Linkage and association studies of single-nucleotide polymorphism-tagged tumor necrosis factor haplotypes in juvenile oligoarthritis. Arthritis Rheum 2002; 46: 3304–3311.

    Article  CAS  PubMed  Google Scholar 

  41. Mulcahy B, Waldron-Lynch F, McDermott MF et al. Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis. Am J Hum Genet 1996; 59: 676–683.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Ota M, Katsuyama Y, Kimura A et al. A second susceptibility gene for developing rheumatoid arthritis in the human MHC is localized within a 70-kb interval telomeric of the TNF genes in the HLA class III region. Genomics 2001; 71: 263–270.

    Article  CAS  PubMed  Google Scholar 

  43. Okamoto K, Makino S, Yoshikawa Y et al. Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis. Am J Hum Genet 2003; 72: 303–312.

    Article  CAS  PubMed  Google Scholar 

  44. Ozaki K, Ohnishi Y, Iida A et al. Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 2002; 32: 650–654.

    Article  CAS  PubMed  Google Scholar 

  45. Mycko M, Kowalski W, Kwinkowski M et al. Multiple sclerosis: the frequency of allelic forms of tumor necrosis factor and lymphotoxin-alpha. J Neuroimmunol 1998; 84: 198–206.

    Article  CAS  PubMed  Google Scholar 

  46. Braun N, Michel U, Ernst BP et al. Gene polymorphism at position −308 of the tumor-necrosis-factor-alpha (TNF-alpha) in multiple sclerosis and it's influence on the regulation of TNF-alpha production. Neurosci Lett 1996; 215: 75–78.

    CAS  PubMed  Google Scholar 

  47. Lucotte G, Bathelier C, Mercier G . TNF-alpha polymorphisms in multiple sclerosis: no association with −238 and −308 promoter alleles, but the microsatellite allele a11 is associated with the disease in French patients. Mult Scler 2000; 6: 78–80.

    CAS  PubMed  Google Scholar 

  48. Sotgiu S, Pugliatti M, Serra C et al. Tumor necrosis factor 2 allele does not contribute to increased tumor necrosis factor-alpha production in Sardinian multiple sclerosis. Ann Neurol 1999; 46: 799–800.

    Article  CAS  PubMed  Google Scholar 

  49. Trojano M, Liguori M, De Robertis F et al. Comparison of clinical and demographic features between affected pairs of Italian multiple sclerosis multiplex families; relation to tumour necrosis factor genomic polymorphisms. J Neurol Sci 1999; 162: 194–200.

    Article  CAS  PubMed  Google Scholar 

  50. Allcock RJ, de la Concha EG, Fernandez-Arquero M et al. Susceptibility to multiple sclerosis mediated by HLA-DRB1 is influenced by a second gene telomeric of the TNF cluster. Hum Immunol 1999; 60: 1266–1273.

    Article  CAS  PubMed  Google Scholar 

  51. Ma JJ, Nishimura M, Mine H et al. HLA-DRB1 and tumor necrosis factor gene polymorphisms in Japanese patients with multiple sclerosis. J Neuroimmunol 1998; 92: 109–112.

    Article  CAS  PubMed  Google Scholar 

  52. Anlar B, Alikasifoglu M, Kose G et al. Tumor necrosis factor-alpha gene polymorphisms in children with multiple sclerosis. Neuropediatrics 2001; 32: 214–216.

    Article  CAS  PubMed  Google Scholar 

  53. Weinshenker BG, Wingerchuk DM, Liu Q et al. Genetic variation in the tumor necrosis factor alpha gene and the outcome of multiple sclerosis. Neurology 1997; 49: 378–385.

    Article  CAS  PubMed  Google Scholar 

  54. He B, Navikas V, Lundahl J, Soderstrom M, Hillert J . Tumor necrosis factor alpha-308 alleles in multiple sclerosis and optic neuritis. J Neuroimmunol 1995; 63: 143–147.

    Article  CAS  PubMed  Google Scholar 

  55. Wingerchuk D, Liu Q, Sobell J, Sommer S, Weinshenker BG . A population-based case–controlstudy of the tumor necrosis factor alpha-308 polymorphism in multiple sclerosis. Neurology 1997; 49: 626–628.

    Article  CAS  PubMed  Google Scholar 

  56. Huizinga TW, Westendorp RG, Bollen EL et al. TNF-alpha promoter polymorphisms, production and susceptibility to multiple sclerosis in different groups of patients. J Neuroimmunol 1997; 72: 149–153.

    Article  CAS  PubMed  Google Scholar 

  57. Epplen C, Jackel S, Santos EJ et al. Genetic predisposition to multiple sclerosis as revealed by immunoprinting. Ann Neurol 1997; 41: 341–352.

    Article  CAS  PubMed  Google Scholar 

  58. Maurer M, Kruse N, Giess R et al. Gene polymorphism at position −308 of the tumor necrosis factor alpha promotor is not associated with disease progression in multiple sclerosis patients. J Neurol 1999; 246: 949–954.

    Article  CAS  PubMed  Google Scholar 

  59. Fernandez-Arquero M, Arroyo R, Rubio A et al. Primary association of a TNF gene polymorphism with susceptibility to multiple sclerosis. Neurology 1999; 53: 1361–1363.

