Skip to main content
Log in

Cytokine gene polymorphisms in ischaemic heart disease: investigation using family-based tests of association

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Atherosclerosis has an inflammatory basis, with cytokines, cellular adhesion molecules and pro-inflammatory cells having important roles in the initiation and progression of this process. Interleukin (IL) 6, IL-10 and transforming growth factor (TGF) β1 have been proposed as important modulators of the atherosclerotic process, with IL-6 having a pro-inflammatory, atherogenic effect and IL-10 and TGF-β1 having anti-inflammatory, protective roles. The possible role of functional polymorphisms in the promoter regions of the IL-6, IL-10 and TGF-β1 genes in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population using two recently described family-based tests of association. We genotyped 1,012 individuals from 386 families with at least one member prematurely affected with IHD. Using the combined transmission disequilibrium test (TDT)/sib-TDT and the pedigree disequilibrium test, no association between any of the IL-6 −174G/C, IL-10 −1082G/A and TGF-β1 −509C/T polymorphisms and IHD was found. Our data demonstrate that, in an Irish population, these polymorphisms are not associated with IHD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

IHD :

Ischaemic heart disease

IL :

Interleukin

PDT :

Pedigree disequilibrium test

TDT :

Transmission disequilibrium test

References

  1. Shea S, Ottman R, Gabrieli C, Stein Z, Nichols A (1984) Family history as an independent risk factor for coronary artery disease. J Am Coll Cardiol 4:793–801

    CAS  PubMed  Google Scholar 

  2. Nora JJ, Lortscher RH, Spangler RD, Nora AH, Kimberling WJ (1980) Genetic epidemiologic study of early onset ischemic heart disease. Circulation 61:503–508

    CAS  PubMed  Google Scholar 

  3. Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U (1994) Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 330:1041–1046

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Ross R. Atherosclerosis-an inflammatory disease (1999) N Engl J Med 340:115–126

    Article  CAS  PubMed  Google Scholar 

  6. Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V (2000) Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 148:209–214

    Article  CAS  PubMed  Google Scholar 

  7. Tedgui A, Mallat Z. Anti-inflammatory mechanisms in the vascular wall (2001) Circ Res 88:877–887

    CAS  PubMed  Google Scholar 

  8. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P (1998) The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 102:1369–1376

    Google Scholar 

  9. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV (1997) An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24:1–8

    CAS  Google Scholar 

  10. Grainger DJ, Heathcote K, Chiano M, Snieder H, Kemp PR, Metcalfe JC, Carter ND, Spector TD (1999) Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet 8:93–97

    Article  CAS  PubMed  Google Scholar 

  11. Spence MS, McGlinchey PG, Patterson CC, Belton C, Murphy G, McMaster D, Fogarty DG, Evans AE, McKeown PP (2002) Family-based investigation of the C677T polymorphism of the methylenetetrahydrofolate reductase gene in ischaemic heart disease. Atherosclerosis 165:293–299

    Article  CAS  PubMed  Google Scholar 

  12. Bernard R, Corday E, Eliasch H, Gonin A, Hiait R, Nikolaeva LF, Oakley CM, Oliver MF, Pisa Z, Piddu V, Rapaport E, Strasser T, Wellens H (1979) Nomenclature and criteria for diagnosis of ischemic heart disease. Report of the Joint International Society and Federation of Cardiology/World Health Organisation task force on standardization of clinical nomenclature. Circulation 59:607–609

    Google Scholar 

  13. Rose GA, Blackburn H, Gillum RF, Prineas RJ (1982) Cardiovascular survey methods, 2nd edn. World Health Organisation, Geneva

  14. Blackburn H, Keys A, Simonson E, Rautaharju P, Punsar S (1960) The electrocardiogram in population studies: a classification system. Circulation 21:1160–1175

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Spielman RS, Ewens WJ (1998) A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am J Hum Genet 62:450–458

    Article  CAS  PubMed  Google Scholar 

  17. Martin ER, Monks SA, Warren LL, Kaplan NL (2000) A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 67:146–154

    Article  CAS  PubMed  Google Scholar 

  18. Miyao Y, Yasue H, Ogawa H, Misumi I, Masuda T, Sakamoto T, Morita E (1993) Elevated plasma interleukin-6 levels in patients with acute myocardial infarction. Am Heart J 126:1299–1304

    Article  CAS  PubMed  Google Scholar 

  19. Neumann FJ, Ott I, Gawaz M, Richardt G, Holzapfel H, Jochum M, Schomig A (1995) Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation 92:748–755

    CAS  PubMed  Google Scholar 

  20. Biasucci LM, Vitelli A, Liuzzo G, Altamura S, Caligiuri G, Monaco C, Rebuzzi AG, Ciliberto G, Maseri A (1996) Elevated levels of interleukin-6 in unstable angina. Circulation 94:874–877

    CAS  PubMed  Google Scholar 

  21. Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH, Heimovitz H, Cohen HJ, Wallace R (1999) Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 106:506–512

    Article  CAS  PubMed  Google Scholar 

  22. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101:1767–1772

    CAS  PubMed  Google Scholar 

  23. Elghannam H, Tavackoli S, Ferlic L, Gotto AM, Ballantyne CM, Marian AJ (2000) A prospective study of genetic markers of susceptibility to infection and inflammation, and the severity, progression, and regression of coronary atherosclerosis and its response to therapy. J Mol Med 78:562–568

    Article  CAS  PubMed  Google Scholar 

  24. Georges JL, Loukaci V, Poirier O, Evans A, Luc G, Arveiler D, Ruidavets JB, Cambien F, Tiret L (2001) Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction: the ECTIM study. J Mol Med 79:300–305

