Archives of Pharmacal Research

, Volume 37, Issue 6, pp 752–759 | Cite as

Effects of inflammatory cytokine gene polymorphisms on warfarin maintenance doses in Korean patients with mechanical cardiac valves

  • In Kyung Yoon
  • Yun Jung Choi
  • Byung Chul Chang
  • Kyung Eun Lee
  • Jeong Yeon Rhie
  • Byung Koo Lee
  • Hye Sun GwakEmail author
Research Article


Cytokines that are involved in inflammation are related to blood coagulation, which could indirectly affect warfarin dose requirements. This study aimed to examine the effects of inflammatory cytokine gene polymorphisms on warfarin dose requirements for Korean patients with mechanical heart valves. In total, 191 patients with mechanical heart valves who were on warfarin anticoagulation therapy and maintained INR levels of 2–3 for three consecutive occasions were retrospectively followed up. In addition to vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 (CYP) 2C9 polymorphisms, the interferon-γ, interleukin-1β (IL1B), interleukin-6, interleukin-10, transforming growth factor-β1 (TGFB1), tumor necrosis factor-α, and C-reactive protein genotypes were determined. The predictive contribution of age, VKORC1, and CYP2C9 to variability was 46.0 %. The addition of IL1B and TGFB1 polymorphisms increased the R 2 to 48.8 % for stable dose requirements, and significantly higher doses were found, especially when the TGFB1 CC genotype was combined with the IL1B TT genotype. Based on the results, it was concluded that inflammatory cytokine genes, such as TGFB1 and IL1B, can be predictive variables for stable warfarin doses in Korean patients.


Warfarin Stable dose INR Genotype Cytokine genes 


Conflict of interest

We declare no conflict of interest.