    Article  CAS  PubMed  Google Scholar 

  60. Verjans GM, van der Linden SM, van Eys GJ, de Waal LP, Kijlstra A . Restriction fragment length polymorphism of the tumor necrosis factor region in patients with ankylosing spondylitis. Arthritis Rheum 1991; 34: 486–489.

    Article  CAS  PubMed  Google Scholar 

  61. Verjans GM, Brinkman BM, Van Doornik CE, Kijlstra A, Verweij CL . Polymorphism of tumour necrosis factor-alpha (TNF-alpha) at position −308 in relation to ankylosing spondylitis. Clin Exp Immunol 1994; 97: 45–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Fraile A, Nieto A, Beraun Y et al. Tumor necrosis factor gene polymorphisms in ankylosing spondylitis. Tissue Antigens 1998; 51: 386–390.

    Article  CAS  PubMed  Google Scholar 

  63. Hohler T, Schaper T, Schneider PM, Meyer zum Buschenfelde KH, Marker-Hermann E . Association of different tumor necrosis factor alpha promoter allele frequencies with ankylosing spondylitis in HLA-B27 positive individuals. Arthritis Rheum 1998; 41: 1489–1492.

    Article  CAS  PubMed  Google Scholar 

  64. Milicic A, Lindheimer F, Laval S et al. Interethnic studies of TNF polymorphisms confirm the likely presence of a second MHC susceptibility locus in ankylosing spondylitis. Genes Immun 2000; 1: 418–422.

    Article  CAS  PubMed  Google Scholar 

  65. Martinez-Borra J, Gonzalez S, Lopez-Vazquez A et al. HLA-B27 alone rather than B27-related class I haplotypes contributes to ankylosing spondylitis susceptibility. Hum Immunol 2000; 61: 131–139.

    Article  CAS  PubMed  Google Scholar 

  66. Gonzalez S, Torre-Alonso JC, Martinez-Borra J et al. TNF-238A promoter polymorphism contributes to susceptibility to ankylosing spondylitis in HLA-B27 negative patients. J Rheumatol 2001; 28: 1288–1293.

    CAS  PubMed  Google Scholar 

  67. Kaijzel EL, Brinkman BM, van Krugten MV et al. Polymorphism within the tumor necrosis factor alpha (TNF) promoter region in patients with ankylosing spondylitis. Hum Immunol 1999; 60: 140–144.

    Article  CAS  PubMed  Google Scholar 

  68. Chagani T, Pare PD, Zhu S et al. Prevalence of tumor necrosis factor-alpha and angiotensin converting enzyme polymorphisms in mild/moderate and fatal/near-fatal asthma. Am J Respir Crit Care Med 1999; 160: 278–282.

    Article  CAS  PubMed  Google Scholar 

  69. Witte JS, Palmer LJ, O'Connor RD, Hopkins PJ, Hall JM . Relation between tumour necrosis factor polymorphism TNFalpha −308 and risk of asthma. Eur J Hum Genet 2002; 10: 82–85.

    Article  CAS  PubMed  Google Scholar 

  70. Winchester EC, Millwood IY, Rand L, Penny MA, Kessling AM . Association of the TNF-alpha −308 (G → A) polymorphism with self-reported history of childhood asthma. Hum Genet 2000; 107: 591–596.

    Article  CAS  PubMed  Google Scholar 

  71. Trabetti E, Patuzzo C, Malerba G et al. Association of a lymphotoxin alpha gene polymorphism and atopy in Italian families. J Med Genet 1999; 36: 323–325.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Louis R, Leyder E, Malaise M, Bartsch P, Louis E . Lack of association between adult asthma and the tumour necrosis factor alpha −308 polymorphism gene. Eur Respir J 2000; 16: 604–608.

    Article  CAS  PubMed  Google Scholar 

  73. Albuquerque RV, Hayden CM, Palmer LJ et al. Association of polymorphisms within the tumour necrosis factor (TNF) genes and childhood asthma. Clin Exp Allergy 1998; 28: 578–584.

    Article  CAS  PubMed  Google Scholar 

  74. Moffatt MF, Cookson WO . Tumour necrosis factor haplotypes and asthma. Hum Mol Genet 1997; 6: 551–554.

    Article  CAS  PubMed  Google Scholar 

  75. Moffatt MF, James A, Ryan G, Musk AW, Cookson WO . Extended tumour necrosis factor/HLA-DR haplotypes and asthma in an Australian population sample. Thorax 1999; 54: 757–761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li Kam Wa TC, Mansur AH, Britton J et al. Association between −308 tumour necrosis factor promoter polymorphism and bronchial hyperreactivity in asthma. Clin Exp Allergy 1999; 29: 1204–1208.

    Article  CAS  PubMed  Google Scholar 

  77. Cabrera M, Shaw MA, Sharples C et al. Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. J Exp Med 1995; 182: 1259–1264.

