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.

  • Original Article
  • Published:

Plasma levels of fibrinogen and C-reactive protein are related to interleukin-6 gene −572C>G polymorphism in subjects with and without hypertension

Journal of Human Hypertension volume 21, pages 875–882 (2007)Cite this article

Abstract

Hypertension is an important risk factor for cardiovascular diseases. There is increasing evidence suggesting that inflammation is involved in the development of hypertension. Interleukin-6 (IL-6) is an important mediator of inflammatory response and the major regulator of hepatic production of acute phase proteins, such as fibrinogen and C-reactive protein (CRP), which have been associated with hypertension and cardiovascular diseases. Therefore, we studied the association of single nucleotide polymorphism (SNP) in the IL-6 gene (IL6) promoter with plasma levels of fibrinogen, CRP and hypertension. Five hundred and two Hong Kong Chinese subjects (282 normotensives and 220 hypertensives) were recruited. IL-6 gene promoter was examined for polymorphism and the study subjects were genotyped for any SNP identified. The IL6 −572C>G polymorphism (rs1800796) was found with a frequency of 0.23 for the minor G allele. Subjects with the −572G allele had significantly higher plasma fibrinogen (3.06±0.57 vs 2.83±0.60, P=0.002) and CRP (interquartile range 0.33–1.56 vs 0.12–0.93, P=0.003) levels than those without. The −572C>G polymorphism was found to be an independent predictor of fibrinogen and CRP levels after adjusting for confounding factors. Plasma concentrations of fibrinogen and CRP correlated with systolic blood pressure. However, the −572C/G genotype frequencies did not differ between hypertensive and normotensive subjects, and there was no association between −572C>G polymorphism and blood pressure. Our results provide evidence that there is a clear genetic influence of IL6 −572C>G polymorphism on plasma levels of fibrinogen and CRP, but this polymorphism does not lead to elevated blood pressure.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Hansson GK . Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685–1695.

    Article  CAS  Google Scholar 

  2. Janus ED, for the Hong Kong Cardiovascular Risk Factor Prevalence Study Group. The Hong Kong Cardiovascular Risk Factor Prevalence Study 1995–1996. The University of Hong Kong: Hong Kong, 1997.

    Google Scholar 

  3. Li JJ, Chen JL . Inflammation may be a bridge connecting hypertension and atherosclerosis. Med Hypotheses 2005; 64: 925–929.

    Article  CAS  Google Scholar 

  4. Kanda T, Takahashi T . Interleukin-6 and cardiovascular diseases. Jpn Heart J 2004; 45: 183–193.

    Article  CAS  Google Scholar 

  5. Kerr R, Stirling D, Ludlam CA . Interleukin 6 and haemostasis. Br J Haematol 2001; 115: 3–12.

    Article  CAS  Google Scholar 

  6. Rott D, Zhu J, Zhou YF, Burnett MS, Zalles-Ganley A, Epstein SE . IL-6 is produced by splenocytes derived from CMV-infected mice in response to CMV antigens, and induces MCP-1 production by endothelial cells: a new mechanistic paradigm for infection-induced atherogenesis. Atherosclerosis 2003; 170: 223–228.

    Article  CAS  Google Scholar 

  7. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 1998; 101: 311–320.

    Article  CAS  Google Scholar 

  8. Castell JV, Gomez-Lechon MJ, David M, Andus T, Geiger T, Trullenque R et al. Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett 1989; 242: 237–239.

    Article  CAS  Google Scholar 

  9. Dong J, Fujii S, Goto D, Furumoto T, Kaneko T, Zaman TA et al. Increased expression of plasminogen activator inhibitor-1 by mediators of the acute phase response: a potential progenitor of vasculopathy in hypertensives. Hypertens Res 2003; 26: 723–729.

    Article  CAS  Google Scholar 

  10. Koenig W . Fibrin(ogen) in cardiovascular disease: an update. Thromb Haemost 2003; 89: 601–609.

    Article  CAS  Google Scholar 

  11. Tracy RP . Inflammation markers and coronary heart disease. Curr Opin Lipidol 1999; 10: 435–441.

    Article  CAS  Google Scholar 

  12. Ernst E, Resch KL . Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993; 118: 956–963.

    Article  CAS  Google Scholar 

  13. Danesh J, Collins R, Appleby P, Peto R . Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA 1998; 279: 1477–1482.

    Article  CAS  Google Scholar 

  14. Luc G, Bard JM, Juhan-Vague I, Ferrieres J, Evans A, Amouyel P et al. C-reactive protein, interleukin-6, and fibrinogen as predictors of coronary heart disease: the PRIME Study. Arterioscler Thromb Vasc Biol 2003; 23: 1255–1261.

    Article  CAS  Google Scholar 

  15. Kuller LH, Tracy RP, Shaten J, Meilahn EN . Relation of C-reactive protein and coronary heart disease in the MRFIT nested case–control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996; 144: 537–547.