  1. Almeida, O.P., P.E. Norman, R. Allcock, F. van Bockxmeer, G.J. Hankey, K. Jamrozik, and L. Flicker. 2009. Polymorphisms of the CRP gene inhibit inflammatory response and increase susceptibility to depression: The Health in Men Study. International Journal of Epidemiology 38: 1049–1059.PubMedCentralPubMedCrossRefGoogle Scholar
  2. Ansell, J., J. Hirsh, L. Poller, H. Bussey, A. Jacobson, and E. Hylek. 2004. The pharmacology and management of the vitamin K antagonists: The seventh ACCP Conference on antithrombotic and thrombolytic therapy. Chest 126: 204S–233S.PubMedCrossRefGoogle Scholar
  3. Awad, M.R., A. El-Glamel, P. Haselton, D.M. Turner, P.J. Sinnott, and I.V. Hutchinson. 1998. Genotypic variation in the transforming growth factor-beta 1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation 66: 1014–1020.PubMedCrossRefGoogle Scholar
  4. Bennermo, M., C. Held, F. Green, L.E. Strandberg, C.G. Ericsson, L.O. Hansson, H. Watkins, A. Hamsten, and P. Tornvall. 2004. Prognostic value of plasma interleukin-6 concentrations and the 174 G>C and 572 G>C promoter polymorphisms of the interleukin-6 gene in patients with acute myocardial infarction treated with thrombolysis. Atherosclerosis 174: 157–163.PubMedCrossRefGoogle Scholar
  5. Biasucci, L.M., G. Liuzzo, A. Buffon, and A. Maseri. 1999. The variable role of inflammation in acute coronary syndromes and in restenosis. Seminars in interventional cardiology 4: 105–110.PubMedGoogle Scholar
  6. Bidwell, J., L. Keen, G. Gallacher, R. Kimberly, T. Huizinga, M.F. McDermott, J. Oksenberg, J. McNicholl, F. Pociot, C. Hardt, and S. D’Alfonso. 1999. Cytokine gene polymorphism in human disease: Online databases, supplement 1. Genes and Immunity 1: 3–19.PubMedCrossRefGoogle Scholar
  7. Bogaty, P., P. Poirier, S. Simard, L. Boyer, S. Solymoss, and G.R. Dagenais. 2001. Biological profiles in subjects with recurrent acute coronary events compared with subjects with long-standing stable angina. Circulation 103: 3062–3068.PubMedCrossRefGoogle Scholar
  8. Caldwell, M.D., T. Awad, J.A. Johnson, B.F. Gage, M. Falkowski, P. Gardina, J. Hubbard, Y. Turpaz, T.Y. Langaee, C. Eby, C.R. King, A. Brower, J.R. Schmelzer, I. Glurich, H.J. Vidaillet, S.H. Yale, K. Qi Zhang, R.L. Berg, and J.K. Burmester. 2008. CYP4F2 genetic variant alters required warfarin dose. Blood 111: 4106–4112.PubMedCentralPubMedCrossRefGoogle Scholar
  9. Casas, J.P., T. Shah, A.D. Hingorani, J. Danesh, and M.B. Pepys. 2008. C-reactive protein and coronary heart disease: A critical review. Journal of Internal Medicine 264: 295–314.PubMedCrossRefGoogle Scholar
  10. Cho, H.J., K.H. Sohn, H.M. Park, K.H. Lee, B. Choi, S. Kim, J.S. Kim, Y.K. On, M.R. Chun, H.J. Kim, J.W. Kim, and S.Y. Lee. 2007. Factors affecting the interindividual variability of warfarin dose requirement in adult Korean patients. Pharmacogenomics 8: 329–337.PubMedCrossRefGoogle Scholar
  11. Cicala, C., and G. Cirino. 1998. Linkage between inflammation and coagulation: An update on the molecular basis of the crosstalk. Life Sciences 62: 1817–1824.PubMedCrossRefGoogle Scholar
  12. Cresey, A.A., A.C. Chang, L. Feigen, T.C. Wün, F.B. Taylor Jr, and L.B. Hinshaw. 1993. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. Journal of Clinical Investigation 91: 2850–2856.CrossRefGoogle Scholar
  13. Crobu, F., L. Palumbo, E. Franco, S. Bergerone, S. Carturan, S. Guarrera, S. Frea, G. Trevi, A. Piazza, and G. Matullo. 2008. Role of TGF-β1 haplotypes in the occurrence of myocardial infarction in young Italian patients. BMC Medical Genetics 9: 1–7.CrossRefGoogle Scholar
  14. De Jonge, E., P.E. Dekkers, A.A. Creasey, C.E. Hack, S.K. Paulson, A. Karim, J. Kesecioglu, M. Levi, S.J. van Deventer, and T. van Der Poll. 2000. Tissue factor pathway inhibitor (TFPI) dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood 95: 1124–1129.PubMedGoogle Scholar
  15. Esmon, C.T. 1994. Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis. Baillieres Clinical Haematology 7: 453–468.CrossRefGoogle Scholar