    Article  CAS  PubMed  Google Scholar 

  78. Karplus TM, Jeronimo SM, Chang H et al. Association between the tumor necrosis factor locus and the clinical outcome of Leishmania chagasi infection. Infect Immun 2002; 70: 6919–6925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Blackwell JM, Black GF, Peacock CS et al. Immunogenetics of leishmanial and mycobacterial infections: the Belem Family Study. Philos Trans Roy Soc London B Biol Sci 1997; 352: 1331–1345.

    Article  CAS  Google Scholar 

  80. Nadel S, Newport MJ, Booy R, Levin M . Variation in the tumor necrosis factor-alpha gene promoter region may be associated with death from meningococcal disease. J Infect Dis 1996; 174: 878–880.

    Article  CAS  PubMed  Google Scholar 

  81. Read RC, Camp NJ, di Giovine FS et al. An interleukin-1 genotype is associated with fatal outcome of meningococcal disease. J Infect Dis 2000; 182: 1557–1560.

    Article  CAS  PubMed  Google Scholar 

  82. Shaw MA, Collins A, Peacock CS et al. Evidence that genetic susceptibility to Mycobacterium tuberculosis in a Brazilian population is under oligogenic control: linkage study of the candidate genes NRAMP1 and TNFA. Tuberc Lung Dis 1997; 78: 35–45.

    Article  CAS  Google Scholar 

  83. Khoo SH, Pepper L, Snowden N et al. Tumour necrosis factor c2 microsatellite allele is associated with the rate of HIV disease progression. AIDS 1997; 11: 423–428.

    Article  CAS  PubMed  Google Scholar 

  84. Roy S, McGuire W, Mascie-Taylor CG et al. Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy. J Infect Dis 1997; 176: 530–532.

    Article  CAS  PubMed  Google Scholar 

  85. Santos AR, Suffys PN, Vanderborght PR et al. Role of tumor necrosis factor-alpha and interleukin-10 promoter gene polymorphisms in leprosy. J Infect Dis 2002; 186: 1687–1691.

    Article  CAS  PubMed  Google Scholar 

  86. Santos AR, Almeida AS, Suffys PN et al. Tumor necrosis factor promoter polymorphism (TNF2) seems to protect against development of severe forms of leprosy in a pilot study in Brazilian patients. Int J Leprosy Other Mycobact Dis 2000; 68: 325–327.

    CAS  Google Scholar 

  87. Shaw MA, Donaldson IJ, Collins A et al. Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes. Genes Immun 2001; 2: 196–204.

    Article  CAS  PubMed  Google Scholar 

  88. Moraes MO, Duppre NC, Suffys PN et al. Tumor necrosis factor-alpha promoter polymorphism TNF2 is associated with a stronger delayed-type hypersensitivity reaction in the skin of borderline tuberculoid leprosy patients. Immunogenetics 2001; 53: 45–47.

    Article  CAS  PubMed  Google Scholar 

  89. Sarno EN, Santos AR, Jardim MR et al. Pathogenesis of nerve damage in leprosy: genetic polymorphism regulates the production of TNF alpha. Leprosy Rev 2000; 71 (Suppl): S154–S158.

    PubMed  Google Scholar 

  90. Bochud PY, Hawn TR, Aderem A . Cutting edge: a Toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J Immunol 2003; 170: 3451–3454.

    Article  CAS  PubMed  Google Scholar 

  91. McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D . Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 1994; 371: 508–510.

    Article  CAS  PubMed  Google Scholar 

  92. May J, Lell B, Luty AJ, Meyer CG, Kremsner PG . Plasma interleukin-10:Tumor necrosis factor (TNF)-alpha ratio is associated with TNF promoter variants and predicts malarial complications. J Infect Dis 2000; 182: 1570–1573.

    Article  CAS  PubMed  Google Scholar 

  93. Flori L, Sawadogo S, Esnault C et al. Linkage of mild malaria to the major histocompatibility complex in families living in Burkina Faso. Hum Mol Genet 2003; 12: 375–378.

    Article  CAS  PubMed  Google Scholar 

  94. Meyer CG, May J, Luty AJ, Lell B, Kremsner PG . TNFalpha-308A associated with shorter intervals of Plasmodium falciparum reinfections. Tissue Antigens 2002; 59: 287–292.

    Article  CAS  PubMed  Google Scholar 

  95. Mombo LE, Ntoumi F, Bisseye C et al. Human genetic polymorphisms and asymptomatic Plasmodium falciparum malaria in Gabonese schoolchildren. Am J Trop Med Hyg 2003; 68: 186–190.

    Article  CAS  PubMed  Google Scholar 

  96. Ubalee R, Suzuki F, Kikuchi M et al. Strong association of a tumor necrosis factor-alpha promoter allele with cerebral malaria in Myanmar. Tissue Antigens 2001; 58: 407–410.

    Article  CAS  PubMed  Google Scholar 

  97. Aidoo M, McElroy PD, Kolczak MS et al. Tumor necrosis factor-alpha promoter variant 2 (TNF2) is associated with pre-term delivery, infant mortality, and malaria morbidity in western Kenya: Asembo Bay Cohort Project IX. Genet Epidemiol 2001; 21: 201–211.

