Effect of Interleukin-6 promoter polymorphisms in survivors of myocardial infarction and matched controls in the North and South of Europe

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.

Keywords

Interleukin 6 - coronary heart disease - myocardial infarction

• 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.