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DOI: 10.1160/TH04-04-0202
Effect of Interleukin-6 promoter polymorphisms in survivors of myocardial infarction and matched controls in the North and South of Europe
The HIFMECH Study This work was supported by the British Heart Foundation (grant RG2000/015).Publication History
Received
01 April 2004
Accepted after resubmission
25 August 2004
Publication Date:
04 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200405/lookinside/thumbnails/10-1160-th04-04-0202-1.jpg)
Summary
Elevated plasma IL-6 levels have been implicated in the pathogenesis of coronary heart disease. We have investigated the association of two polymorphisms in the promoter of IL-6 (-572G>C and -174G>C) with levels of inflammatory markers and risk of myocardial infarction (MI) in a European study of MI survivors and age-matched controls from two high-risk centres in the North of Europe, and two low risk centres in the South. IL-6 and CRP levels were similar in controls in both regions, but were higher in cases. For the -174G>C polymorphism the rare -174C allele showed a regional difference in allele frequency, being more common in the North European group (0.43 vs 0.28; p < 0.0005), where -174C allele carriers showed an apparent reduced risk of MI compared to -174GG homozygotes (OR 0.53, 95%CI 0.32, 0.86). No such effect was observed in the South or with the -572G>C in either group. Neither genotype was associated with a significant effect on plasma IL-6 levels in either cases or controls. Furthermore, no regional difference was observed in the frequency of the -572G>C SNP, suggesting that these polymorphisms are unlikely to be contributing to the observed increased risk of cardiovascular disease in Northern Europe.
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References
- 1 Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340: 115-26.
- 2 Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J 1990; 265: 621-36.
- 3 Biasucci LM, Liuzzo G, Fantuzzi G. et al. Increasing levels of Interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation 1999; 99: 2079-84.
- 4 Ridker PM, Rifai N, Stampfer MJ. et al. Plasma concentration of Interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767-72.
- 5 Fishman D, Faulds G, Jeffrey R. et al. 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 1998; 102: 1369-76.
- 6 Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on Interleukin 6 transcriptional regulation. J Biol Chem 2000; 275: 18138-44.
- 7 Brull DJ, Montgomery HE, Sanders J. et al. Interleukin-6 gene -174G>C and -572G>C promoter polymorphisms are strong predictors of plasma Interleukin-6 levels after coronary artery bypass graft surgery. Arterioscler Thromb Vasc Biol 2001; 21: 1458-63.
- 8 Kilpinen S, Hulkkonen J, Wang XY. et al. The promoter polymorphism of the interleukin-6 gene regulates interleukin-6 production in neonates but not in adults. Eur Cytokine Netw 2001; 12: 62-8.
- 9 Ferrari SL, Ahn-Luong L, Garnero P. et al. Two promoter polymorphisms regulating Interleukin-6 gene expression are associated with circulating levels of C-Reactive Protein and markers of bone resorption in postmenopausal women. J Clin Endocrinol Metab 2003; 88: 255-9.
- 10 Rivera-Chavez FA, Peters-Hybki D, Barber RC. et al. Interleukin-6 promoter haplotypes and interleukin-6 cytokine responses. Shock 2003; 20: 218-23.
- 11 Georges JL, Loukaci V, Poirier O. et al. Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction: The ECTIM study: Etude Cas-Temoin de l’Infarctus du Myocarde. J Mol Med 2001; 79: 300-5.
- 12 Humphries SE, Luong L, Ogg MS. et al. 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 2001; 22: 2243-52.
- 13 Basso F, Lowe GO, Rumley A. et al. Interleukin-6 -174G>C polymorphism and risk of coronary heart disease in West of Scotland coronary prevention study (WOSCOPS). Arterioscler Thromb Vasc Biol 2002; 22: 599-604.
- 14 Jenny NS, Tracy RP, Ogg MS. et al. In the elderly, Interleukin-6 plasma levels and the -174G>C polymorphism are associated with the development of cardiovascular disease. Arterioscler Thromb Vasc Biol 2002; 22: 2066-71.
- 15 Nauck M, Winkelmann B, Hoffmann MM. et al. The interleukin-6 G(-174)C promoter polymorphism in the LURIC cohort: no association with plasma interleukin-6, coronary artery disease, and myocardial infarction. J Mol Med 2002; 80: 507-13.
- 16 Bennet AM, Prince J, Fei G-Z. et al. Interleukin-6 serum levels and genotypes influence the risk for myocardial infarction. Atherosclerosis 2003; 171: 359-67.
- 17 Sans S, Kesteloot H, Kromhout D. The burden of cardiovascular disease mortality in Europe. Task force of the European Society of Cardiology on cardiovascular mortality and morbidity. Eur Heart J 1997; 18: 1231-48.
- 18 Hamsten A, Margaglione M, Silveira A. et al. High plasma concentration of Lp(a) ia a risk factor for myocardial infarction in Southern but not Northern Europe (the HIFMECH study). J Int Med. 2003 submitted.
- 19 Harris TB, Ferrucci L, Tracy RP. et al. Associations of elevated interleukin-6 and Creactive protein levels with mortality in the elderly. Am J Med 1999; 106: 506-12.
- 20 Berk BC, Weintraub W, Alexander RW. Elevation of C-reactive protein in active coronary artery disease. Am J Cardiol 1990; 65: 168-72.
- 21 Lowe GDO. Fibrinogen and cardiovascular disease: historical introduction. Eur Heart J 1995; 16 Suppl A 2-5.
- 22 Ikeda U, Ohkawa F, Seino Y. et al. Serum interleukin 6 levels become elevated in acute myocardial infarction. J Mol Cell Cardiol 1992; 24: 579-84.
- 23 Elghannam H, Tavackoli S, Ferlic L. et al. A prospective study of genetic markers of susceptibility to infection and inflammation, and the severity, progression, and regression of coronary athersclerosis and its response to therapy. J Mol Med 2000; 78: 562-8.
- 24 Margaglione M, Bossone A, Cappucci G. et al. The effect of interleukin-6 C/G-174 polymorphism and circulating interleukin-6 on fibrinogen plasma levels. Haematologica 2001; 86: 199-204.
- 25 Seltzer CC. Framingham study data and “established wisdom” about cigarette smoking and coronary heart disease. J Clin Epidemiol 1989; 42: 743-50.
- 26 Castelli WP. Diet, smoking, and alcohol: influence on coronary heart disease risk. Am J Kidney Dis 1990; 16 (Suppl. 01) 41-46.
- 27 Weintraub WS. Cigarette smoking as a risk factor for coronary artery disease. Adv Exp Med Biol 1990; 273: 27-37.