Human Genetics

, Volume 107, Issue 6, pp 591–596

Association of the TNF-α-308 (G→A) polymorphism with self-reported history of childhood asthma

  • Elizabeth C. Winchester
  • Iona Y. Millwood
  • Lucinda Rand
  • Michelle A. Penny
  • Anna M. Kessling
Original Investigations


Asthma is a complex disease involving genetic and environmental aetiology. The tumour necrosis factor-alpha (TNF- α) and angiotensin-converting enzyme (ACE) genes have been implicated in asthma pathogenesis. This study investigated the association of a G-308A variant of TNF- α and an insertion/deletion (I/D) variant of ACE with a self-reported history of childhood asthma, in two population groups. At Northwick Park Hospital, London, 1,811 pregnant women attending for antenatal care were recruited. Participants with a self-reported history of childhood asthma, determined by a researcher-administered questionnaire, and controls with no personal or family history of asthma, of UK/Irish (cases n=20; controls n=416) and South Asian (cases n=6; controls n=275) origin were used in this study. Participants were genotyped for the TNF-α-308 and ACE I/D variants by a PCR-RFLP and PCR approach. The TNF-α-308 allele 2 (−308A) was significantly associated with self-reported childhood asthma in the UK/Irish (Odds ratios (OR): 2.6; 95% confidence intervals (CI): 1.1–6.2; P=0.03) but not in the South Asian population. The ACE DD genotype was not associated with childhood asthma in either population group. Gametic phase disequilibrium between the TNF-α-308 and ACE I/D variants was significantly different from zero in UK/Irish cases (Δ=0.09; P=0.034). The TNF-α-308 allele 2 or a linked major histocompatibility complex (MHC) variant may be a genetic risk factor for childhood asthma in the UK/Irish sample.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Albuquerque RV, Hayden CM, Palmer LJ, Laing IA, Rye PJ, Gibson NA, Burton PR, Goldblatt J, Lesouef PN (1998) Association of polymorphisms within the tumour necrosis factor (TNF) genes and childhood asthma. Clin Exp Allergy 28: 578–584PubMedCrossRefGoogle Scholar
  2. Barnes KC (1999) Gene-environment and gene-gene interaction studies in the molecular genetic analysis of asthma and atopy. Clin Exp Allergy 29(S4): 47–51PubMedGoogle Scholar
  3. Barnes PJ (1989) New concepts in the pathogenesis of bronchial hyperresponsiveness and asthma. J Allergy Clin Immunol 83: 1013–1026PubMedCrossRefGoogle Scholar
  4. Benessiano J, Crestani B, Mestari F, Klouche W, Neukirch F, Hacein-Bey S, Durand G, Aubier M (1997) High frequency of a deletion polymorphism of the angiotensin-converting enzyme gene in asthma. J Allergy Clin Immunol 99: 53–57PubMedCrossRefGoogle Scholar
  5. Bouma G, Crusius JB, Oudkerk Pool M, Kolkman JJ, Von Blomberg BM, Kostense PJ, Giphart MJ, Schreuder GM, Meuwissen SG, Pena AS (1996) 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 43: 456–463PubMedCrossRefGoogle Scholar
  6. Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, Heusser CH, Howarth PH, Holgate ST (1994) Interleukin-4, -5, and -6 and tumour necrosis factor in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol 10: 471–480PubMedGoogle Scholar
  7. Braun N, Michel U, Ernst BP, Metzner R, Bitsch A, Weber F, Rieckmann P (1996) Gene polymorphism at position −308 of the tumor-necrosis-factor-α (TNF-α) in multiple sclerosis and its influence on the regulation of TNF-α production. Neurosci Lett 215: 75–78PubMedGoogle Scholar