    Article  CAS  PubMed  Google Scholar 

  98. Wattavidanage J, Carter R, Perera KL et al. TNFalpha*2 marks high risk of severe disease during Plasmodium falciparum malaria and other infections in Sri Lankans. Clin Exp Immunol 1999; 115: 350–355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Stirnadel HA, Stockle M, Felger I et al. Malaria infection and morbidity in infants in relation to genetic polymorphisms in Tanzania. Trop Med Int Health 1999; 4: 187–193.

    Article  CAS  PubMed  Google Scholar 

  100. Miyazoe S, Hamasaki K, Nakata K et al. Influence of interleukin-10 gene promoter polymorphisms on disease progression in patients chronically infected with hepatitis B virus. Am J Gastroenterol 2002; 97: 2086–2092.

    Article  CAS  PubMed  Google Scholar 

  101. Kim YJ, Lee HS, Yoon JH et al. Association of TNF-alpha promoter polymorphisms with the clearance of hepatitis B virus infection. Hum Mol Genet 2003; 12: 2541–2546.

    Article  CAS  PubMed  Google Scholar 

  102. Hohler T, Kruger A, Gerken G et al. A tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism is associated with chronic hepatitis B infection. Clin Exp Immunol 1998; 111: 579–582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Yu ML, Dai CY, Chiu CC et al. Tumor necrosis factor alpha promoter polymorphisms at position −308 in Taiwanese chronic hepatitis C patients treated with interferon-alpha. Antiviral Res 2003; 59: 35–40.

    Article  CAS  PubMed  Google Scholar 

  104. Constantini PK, Wawrzynowicz-Syczewska M, Clare M et al. Interleukin-1, interleukin-10 and tumour necrosis factor-alpha gene polymorphisms in hepatitis C virus infection: an investigation of the relationships with spontaneous viral clearance and response to alpha-interferon therapy. Liver 2002; 22: 404–412.

    Article  CAS  PubMed  Google Scholar 

  105. Rosen HR, McHutchison JG, Conrad AJ et al. Tumor necrosis factor genetic polymorphisms and response to antiviral therapy in patients with chronic hepatitis C. Am J Gastroenterol 2002; 97: 714–720.

    Article  CAS  PubMed  Google Scholar 

  106. Vidigal PG, Germer JJ, Zein NN . Polymorphisms in the interleukin-10, tumor necrosis factor-alpha, and transforming growth factor-beta1 genes in chronic hepatitis C patients treated with interferon and ribavirin. J Hepatol 2002; 36: 271–277.

    Article  CAS  PubMed  Google Scholar 

  107. Kimball P, Elswick RK, Shiffman M . Ethnicity and cytokine production gauge response of patients with hepatitis C to interferon-alpha therapy. J Med Virol 2001; 65: 510–516.

    Article  CAS  PubMed  Google Scholar 

  108. Knolle PA, Kremp S, Hohler T et al. Viral and host factors in the prediction of response to interferon-alpha therapy in chronic hepatitis C after long-term follow-up. J Viral Hepatitis 1998; 5: 399–406.

    Article  CAS  Google Scholar 

  109. Yee LJ, Tang J, Herrera J, Kaslow RA, van Leeuwen DJ . Tumor necrosis factor gene polymorphisms in patients with cirrhosis from chronic hepatitis C virus infection. Genes Immun 2000; 1: 386–390.

    Article  CAS  PubMed  Google Scholar 

  110. Schiemann U, Glas J, Torok P et al. Response to combination therapy with interferon alfa-2a and ribavirin in chronic hepatitis C according to a TNF-alpha promoter polymorphism. Digestion 2003; 68: 1–4.

    Article  CAS  PubMed  Google Scholar 

  111. Tokushige K, Tsuchiya N, Hasegawa K et al. Influence of TNF gene polymorphism and HLA-DRB1 haplotype in Japanese patients with chronic liver disease caused by HCV. Am J Gastroenterol 2003; 98: 160–166.

    Article  CAS  PubMed  Google Scholar 

  112. Wang Y, Kato N, Hoshida Y et al. Interleukin-1beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology 2003; 37: 65–71.

    Article  CAS  PubMed  Google Scholar 

  113. Tambur AR, Ortegel JW, Ben Ari Z et al. Role of cytokine gene polymorphism in hepatitis C recurrence and allograft rejection among liver transplant recipients. Transplantation 2001; 71: 1475–1480.

    Article  CAS  PubMed  Google Scholar 

  114. Powell EE, Edwards-Smith CJ, Hay JL et al. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 2000; 31: 828–833.

    Article  CAS  PubMed  Google Scholar 

  115. Jonsson JR, Hong C, Purdie DM et al. Role of cytokine gene polymorphisms in acute rejection and renal impairment after liver transplantation. Liver Transplant 2001; 7: 255–263.

    Article  CAS  Google Scholar 

  116. Lio D, Caruso C, Di Stefano R et al. IL-10 and TNF-alpha polymorphisms and the recovery from HCV infection. Hum Immunol 2003; 64: 674–680.

    Article  CAS  PubMed  Google Scholar 

  117. Hohler T, Kruger A, Gerken G et al. Tumor necrosis factor alpha promoter polymorphism at position −238 is associated with chronic active hepatitis C infection. J Med Virol 1998; 54: 173–177.