    Article  CAS  Google Scholar 

  16. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH . Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973–979.

    Article  CAS  Google Scholar 

  17. Ridker PM, Hennekens CH, Buring JE, Rifai N . C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342: 836–843.

    Article  CAS  Google Scholar 

  18. de Maat MP, Pietersma A, Kofflard M, Sluiter W, Kluft C . Association of plasma fibrinogen levels with coronary heart disease, smoking and inflammatory markers. Atherosclerosis 1996; 121: 185–191.

    Article  CAS  Google Scholar 

  19. Davey Smith G, Lawlor DA, Harbord R, Timpson N, Rumley A, Lowe GD et al. Association of C-reactive protein with blood pressure and hypertension: life course confounding and mendelian randomization tests of causality. Arterioscler Thromb Vasc Biol 2005; 25: 1051–1056.

    Article  Google Scholar 

  20. Schillaci G, Pirro M, Gemelli F, Pasqualini L, Vaudo G, Marchesi S et al. Increased C-reactive protein concentrations in never-treated hypertension: the role of systolic and pulse pressures. J Hypertens 2003; 21: 1841–1846.

    Article  CAS  Google Scholar 

  21. Landin K, Tengborn L, Smith U . Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease. J Intern Med 1990; 227: 273–278.

    Article  CAS  Google Scholar 

  22. Bo M, Raspo S, Morra F, Cassader M, Isaia G, Poli L . Body fat is the main predictor of fibrinogen levels in healthy non-obese men. Metabolism 2004; 53: 984–988.

    Article  CAS  Google Scholar 

  23. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM . C-reactive protein and the risk of developing hypertension. JAMA 2003; 290: 2945–2951.

    Article  CAS  Google Scholar 

  24. de Maat MP, de Bart AC, Hennis BC, Meijer P, Havelaar AC, Mulder PG et al. Interindividual and intraindividual variability in plasma fibrinogen, TPA antigen, PAI activity, and CRP in healthy, young volunteers and patients with angina pectoris. Arterioscler Thromb Vasc Biol 1996; 16: 1156–1162.

    Article  CAS  Google Scholar 

  25. de Maat MP, Bladbjerg EM, Hjelmborg JB, Bathum L, Jespersen J, Christensen K . Genetic influence on inflammation variables in the elderly. Arterioscler Thromb Vasc Biol 2004; 24: 2168–2173.

    Article  CAS  Google Scholar 

  26. Folsom AR, Qamhieh HT, Flack JM, Hilner JE, Liu K, Howard BV et al. Plasma fibrinogen: levels and correlates in young adults. The Coronary Artery Risk. Development in Young Adults (CARDIA) Study. Am J Epidemiol 1993; 138: 1023–1036.

    Article  CAS  Google Scholar 

  27. Scott EM, Ariens RA, Grant PJ . Genetic and environmental determinants of fibrin structure and function: relevance to clinical disease. Arterioscler Thromb Vasc Biol 2004; 24: 1558–1566.

    Article  CAS  Google Scholar 

  28. Souto JC, Almasy L, Borrell M, Gari M, Martinez E, Mateo J et al. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 2000; 101: 1546–1551.

    Article  CAS  Google Scholar 

  29. Morita A, Nakayama T, Doba N, Hinohara S, Soma M . Polymorphism of the C-reactive protein (CRP) gene is related to serum CRP level and arterial pulse wave velocity in healthy elderly Japanese. Hypertens Res 2006; 29: 323–331.

    Article  CAS  Google Scholar 

  30. Jeng JR, Wang JH, Liu WS, Chen SP, Chen MY, Wu MH et al. Association of interleukin-6 gene G−174C polymorphism and plasma plasminogen activator inhibitor-1 level in Chinese patients with and without hypertension. Am J Hypertens 2005; 18: 517–522.

    Article  CAS  Google Scholar 

  31. Brull D, Montgomery H, Sanders J, Dhamrait S, Luong L, Rumley A et al. Interleukin-6 gene −174G>C and −572G>C promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol 2001; 21: 1458–1463.

    Article  CAS  Google Scholar 

  32. Margaglione M, Bossone A, Cappucci G, Colaizzo D, Grandone E, Di Minno G . The effect of the interleukin-6 c/g−174 polymorphism and circulating interleukin-6 on fibrinogen plasma levels. Haematologica 2001; 86: 199–204.

    CAS  PubMed  Google Scholar 

  33. Vickers MA, Green FR, Terry C, Mayosi BM, Julier C, Lathrop M et al. Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein. Cardiovasc Res 2002; 53: 1029–1034.

    Article  CAS  Google Scholar 

  34. Malarstig A, Wallentin L, Siegbahn A . Genetic variation in the interleukin-6 gene in relation to risk and outcomes in acute coronary syndrome. Thromb Res 2006; 119: 467–473.