    Article  CAS  PubMed  Google Scholar 

  25. Humphries SE, Luong LA, Ogg MS, Hawe E, Miller GJ (2001) The interleukin-6 −174G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. Eur Heart J 22:2243–2252

    Article  CAS  PubMed  Google Scholar 

  26. Basso F, Lowe GDO, Rumley A, McMahon AD, Humphries SE (2002) Interleukin-6 −174G>C polymorphism and risk of coronary heart disease in West of Scotland Coronary Prevention Study (WOSCOPS). Arterioscler Thromb Vasc Biol 22:599–604

    Article  CAS  PubMed  Google Scholar 

  27. Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H, Sone T, Tanaka M, Yokota M (2002) Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med 347:1916–1923

    Article  CAS  PubMed  Google Scholar 

  28. Terry CF, Loukaci V, Green FR (2000) Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 275:18138–18144

    Article  CAS  PubMed  Google Scholar 

  29. Uyemura K, Demer LL, Castle SC, Jullien D, Berliner JA, Gately MK, Warrier RR, Pham N, Fogelman AM, Modlin RL (1996) Cross-regulatory roles of interleukin (IL)-12 and IL-10 in atherosclerosis. J Clin Invest 97:2130–2138

    CAS  PubMed  Google Scholar 

  30. Mallat Z, Heymes C, Ohan J, Faggin E, Leseche G, Tedgui A (1999) Expression of interleukin-10 in advanced human atherosclerotic plaques: relation to inducible nitric oxide synthase expression and cell death. Arterioscler Thromb Vasc Biol 19:611–616

    CAS  PubMed  Google Scholar 

  31. Smith DA, Irving SD, Sheldon J, Cole D, Kaski JC (2001) Serum levels of the anti-inflammatory cytokine interleukin-10 are decreased in patients with unstable angina. Circulation 104:746–749

    CAS  PubMed  Google Scholar 

  32. Kube D, Platzer C, von Knethen A, Straub H, Bohlen H, Hafner M, Tesch H (1995) Isolation of the human interleukin 10 promoter. Characterization of the promoter activity in Burkitt’s lymphoma cell lines. Cytokine 7:1–7

    Article  CAS  PubMed  Google Scholar 

  33. Rees LEN, Wood NAP, Gillespie KM, Lai KN, Gaston K, Mathieson PW (2002) The interleukin-10–1082G/A polymorphism: allele frequency in different populations and functional significance. Cell Mol Life Sci 59:560–569

    Article  CAS  PubMed  Google Scholar 

  34. Donger C, Georges JL, Nicaud V, Morrison C, Evans A, Kee F, Arveiler D, Tiret L, Cambien F (2001) New polymorphisms in the interleukin-10 gene—relationships to myocardial infarction. Eur J Clin Invest 31:9–14

    Article  CAS  PubMed  Google Scholar 

  35. Koch W, Kastrati A, Bottiger C, Mehilli J, von Beckerath N, Schomig A (2001) Interleukin-10 and tumor necrosis factor gene polymorphisms and risk of coronary artery disease and myocardial infarction. Atherosclerosis 159:137–144

    Article  CAS  PubMed  Google Scholar 

  36. Metcalfe JC, Grainger DJ (1995) Transforming growth factor-β and the protection from cardiovascular injury hypothesis. Biochem Soc Trans 23:403–406

    CAS  PubMed  Google Scholar 

  37. Grainger DJ, Kemp PR, Metcalfe JC, Liu AC, Lawn RM, Williams NR, Grace AA, Schofield PM, Chauhan A (1995) The serum concentration of active transforming growth factor-β is severely depressed in advanced atherosclerosis. Nat Med 1:74–79

    CAS  PubMed  Google Scholar 

  38. Cambien F, Ricard S, Troesch A, Mallet C, Generenaz L, Evans A, Arveiler D, Luc G, Ruidavets JB, Poirier O (1996) Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Temoin de l’Infarctus du Myocarde (ECTIM) Study. Hypertension 28:881–887

    CAS  PubMed  Google Scholar 

  39. Syrris P, Carter ND, Metcalfe JC, Kemp PR, Grainger DJ, Kaski JC, Crossman DC, Francis SE, Gunn J, Jeffery S, Heathcote K (1998) Transforming growth factor-beta1 gene polymorphisms and coronary artery disease. Clin Sci (Colch) 95:659–667

    Google Scholar 

  40. Wang XL, Sim AS, Wilcken DE (1998) A common polymorphism of the transforming growth factor-beta1 gene and coronary artery disease. Clin Sci (Colch) 95:745–756

    Google Scholar 

  41. Yokota M, Ichihara S, Lin TL, Nakashima N, Yamada Y (2000) Association of a T29→C polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation 101:2783–2787

    CAS  PubMed  Google Scholar 

  42. Lander ES, Schork NJ (1994) Genetic dissection of complex traits. Science 265:2037–2048

    Google Scholar 

  43. Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273:1516–1517

    Google Scholar 

  44. Cardon LR, Palmer LJ (2003) Population stratification and spurious allelic association. Lancet 361:598–604

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the Research and Development Office, Northern Ireland, a Royal Victoria Hospital Research Fellowship, the Northern Ireland Chest, Heart and Stroke Association, and the Heart Trust Fund (Royal Victoria Hospital). We thank Christine Belton and Jill Kilner for their technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pascal P. McKeown.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McGlinchey, P.G., Spence, M.S., Patterson, C.C. et al. Cytokine gene polymorphisms in ischaemic heart disease: investigation using family-based tests of association. J Mol Med 82, 756–761 (2004). https://doi.org/10.1007/s00109-004-0576-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-004-0576-6

Keywords

Navigation