Interleukin-6 and interleukin-6 promoter polymorphism (−174) G>C in patients with spontaneous venous thromboembolism

Rainer Vormittag; Kety Hsieh; Alexandra Kaider; Erich Minar; Christine Bialonczyk; Mirko Hirschl; Christine Mannhalter; Ingrid Pabinger

doi:10.1160/TH05-12-0816

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(05): 802-806
DOI: 10.1160/TH05-12-0816

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Interleukin-6 and interleukin-6 promoter polymorphism (−174) G>C in patients with spontaneous venous thromboembolism

Rainer Vormittag

¹Division of Haematology and Haemostaseology, Department of Internal Medicine I Vienna, Austria

,

Kety Hsieh

²Department of Radiology, Vienna, Austria

,

Alexandra Kaider

³Section of Clinical Biometrics, Department of Medical Computer Sciences Vienna, Austria

,

Erich Minar

⁴Division of Angiology, Department of Internal Medicine II, Vienna, Austria

,

Christine Bialonczyk

⁶Department of Dermatology, Wilhelminenspital Vienna, Vienna, Austria

,

Mirko Hirschl

⁷7Department of Angiology, Hanusch-Krankenhaus Vienna, Vienna, Austria

,

Christine Mannhalter

⁵Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Vienna, Vienna, Austria

,

Ingrid Pabinger

¹Division of Haematology and Haemostaseology, Department of Internal Medicine I Vienna, Austria

› Author Affiliations

Abstract

Summary

Increased levels of interleukin-6 (IL-6) have been reported in patients with a history of venous thromboembolism (VTE); however, prospective studies did not confirm an association between inflammatory markers that are highly correlated with IL-6 and the risk of VTE. It was the aim of our study to investigate the association of IL-6 and its promoter polymorphism (−174) G>C with the risk of spontaneous VTE. IL-6 was measured in 128 patients with deep venous thrombosis (DVT, 70 w / 58 m),105 with pulmonary embolism (PE, 58w/ 47 m) and 122 healthy controls (60 w / 62 m) with a highly sensitive ELISA (Quantikine⁻ HS Human IL-6 Immunoassay, RnDSystems^®). The promoter polymorphism was determined by genotyping, allele specific PCR was followed by high resolution gel-electrophoresis. Median concentrations [interquartile ranges] were 2.37 [1.51–3.89] (pg/ ml) in patients with DVT, 2.83 [1.83–4.87] in those with PE and 2.51 [1.71–4.78] in controls (p = 0.6, p = 0.4). Hetero- or homozygous carriers of the C allele (71% in DVT, 67% in PE and 59% among controls) did not have higher IL-6 levels than homozygous carriers of the G allele (median 2.60 vs. 2.59 pg/ml, p = 0.7). In conclusion, we found no association of IL-6 and its promoter polymorphism (−174) G>C with the risk of spontaneous VTE.

Keywords

Interleukin-6 - interleukin-6 promoter polymorphism - pulmonary embolism - venous thrombosis