    Article  CAS  PubMed  Google Scholar 

  118. Stuber F, Udalova IA, Book M 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 1995; 46: 42–50.

    PubMed  Google Scholar 

  119. Mira JP, Cariou A, Grall F et al. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA 1999; 282: 561–568.

    Article  CAS  PubMed  Google Scholar 

  120. O'Keefe GE, Hybki DL, Munford RS . The G → A single nucleotide polymorphism at the −308 position in the tumor necrosis factor-alpha promoter increases the risk for severe sepsis after trauma. J Trauma 2002; 52: 817–825.

    CAS  PubMed  Google Scholar 

  121. Tang GJ, Huang SL, Yien HW et al. Tumor necrosis factor gene polymorphism and septic shock in surgical infection. Crit Care Med 2000; 28: 2733–2736.

    Article  CAS  PubMed  Google Scholar 

  122. Waterer GW, Quasney MW, Cantor RM, Wunderink RG . Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations. Am J Respir Crit Care Med 2001; 163: 1599–1604.

    Article  CAS  PubMed  Google Scholar 

  123. Padyukov L, Hahn-Zoric M, Lau YL, Hanson LA . Different allelic frequencies of several cytokine genes in Hong Kong Chinese and Swedish Caucasians. Genes Immun 2001; 2: 280–283.

    Article  CAS  PubMed  Google Scholar 

  124. Zheng C, Huang DR, Bergenbrant S et al. Interleukin 6, tumour necrosis factor alpha, interleukin 1beta and interleukin 1 receptor antagonist promoter or coding gene polymorphisms in multiple myeloma. Br J Haematol 2000; 109: 39–45.

    Article  CAS  PubMed  Google Scholar 

  125. Huang D, Giscombe R, Zhou Y, Lefvert AK . Polymorphisms in CTLA-4 but not tumor necrosis factor-alpha or interleukin 1beta genes are associated with Wegener's granulomatosis. J Rheumatol 2000; 27: 397–401.

    CAS  PubMed  Google Scholar 

  126. Huang DR, Pirskanen R, Matell G, Lefvert AK . Tumour necrosis factor-alpha polymorphism and secretion in myasthenia gravis. J Neuroimmunol 1999; 94: 165–171.

    Article  CAS  PubMed  Google Scholar 

  127. Wu MS, Huang SP, Chang YT et al. Tumor necrosis factor-alpha and interleukin-10 promoter polymorphisms in Epstein–Barr virus-associated gastric carcinoma. J Infect Dis 2002; 185: 106–109.

    Article  CAS  PubMed  Google Scholar 

  128. Huang SL, Su CH, Chang SC . Tumor necrosis factor-alpha gene polymorphism in chronic bronchitis. Am J Respir Crit Care Med 1997; 156: 1436–1439.

    Article  CAS  PubMed  Google Scholar 

  129. Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506–516.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Pritchard JK, Rosenberg NA . Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet 1999; 65: 220–228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Jeffreys AJ, Kauppi L, Neumann R . Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet 2001; 29: 217–222.

    Article  CAS  PubMed  Google Scholar 

  132. Kauppi L, Sajantila A, Jeffreys AJ . Recombination hotspots rather than population history dominate linkage disequilibrium in the MHC class II region. Hum Mol Genet 2003; 12: 33–40.

    Article  CAS  PubMed  Google Scholar 

  133. Cullen M, Perfetto SP, Klitz W, Nelson G, Carrington M . High-resolution patterns of meiotic recombination across the human major histocompatibility complex. Am J Hum Genet 2002; 71: 759–776.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Ahmad T, Neville M, Marshall SE et al. Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHC. Hum Mol Genet 2003; 12: 647–656.

    Article  CAS  PubMed  Google Scholar 

  135. Pociot F, Wilson AG, Nerup J, Duff GW . No independent association between a tumor necrosis factor-alpha promotor region polymorphism and insulin-dependent diabetes mellitus. Eur J Immunol 1993; 23: 3050–3053.

    Article  CAS  PubMed  Google Scholar 

  136. Jawaheer D, Li W, Graham RR et al. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. Am J Hum Genet 2002; 71: 585–594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Baena A, Leung JY, Sullivan AD et al. TNF-alpha promoter single nucleotide polymorphisms are markers of human ancestry. Genes Immun 2002; 3: 482–487.

    Article  CAS  PubMed  Google Scholar 

  138. Ackerman H, Usen S, Mott R et al. Haplotypic analysis of the TNF locus by association efficiency and entropy. Genome Biol 2003; 4: R24.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Ackerman HC, Ribas G, Jallow M et al. Complex haplotypic structure of the central MHC region flanking TNF in a West African population. Genes Immun 2003; 4: 476–486.

    Article  CAS  PubMed  Google Scholar 

  140. de Vries RR . HLA and disease: past, present and future. Neth J Med 1994; 45: 302–308.

    CAS  PubMed  Google Scholar 

  141. Tomlinson IP, Bodmer WF . The HLA system and the analysis of multifactorial genetic disease. Trends Genet 1995; 11: 493–498.