  8. Brinkman BM, Zuijdeest D, Kaijzel EL, Breedveld FC, Verweij CL (1996) Relevance of the tumor necrosis factor alpha (TNF alpha) −308 promoter polymorphisms in TNF alpha gene regulation. J Inflamm 46: 32–41Google Scholar
  9. Broide DH, Lotz M, Cuomo AJ, Coburn DA, Federman EC, Wasserman SI (1992) Cytokines in symptomatic asthma airways. J Allergy Clin Immunol 89: 958–967PubMedCrossRefGoogle Scholar
  10. Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D, Luc G, Bard JM, Bara L, Ricard S, Tiret L, Amouyel P, Alhenc-Gelas F, Soubrier F (1992) Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 359: 641–644PubMedCrossRefGoogle Scholar
  11. Campbell DA, Li Kam Wa E, Britton J, Holgate ST, Markham AF, Morrison JFJ (1996) Polymorphism at the tumour necrosis factor locus and asthma. Monogr Allergy 33: 125–137PubMedGoogle Scholar
  12. Carroll MC, Katzman P, Alicot EM, Koller BH, Geraghty DE, Orr HT, Strominger JL, Spies T (1987) Linkage map of the human major histocompatibility complex including the tumour necrosis factor genes. Proc Natl Acad Sci U S A 84: 8535–8539PubMedCrossRefGoogle Scholar
  13. Chagani T, Pare PD, Shoukang Z, Weir TD, Bai TR, Behbehani NA, Fitzgerald M, Sandford AJ (1999) Prevalence of tumour necrosis factor-α and angiotensin converting enzyme polymorphisms in mild/moderate and fatal/near-fatal asthma. Am J Respir Crit Care Med 160: 278–282PubMedGoogle Scholar
  14. Cookson W (1999) The alliance of genes and environment in asthma and allergy. Nature 402(S): B5-B11PubMedCrossRefGoogle Scholar
  15. Costerousse O, Allegrini J, Lopez M, Alhenc-Gelas F (1993) Angiotensin I-converting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in T-lymphocytes. Biochem J 290: 33–40PubMedGoogle Scholar
  16. Erdos EG (1990) Angiotensin I converting enzyme and the changes in our concept through the years. Hypertension 16: 363–370PubMedGoogle Scholar
  17. Gao P-S, Mao X-Q, Kawai M, Enomoto T, Sasaki S, Shaldon SR, Dake Y, Kitano H, Coull P, Hagihara A, Shirakawa T, Hopkin JM (1998) Lack of association between ACE gene polymorphisms and atopy and asthma in British and Japanese populations. Clin Genet 54: 245–247PubMedGoogle Scholar
  18. Gosset P, Tsicopoulos A, Wallaert B, Vannimenus C, Joseph M, Tonnel B, Capron A (1991) Increased secretion of tumour necrosis factor alpha and interleukin-6 by alveolar macrophages consecutive to the development of the late asthmatic reaction. J Allergy Clin Immunol 88: 561–571PubMedCrossRefGoogle Scholar
  19. Hakonarson H, Herrick DJ, Serrano PG, Grunstein MM (1996) Mechanisms of cytokine-induced modulation of beta-adrenoceptor responsiveness in airway smooth muscle. J Clin Invest 97: 2593–2600PubMedCrossRefGoogle Scholar
  20. Haviland MB, Kessling AM, Davignon J, Sing CF (1991) Estimation of Hardy-Weinberg and pairwise disequilibrium in the apolipoprotein AI-CIII-AIV gene cluster. Am J Hum Genet 49: 350–365PubMedGoogle Scholar
  21. Hollá L, Vaskú A, Znojil V, Sisková L, Vácha J, (1999) Association of 3 gene polymorphisms with atopic diseases. J Allergy Clin Immunol 103: 702–708PubMedCrossRefGoogle Scholar
  22. Hubert C, Houot AM, Corvol P, Soubrier F (1991) Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. J Biol Chem 266: 15377–15383PubMedGoogle Scholar