Full Text

References

References
1 Kerr R, Stirling D, Ludlam CA. Interleukin 6 and haemostasis. Br J Haematol 2001; 115: 3-12.
2 Fishman D, Faulds G, Jeffery 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.
3 Reitsma PH, Rosendaal FR. Activation of innate immunity in patients with venous thrombosis: the Leiden Thrombophilia Study. J Thromb Haemost 2004; 02: 619-22.
4 van Aken BE, den Heijer M, Bos GM. et al. Recurrent venous thrombosis and markers of inflammation. Thromb Haemost 2000; 83: 536-9.
5 Salobir B, Sabovic M. Possible vascular-bed-specific role of interleukin-6 in young women with a history of myocardial infarction, lacunar cerebral infarction and deep vein thrombosis. Cytokine 2004; 25: 265-72.
6 Salobir B, Sabovic M. Interleukin-6 and antiphospholipid antibodies in women with contraceptive-related thromboembolic disease. Obstet Gynecol 2004; 104: 564-70.
7 Tsai AW, Cushman M, Rosamond WD. et al. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). Am J Med 2002; 113: 636-42.
8 Ridker PM, Cushman M, Stampfer MJ. et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336: 973-9.
9 Wilkerson WR, Sane DC. Aging and thrombosis. Semin Thromb Hemost 2002; 28: 555-68.
10 Neumann FJ, Ott I, Marx N. et al. Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity. Arterioscler Thromb Vasc Biol 1997; 17: 3399-405.
11 Chin BS, Conway DS, Chung NA. et al. Interleukin-6, tissue factor and von Willebrand factor in acute decompensated heart failure: relationship to treatment and prognosis. Blood Coagul Fibrinolysis 2003; 14: 515-21.
12 Amrani DL. Regulation of fibrinogen biosynthesis: glucocorticoid and interleukin-6 control. Blood Coagul Fibrinolysis 1990; 01: 443-6.
13 Ray A. A SAF binding site in the promoter region of human gamma-fibrinogen gene functions as an IL-6 response element. J Immunol 2000; 165: 3411-7.
14 Haidaris PJ. Induction of fibrinogen biosynthesis and secretion from cultured pulmonary epithelial cells. Blood 1997; 89: 873-82.
15 Undar L, Ertugrul C, Altunbas H. et al. Circadian variations in natural coagulation inhibitors protein C, protein S and antithrombin in healthy men: a possible association with interleukin-6. Thromb Haemost 1999; 81: 571-5.
16 Hooper WC, Phillips DJ, Evatt BL. Endothelial cell protein S synthesis is upregulated by the complex of IL-6 and soluble IL-6 receptor. Thromb Haemost 1997; 77: 1014-9.
17 Stirling D, Hannant WA, Ludlam CA. Transcriptional activation of the factor VIII gene in liver cell lines by interleukin-6. Thromb Haemost 1998; 79: 74-8.
18 Kyrle PA, Minar E, Hirschl M. et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-62.
19 Tracy RP, Arnold AM, Ettinger W. et al. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study. Arterioscler Thromb Vasc Biol 1999; 19: 1776-83.
20 Haring D, Endler G, Hsieh K. et al. Comparison of methods for determination of interleukin 6 G(−174)C promoter polymorphism. Biotechniques 2002; 33: 1114-7.
21 Pabinger I, Grafenhofer H, Kaider A. et al. Preeclampsia and fetal loss in women witha history of venous thromboembolism. Arterioscler Thromb Vasc Biol 2001; 21: 874-9.
22 Tsai AW, Cushman M, Rosamond WD. et al. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). Am J Med 2002; 113: 636-42.
23 Vormittag R, Vukovich T, Schonauer V. et al. Basal high-sensitivity-C-reactive protein levels in patients with spontaneous venous thromboembolism. Thromb Haemost 2005; 93: 488-93.
24 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.
25 Brull DJ, Leeson CP, Montgomery HE. et al. The effect of the Interleukin-6-174G > C promoter gene polymorphism on endothelial function in healthy volunteers. Eur J Clin Invest 2002; 32: 153-7.
26 Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 2000; 275: 18138-44.
27 Lei SF, Deng FY, Liu XH. et al. Polymorphisms of four bone mineral density candidate genes in Chinese populations and comparison with other populations of different ethnicity. J Bone Miner Metab 2003; 21: 34-42.
28 Yudkin JS, Kumari M, Humphries SE. et al. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?. Atherosclerosis 2000; 148: 209-14.
29 Acalovschi D, Wiest T, Hartmann M. et al. Multiple levels of regulation of the interleukin-6 system in stroke. Stroke 2003; 34: 1864-9.
30 Pola R, Flex A, Gaetani E. et al. Synergistic effect of −174 G/C polymorphism of the interleukin-6 gene promoter and 469 E/K polymorphism of the intercellular adhesion molecule-1 gene in Italian patients with history of ischemic stroke. Stroke 2003; 34: 881-5.
31 Greisenegger S, Endler G, Haering D. et al. The (−174) G/C polymorphism in the interleukin-6 gene is associated with the severity of acute cerebrovascular events. Thromb Res 2003; 110: 181-6.
32 Exner M, Schillinger M, Minar E. et al. Interleukin-6 promoter genotype and restenosis after femoropopliteal balloon angioplasty: initial observations. Radiology 2004; 231: 839-44.
33 Endler G, Marsik C, Joukhadar C. et al. The interleukin-6 G(−174)C promoter polymorphism does not determine plasma interleukin-6 concentrations in experimental endotoxemia in humans. Clin Chem 2004; 50: 195-200.
34 Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000; 102: 2165-8.
35 Stouthard JM, Levi M, Hack CE. et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996; 76: 738-42.