    Article  CAS  PubMed  Google Scholar 

  142. Newton J, Brown MA, Milicic A et al. The effect of HLA-DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin alpha-tumor necrosis factor haplotype. Arthritis Rheum 2003; 48: 90–96.

    Article  CAS  PubMed  Google Scholar 

  143. Scriver CR, Waters PJ . Monogenic traits are not simple: lessons from phenylketonuria. Trends Genet 1999; 15: 267–272.

    Article  CAS  PubMed  Google Scholar 

  144. Weatherall DJ . Phenotype–genotype relationships in monogenic disease: lessons from the thalassaemias. Nat Rev Genet 2001; 2: 245–255.

    Article  CAS  PubMed  Google Scholar 

  145. Mickle JE, Cutting GR . Genotype–phenotype relationships in cystic fibrosis. Med Clin N Am 2000; 84: 597–607.

    Article  CAS  PubMed  Google Scholar 

  146. Summers KM . Relationship between genotype and phenotype in monogenic diseases: relevance to polygenic diseases. Hum Mutat 1996; 7: 283–293.

    Article  CAS  PubMed  Google Scholar 

  147. Jaffe A, Bush A . Cystic fibrosis: review of the decade. Monaldi Arch Chest Dis 2001; 56: 240–247.

    CAS  PubMed  Google Scholar 

  148. Weiss KM, Terwilliger JD . How many diseases does it take to map a gene with SNPs? Nat Genet 2000; 26: 151–157.

    Article  CAS  PubMed  Google Scholar 

  149. Cardon LR, Bell JI . Association study designs for complex diseases. Nat Rev Genet 2001; 2: 91–99.

    Article  CAS  PubMed  Google Scholar 

  150. Risch NJ . Searching for genetic determinants in the new millennium. Nature 2000; 405: 847–856.

    Article  CAS  PubMed  Google Scholar 

  151. Altshuler D, Kruglyak L, Lander E . Genetic polymorphisms and disease. N Engl J Med 1998; 338: 1626.

    Article  CAS  PubMed  Google Scholar 

  152. Dahlman I, Eaves IA, Kosoy R et al. Parameters for reliable results in genetic association studies in common disease. Nat Genet 2002; 30: 149–150.

    Article  CAS  PubMed  Google Scholar 

  153. Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K . A comprehensive review of genetic association studies. Genet Med 2002; 4: 45–61.

    Article  CAS  PubMed  Google Scholar 

  154. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN . Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003; 33: 177–182.

    Article  CAS  PubMed  Google Scholar 

  155. Editorial. Freely associating. Nat Genet 1999; 22: 1–2.

  156. de Jong MM, Nolte IM, de Vries EG et al. The HLA class III subregion is responsible for an increased breast cancer risk. Hum Mol Genet 2003; 12: 2311–2319.

    Article  CAS  PubMed  Google Scholar 

  157. Geist LJ, Hopkins HA, Dai LY et al. Cytomegalovirus modulates transcription factors necessary for the activation of the tumor necrosis factor-alpha promoter. Am J Respir Cell Mol Biol 1997; 16: 31–37.

    Article  CAS  PubMed  Google Scholar 

  158. Wedel A, Sulski G, Ziegler-Heitbrock HW . CCAAT/enhancer binding protein is involved in the expression of the tumour necrosis factor gene in human monocytes. Cytokine 1996; 8: 335–341.

    Article  CAS  PubMed  Google Scholar 

  159. Pope RM, Leutz A, Ness SA . C/EBP beta regulation of the tumor necrosis factor alpha gene. J Clin Invest 1994; 94: 1449–1455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Zagariya A, Mungre S, Lovis R et al. Tumor necrosis factor alpha gene regulation: enhancement of C/EBPbeta-induced activation by c-Jun. Mol Cell Biol 1998; 18: 2815–2824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. McCaffrey PG, Goldfeld AE, Rao A . The role of NFATp in cyclosporin A-sensitive tumor necrosis factor-alpha gene transcription. J Biol Chem 1994; 269: 30445–30450.

    CAS  PubMed  Google Scholar 

  162. Tsai EY, Jain J, Pesavento PA, Rao A, Goldfeld AE . Tumor necrosis factor alpha gene regulation in activated T cells involves ATF-2/Jun and NFATp. Mol Cell Biol 1996; 16: 459–467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Tsai EY, Yie J, Thanos D, Goldfeld AE . Cell-type-specific regulation of the human tumor necrosis factor alpha gene in B cells and T cells by NFATp and ATF-2/JUN. Mol Cell Biol 1996; 16: 5232–5244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kramer B, Meichle A, Hensel G, Charnay P, Kronke M . Characterization of an Krox-24/Egr-1-responsive element in the human tumor necrosis factor promoter. Biochim Biophys Acta 1994; 1219: 413–421.

    Article  CAS  PubMed  Google Scholar 

  165. Leitman DC, Ribeiro RC, Mackow ER, Baxter JD, West BL . Identification of a tumor necrosis factor-responsive element in the tumor necrosis factor alpha gene. J Biol Chem 1991; 266: 9343–9346.