  23. Jacob CO, Fronek Z, Lewis GD, Koo M, Hansen JA, McDevitt HO (1990) Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupes erythematosus. Proc Natl Acad Sci U S A 87: 1233–1237PubMedCrossRefGoogle Scholar
  24. Kharitonov SA, Sapienza MM, Chung KF, Barnes PJ (1999) Prostaglandins mediate bradykinin-induced reduction of exhaled nitric oxide in asthma. Eur Respir J 14: 1023–1027PubMedCrossRefGoogle Scholar
  25. Kroeger KM, Carville KS, Abraham LJ (1997) The −308 tumour necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol 34: 391–399PubMedCrossRefGoogle Scholar
  26. Kuoppala A, Lindstedt KA, Saarinen J, Kovanen PT, Kokkonen JO (2000) Inactivation of bradykinin by angiotensin-converting enzyme and by carboxypeptidase N in human plasma. Am J Physiol Heart Circ Physiol 278: H1069-H1074PubMedGoogle Scholar
  27. Li Kam Wa TC, Mansur AH, Britton J, Williams G, Pavord I, Richards K, Campbell DA, Morton N, Holgate ST, Morrison JF (1999) Association between −308 tumour necrosis factor promoter polymorphism and bronchial hyperreactivity in asthma. Clin Exp Allergy 29: 1204–1208CrossRefGoogle Scholar
  28. Malerba G, Trabetti E, Patuzzo C, Lauciello MC, Galavotti R, Pescollderungg L, Boner AL, Pignatti PF (1999) Candidate genes and a genome-wide search in Italian families with atopic asthmatic children. Clin Exp Allergy 29(S4): 27–30PubMedGoogle Scholar
  29. Millar EA, Angus RM, Hulks G, Morton JJ, Connell JMC, Thomson NC (1994) Activity of the renin-angiotensin system in acute severe asthma and the effect of angiotensin II on lung function. Thorax 49: 492–495PubMedCrossRefGoogle Scholar
  30. Moffatt MF, Cookson WOCM (1997) Tumour necrosis factor haplotypes and asthma. Hum Mol Genet 6: 551–554PubMedCrossRefGoogle Scholar
  31. Moffatt MF, Cookson WOCM (1999) Genetics of asthma and inflammation: the status. Curr Opin Immunol 11: 606–609PubMedCrossRefGoogle Scholar
  32. Moffatt, MF, James A, Ryan G, Musk AW, Cookson WOCM (1999) Extended tumour necrosis factor/HLA-DR haplotypes and asthma in an Australian population sample. Thorax 54: 757–761PubMedCrossRefGoogle Scholar
  33. Nakahama H, Obata K, Nakajima T, Nakamura H, Kitada O, Sugita M, Fujita Y, Kawada N, Moriyama T, (1999) Renin-angiotensin system component gene polymorphism in Japanese bronchial asthma patients. J Asthma 36: 187–193PubMedCrossRefGoogle Scholar
  34. Odawara M, Matsunuma A, Yamashita K, (1996) A pitfall in the Association Study of ACE gene polymorphism. Diabetes Care 19: 543–544PubMedGoogle Scholar
  35. Pociot F, Wilson AG, Neruup J, Duff GW (1993) No independent association between a tumour necrosis factor alpha promoter polymorphism and insulin-dependent diabetes mellitus. Eur J Immunol 23: 3050–3053PubMedCrossRefGoogle Scholar
  36. Rigat B, Hubert C, Gelas FA, Cambian F, Corvol P, Soubrier F (1990) An insertion/deletion polymorphism in the angiotensinconverting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86: 1343–1346PubMedCrossRefGoogle Scholar
  37. Rigat B, Hubert C, Corvol P, Soubrier F (1992) PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Res 20: 1433PubMedCrossRefGoogle Scholar
  38. Saha N, Talmud PJ, Tay JS, Humphries SE, Basair J (1996) Lack of association of angiotensin-converting enzyme (ACE). Gene insertion/deletion polymorphism with CAD in two Asian populations. Clin Genet 50: 121–125PubMedCrossRefGoogle Scholar
  39. Sandford AJ, Pare PD (2000) The genetics of asthma. Am J Respir Crit Care Med 161: S202-S206PubMedGoogle Scholar