    Article  Google Scholar 

  35. Janus ED, Wat NMS, Lam KSL, Cockram CS, Siu STS, Liu LJ et al. The prevalence of diabetes, association with cardiovascular risk factors and implications of diagnostic criteria (ADA 1997 and WHO 1998) in a 1996 community-based population study in Hong Kong Chinese. Diabetes Med 2000; 17: 741–745.

    Article  CAS  Google Scholar 

  36. Cheung BMY, Lam TH, Lam KSL, Tam SCF, Wat NMS, Man YB et al. The Hong Kong Cardiovascular Risk Factor Prevalence Survey cohort – results at 7 years. J Hypertens 2004; 22 (Suppl 2): S268–S269.

    Article  Google Scholar 

  37. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC . Homeostasis model assessment: insulin resistance and beta-cell function from fasting glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.

    Article  CAS  Google Scholar 

  38. Osiri M, McNicholl J, Moreland LW, Bridges Jr SL . A novel single nucleotide polymorphism and five probable haplotypes in the 5' flanking region of the IL-6 gene in African-Americans. Genes Immun 1999; 1: 166–167.

    Article  CAS  Google Scholar 

  39. Liu Y, Berthier-Schaad Y, Fallin MD, Fink NE, Tracy RP, Klag MJ et al. IL-6 haplotypes, inflammation, and risk for cardiovascular disease in a multiethnic dialysis cohort. J Am Soc Nephrol 2006; 17: 863–870.

    Article  CAS  Google Scholar 

  40. Sie MP, Sayed-Tabatabaei FA, Oei HH, Uitterlinden AG, Pols HA, Hofman A et al. Interleukin 6 −174g/c promoter polymorphism and risk of coronary heart disease; results from the Rotterdam study and a meta-analysis. Arterioscler Thromb Vasc Biol 2006; 26: 212–217.

    Article  CAS  Google Scholar 

  41. Fu HX, Zhang JY, Li GS, Li Y, Xu JL, Zhao ZN . Study on linkage between polymorphism of interleukin 6 gene −572C/G and susceptibility to myocardial infarction. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2006; 23: 245–249.

    CAS  PubMed  Google Scholar 

  42. Fu HX, Li GS, Li Y, Xu JL, Zhang JY . Interleukin-6-597G/A and −572C/G polymorphisms and risk of coronary heart disease. Zhonghua Xin Xue Guan Bing Za Zhi 2006; 34: 519–522.

    CAS  PubMed  Google Scholar 

  43. Lane DA, Grant PJ . Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 2000; 95: 1517–1532.

    CAS  PubMed  Google Scholar 

  44. Lele RD . Hypertension: molecular approach. J Assoc Physicians India 2004; 52: 53–62.

    CAS  PubMed  Google Scholar 

  45. Thomas GN, Critchley JA, Tomlinson B, Anderson PJ, Lee ZS, Chan JC . Obesity, independent of insulin resistance, is a major determinant of blood pressure in normoglycemic Hong Kong Chinese. Metabolism 2000; 49: 1523–1528.

    Article  CAS  Google Scholar 

  46. Devaraj S, Du Clos TW, Jialal I . Binding and Internalization of C-reactive protein by Fcgamma receptors on human aortic endothelial cells mediates biological effects. Arterioscler Thromb Vasc Biol 2005; 25: 1359–1363.

    Article  CAS  Google Scholar 

  47. Jialal I, Devaraj S, Venugopal SK . C-reactive protein: risk marker or mediator in atherothrombosis? Hypertension 2004; 44: 6–11.

    Article  CAS  Google Scholar 

  48. Venugopal SK, Devaraj S, Jialal I . Effect of C-reactive protein on vascular cells: evidence for a proinflammatory, proatherogenic role. Curr Opin Nephrol Hypertens 2005; 14: 33–37.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Analysis using the Sequenom genotyping system was performed with the help of Dr William Mak and Miss Phoebe Ng of the genome Research Centre, University of Hong Kong. LYF Wong received a Department of Medicine Seeding Grant to RAP/PDF, University of Hong Kong to study the effect of genetic variations in IL-6 gene on hypertension.

Author information

Authors and Affiliations

  1. Department of Medicine, The University of Hong Kong, Hong Kong SAR, China

    L Y F Wong, R Y H Leung, K L Ong & B M Y Cheung

Authors
  1. L Y F Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Y H Leung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K L Ong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B M Y Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B M Y Cheung.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wong, L., Leung, R., Ong, K. et al. Plasma levels of fibrinogen and C-reactive protein are related to interleukin-6 gene −572C>G polymorphism in subjects with and without hypertension. J Hum Hypertens 21, 875–882 (2007). https://doi.org/10.1038/sj.jhh.1002233

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.jhh.1002233

Keywords

This article is cited by

Search

Advanced search

Quick links