    CAS  PubMed  Google Scholar 

  166. Newell CL, Deisseroth AB, Lopez-Berestein G . Interaction of nuclear proteins with an AP-1/CRE-like promoter sequence in the human TNF-alpha gene. J Leukocyte Biol 1994; 56: 27–35.

    Article  CAS  PubMed  Google Scholar 

  167. Novotny V, Prieschl EE, Csonga R, Fabjani G, Baumruker T . Nrf1 in a complex with fosB, c-jun, junD and ATF2 forms the AP1 component at the TNF alpha promoter in stimulated mast cells. Nucleic Acids Res 1998; 26: 5480–5485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Prieschl EE, Novotny V, Csonga R et al. A novel splice variant of the transcription factor Nrf1 interacts with the TNFalpha promoter and stimulates transcription. Nucleic Acids Res 1998; 26: 2291–2297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Kramer B, Wiegmann K, Kronke M . Regulation of the human TNF promoter by the transcription factor Ets. J Biol Chem 1995; 270: 6577–6583.

    Article  CAS  PubMed  Google Scholar 

  170. Udalova IA, Knight JC, Vidal V, Nedospasov SA, Kwiatkowski D . Complex NF-kappaB interactions at the distal tumor necrosis factor promoter region in human monocytes. J Biol Chem 1998; 273: 21178–21186.

    Article  CAS  PubMed  Google Scholar 

  171. Kuprash DV, Udalova IA, Turetskaya RL et al. Similarities and differences between human and murine TNF promoters in their response to lipopolysaccharide. J Immunol 1999; 162: 4045–4052.

    CAS  PubMed  Google Scholar 

  172. Myokai F, Takashiba S, Lebo R, Amar S . A novel lipopolysaccharide-induced transcription factor regulating tumor necrosis factor alpha gene expression: molecular cloning, sequencing, characterization, and chromosomal assignment. Proc Natl Acad Sci USA 1999; 96: 4518–4523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Takashiba S, Van Dyke TE, Shapira L, Amar S . Lipopolysaccharide-inducible and salicylate-sensitive nuclear factor(s) on human tumor necrosis factor alpha promoter. Infect Immun 1995; 63: 1529–1534.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Pociot F, D'Alfonso S, Compasso S, Scorza R, Richiardi PM . Functional analysis of a new polymorphism in the human TNF alpha gene promoter. Scand J Immunol 1995; 42: 501–504.

    Article  CAS  PubMed  Google Scholar 

  175. Tarkowski E, Liljeroth AM, Nilsson A et al. TNF gene polymorphism and its relation to intracerebral production of TNFalpha and TNFbeta in AD. Neurology 2000; 54: 2077–2081.

    Article  CAS  PubMed  Google Scholar 

  176. Somoskovi A, Zissel G, Seitzer U et al. Polymorphisms at position −308 in the promoter region of the TNF-alpha and in the first intron of the TNF-beta genes and spontaneous and lipopolysaccharide-induced TNF-alpha release in sarcoidosis. Cytokine 1999; 11: 882–887.

    Article  CAS  PubMed  Google Scholar 

  177. Turner DM, Grant SC, Lamb WR et al. A genetic marker of high TNF-alpha production in heart transplant recipients. Transplantation 1995; 60: 1113–1117.

    Article  CAS  PubMed  Google Scholar 

  178. Hoffmann SC, Stanley EM, Darrin CE et al. Association of cytokine polymorphic inheritance and in vitro cytokine production in anti-CD3/CD28-stimulated peripheral blood lymphocytes. Transplantation 2001; 72: 1444–1450.

    Article  CAS  PubMed  Google Scholar 

  179. Ito M, Takahashi H, Fuse K et al. Polymorphisms of tumor necrosis factor-alpha and interleukin-10 genes in Japanese patients with idiopathic dilated cardiomyopathy. Jpn Heart J 2000; 41: 183–191.

    Article  CAS  PubMed  Google Scholar 

  180. Kubota T, McNamara DM, Wang JJ et al. Effects of tumor necrosis factor gene polymorphisms on patients with congestive heart failure. VEST Investigators for TNF Genotype Analysis. Vesnarinone Survival Trial. Circulation 1998; 97: 2499–2501.

    Article  CAS  PubMed  Google Scholar 

  181. de Jong BA, Westendorp RG, Bakker AM, Huizinga TW . Polymorphisms in or near tumour necrosis factor (TNF)-gene do not determine levels of endotoxin-induced TNF production. Genes Immun 2002; 3: 25–29.

    Article  CAS  PubMed  Google Scholar 

  182. Bouma G, Crusius JB, Oudkerk Pool M et al. Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles. Relevance for inflammatory bowel disease. Scand J Immunol 1996; 43: 456–463.

    Article  CAS  PubMed  Google Scholar 

  183. Fernandes H, Koneru B, Fernandes N et al. Investigation of promoter polymorphisms in the tumor necrosis factor-alpha and interleukin-10 genes in liver transplant patients. Transplantation 2002; 73: 1886–1891.

    Article  CAS  PubMed  Google Scholar 

  184. Fijen JW, Tulleken JE, Hepkema BG et al. The influence of tumor necrosis factor-alpha and interleukin-10 gene promoter polymorphism on the inflammatory response in experimental human endotoxemia. Clin Infect Dis 2001; 33: 1601–1603.