  40. Sandford A, Weir T, Pare P (1996) The genetics of asthma. Am J Respir Crit Care Med 153: 1749–1765PubMedGoogle Scholar
  41. Shah A, Church MK, Holgate ST (1995) Tumour necrosis factor alpha: a potential mediator of asthma. Clin Exp Allergy 25: 1038–1044PubMedCrossRefGoogle Scholar
  42. Skoog T, van’t Hooft FM, Kallin B, Jovinge S, Boquist S, Nilsson J, Eriksson P, Hamsten A (1999) A common functional polymorphism (C→A substitution at position −863) in the promoter region of the tumour necrosis factor-α (TNF-α) gene associated with reduced circulating levels of TNF-α. Hum Mol Genet 8: 1443–1449PubMedCrossRefGoogle Scholar
  43. Stuber F, Udalova IA, Book M, Drutskaya LN, Kuprash DV, Turetskaya RL, Schade FU, Nedospasov SA (1996) −308 Tumour 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: 42–50Google Scholar
  44. Tan EC, Lee BW, Tay AWN, Chew FT, Tay AHN (1999) Asthma and TNF variants in Chinese and Malays. Allergy 54: 401–408CrossRefGoogle Scholar
  45. The MHC sequencing consortium (1999) Complete sequence and gene map of a human major histocompatibility complex. Nature 401: 921–923CrossRefGoogle Scholar
  46. Tomita H, Sato S, Matsuda R, Ogisu N, Mori T, Niimi T, Shimizu S (1998) Genetic polymorphism of the angiotensin-converting enzyme (ACE) in asthmatic patients. Respir Med 92: 1305–1310PubMedCrossRefGoogle Scholar
  47. Virchow JC, Walker C, Hafner D, Kortsik C, Werner P, Matthys H, Kroegal C (1995) T cells and cytokines in bronchoalveolar lavage fluid after segmental allergen provocation in atopic asthma. Am J Respir Crit Care Med 151: 960–968PubMedGoogle Scholar
  48. Walston J, Seibert M, Yen C-J, Cheskin LJ, Andersen RE (1999) Tumor necrosis factor-α-238 and −308 polymorphisms do not associate with traits related to obesity and insulin resistance. Diabetes 48: 2096–2098PubMedCrossRefGoogle Scholar
  49. Weir BS, Cockerham CC (1989) Complete characterization of disequilibrium at two loci. In: Feldman MW (ed) Mathematical evolutionary theory. Princeton University Press, Princeton, NJ, pp 86–110Google Scholar
  50. Wilson AG, di Giovine FS, Blakemore AIF, Duff GW (1992) Single base polymorphism in the human tumour necrosis factor alpha (TNF-α) gene detectable by NcoI restriction of PCR product. Hum Mol Genet 1: 353PubMedCrossRefGoogle Scholar
  51. Wilson AG, de Vries N, van de Putte LB, Duff GW (1995) A tumour necrosis factor alpha polymorphism is not associated with rheumatoid arthritis. Ann Rheum Dis 54: 601–603PubMedCrossRefGoogle Scholar
  52. Wilson AG, Symons JA, McDowell TL, McDervitt HO, Duff GW (1997) Effects of a polymorphism in the tumour necrosis factor a promoter on transcriptional activation. Proc Natl Acad Sci U S A 94: 3195–3199PubMedCrossRefGoogle Scholar
  53. Young RP, Dekker JW, Wordsworth BP, Schou C, Pile KD, Matthiesen F, Rosenberg WM, Bell JI, Hopkin JM, Cookson WO (1994) HLA-DR and HLA-DP genotypes and immunoglobulin E responses to common major allergens. Clin Exp Allergy 24: 431–439PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2000

Authors and Affiliations

  • Elizabeth C. Winchester
    • 1
  • Iona Y. Millwood
    • 1
  • Lucinda Rand
    • 1
  • Michelle A. Penny
    • 1
  • Anna M. Kessling
    • 1
  1. 1.Department of Medical and Community GeneticsImperial College School of Medicine, Kennedy Galton CentreHarrowUK

Personalised recommendations