    Article  CAS  PubMed  Google Scholar 

  185. Brinkman BM, Zuijdeest D, Kaijzel EL, Breedveld FC, Verweij CL . Relevance of the tumor necrosis factor alpha (TNF alpha) −308 promoter polymorphism in TNF alpha gene regulation (see comments). J Inflamm 1995; 46: 32–41.

    PubMed  Google Scholar 

  186. Stuber F, Udalova IA, Book M 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 (see comments). J Inflamm 1995; 46: 42–50.

    PubMed  Google Scholar 

  187. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW . Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997; 94: 3195–3199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Wu WS, McClain KL . DNA polymorphisms and mutations of the tumor necrosis factor-alpha (TNF-alpha) promoter in Langerhans cell histiocytosis (LCH). J Interferon Cytokine Res 1997; 17: 631–635.

    Article  CAS  PubMed  Google Scholar 

  189. Brinkman BM, Zuijdeest D, Kaijzel EL, Breedveld FC, Verweij CL . Relevance of the tumor necrosis factor alpha (TNF alpha) −308 promoter polymorphism in TNF alpha gene regulation. J Inflamm 1995; 46: 32–41.

    PubMed  Google Scholar 

  190. Kaijzel EL, van Krugten MV, Brinkman BM et al. Functional analysis of a human tumor necrosis factor alpha (TNF-alpha) promoter polymorphism related to joint damage in rheumatoid arthritis. Mol Med 1998; 4: 724–733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Bayley JP, de Rooij H, van den Elsen PJ, Huizinga TW, Verweij CL . Functional analysis of linker-scan mutants spanning the −376, −308, −244, and −238 polymorphic sites of the TNF-alpha promoter. Cytokine 2001; 14: 316–323.

    Article  CAS  PubMed  Google Scholar 

  192. Kroeger KM, Carville KS, Abraham LJ . The −308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol 1997; 34: 391–399.

    Article  CAS  PubMed  Google Scholar 

  193. Kroeger KM, Steer JH, Joyce DA, Abraham LJ . Effects of stimulus and cell type on the expression of the −308 tumour necrosis factor promoter polymorphism. Cytokine 2000; 12: 110–119.

    Article  CAS  PubMed  Google Scholar 

  194. Fong CL, Siddiqui AH, Mark DF . Identification and characterization of a novel repressor site in the human tumor necrosis factor alpha gene. Nucleic Acids Res 1994; 22: 1108–1114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Fong CL, Mark DF . The NF-kappa B-like site in the TNF-alpha repressor element is essential for its repressor function. Biochem Biophys Res Commun 1995; 212: 879–886.

    Article  CAS  PubMed  Google Scholar 

  196. Brinkman BM, Huizinga TW, Breedveld FC, Verweij CL . Allele-specific quantification of TNFA transcripts in rheumatoid arthritis. Hum Genet 1996; 97: 813–818.

    Article  CAS  PubMed  Google Scholar 

  197. Kaijzel EL, Bayley JP, van Krugten MV et al. Allele-specific quantification of tumor necrosis factor alpha (TNF) transcription and the role of promoter polymorphisms in rheumatoid arthritis patients and healthy individuals. Genes Immun 2001; 2: 135–144.

    Article  CAS  PubMed  Google Scholar 

  198. Knight JC, Keating BJ, Rockett KA, Kwiatkowski DP . In vivo characterization of regulatory polymorphisms by allele-specific quantification of RNA polymerase loading. Nat Genet 2003; 33: 469–475.

    Article  CAS  PubMed  Google Scholar 

  199. Kochanek S, Radbruch A, Tesch H, Renz D, Doerfler W . DNA methylation profiles in the human genes for tumor necrosis factors alpha and beta in subpopulations of leukocytes and in leukemias. Proc Natl Acad Sci USA 1991; 88: 5759–5763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Kochanek S, Toth M, Dehmel A, Renz D, Doerfler W . Interindividual concordance of methylation profiles in human genes for tumor necrosis factors alpha and beta. Proc Natl Acad Sci USA 1990; 87: 8830–8834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Takei S, Fernandez D, Redford A, Toyoda H . Methylation status of 5′-regulatory region of tumor necrosis factor alpha gene correlates with differentiation stages of monocytes. Biochem Biophys Res Commun 1996; 220: 606–612.

    Article  CAS  PubMed  Google Scholar 

  202. Muiznieks I, Doerfler W . The impact of 5′-CG-3′ methylation on the activity of different eukaryotic promoters: a comparative study. FEBS Lett 1994; 344: 251–254.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

    J-P Bayley

  2. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

    T H M Ottenhoff

  3. Department of Molecular Cell Biology, VU University Medical Center, PO Box 7057, Amsterdam, 1007 MB, The Netherlands

    C L Verweij

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Bayley, JP., Ottenhoff, T. & Verweij, C. Is there a future for TNF promoter polymorphisms?. Genes Immun 5, 315–329 (2004). https://doi.org/10.1038/sj.gene.6364055

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