  16. Esmon, C.T. 2002. New mechanisms for vascular control of inflammation mediated by natural anticoagulant proteins. Journal of Experimental Medicine 196: 561–564.PubMedCentralPubMedCrossRefGoogle Scholar
  17. Ford, E.S., and W.H. Giles. 2000. Serum C-reactive protein and fibrinogen concentrations and self-reported angina pectoris and myocardial infarction: Findings from National Health and Nutrition Examination Survey III. Journal of Clinical Epidemiology 53: 95–102.PubMedCrossRefGoogle Scholar
  18. Frangogiannis, N.G., C.W. Smith, and M.L. Entman. 2002. The inflammatory response in myocardial infarction. Cardiovascular Research 53: 31–47.PubMedCrossRefGoogle Scholar
  19. Fuster, V., L. Badimon, J.J. Badimon, and J.H. Chesebro. 1992. The pathogenesis of coronary artery disease and the acute coronary syndrome. New England Journal of Medicine 326: 242–250.PubMedCrossRefGoogle Scholar
  20. Hanson, G. 2005. Inflammation, atherosclerosis, and coronary artery disease. New England Journal of Medicine 352: 1685–1695.CrossRefGoogle Scholar
  21. Hutchinson, J.V., V. Pravica, and P.J. Sinnot. 1998. Genetic regulation of cytokine synthesis: Consequences for acute and chronic organ allograft rejection. Graft 1: 15–21.Google Scholar
  22. Kobayashi, M., K. Shimada, and T. Ozawa. 1990. Human recombinant interleukin-1 beta and tumor necrosis factor alpha-mediated suppression of heparin-like compounds on cultured porcine aortic endothelial cells. Journal of Cellular Physiology 144: 383–390.PubMedCrossRefGoogle Scholar
  23. Lazo-Langner, A., G.A. Knoll, P.S. Wells, N. Carson, and M.A. Rodger. 2006. The risk of dialysis access thrombosis is related to the transforming growth factor-beta1 production haplotype and is modified by polymorphisms in the plasminogen activator inhibitor-type 1 gene. Blood 108: 4052–4058.PubMedCrossRefGoogle Scholar
  24. Lee, K.E., B.C. Chang, H.O. Kim, I.K. Yoon, N.R. Lee, H.Y. Park, and H.S. Gwak. 2012. Effects of CYP4F2 gene polymorphisms on warfarin clearance and sensitivity in Korean patients with mechanical cardiac valves. Therapeutic Drug Monitoring 34: 275–282.PubMedCrossRefGoogle Scholar
  25. Levi, M., T. Van der Poll, and H.R. Buller. 2004. Bidirectional relation between inflammation and coagulation. Circulation 109: 2698–2704.PubMedCrossRefGoogle Scholar
  26. Levi, M., and T. Van der Poll. 2005. Two-way interactions between inflammation and coagulation. Trends in Cardiovascular Medicine 15: 254–259.PubMedCrossRefGoogle Scholar
  27. Libby, P. 2002. Inflammation in atherosclerosis. Nature 420: 868–874.PubMedCrossRefGoogle Scholar
  28. Libby, P., P.M. Ridker, and A. Maseri. 2002. Inflammation and atherosclerosis. Circulation 105: 1135–1143.PubMedCrossRefGoogle Scholar
  29. Lindahl, B., H. Toss, A. Siegbahn, P. Venge, and L. Wallentin. 2001. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during instability in coronary artery disease. The New England Journal of Medicine 343: 1139–1147.CrossRefGoogle Scholar
  30. Lindmark, E., E. Diderholm, L. Wallentin, and A. Siegbahn. 2001. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: Effects of an early invasive or non invasive strategy. Journal of American Medical Association 286: 2107–2113.CrossRefGoogle Scholar
  31. Manginas, A., A. Tsiavou, A. Chiadaroglou, G. Giamouzis, D. Degiannis, D. Panagiotakos, and D.V. Cokkinos. 2008. Inflammatory cytokine gene variants in coronary artery disease patients in Greece. Coronary Artery Disease 19: 575–582.PubMedCrossRefGoogle Scholar
  32. Minkelen, R.V., M.C. De Visser, J.J. Houwing-Duistermaat, H.L. Vos, R.M. Bertina, and F.R. Rosendaal. 2007. Haplotypes of IL1B, IL1RN, IL1R1, and IL1R2 and the risk of venous thrombosis. Arteriosclerosis Thrombosis and Vascular Biology 27: 1486–1491.CrossRefGoogle Scholar
  33. Nawroth, P.P., and D.M. Stern. 1986. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. Journal of Experimental Medicine 163: 740–745.PubMedCrossRefGoogle Scholar
  34. Ognjanovic, S., J. Yamamoto, B. Saltzman, A. Franke, M. Ognjanovic, L. Yokochi, T. Vogt, R. Decker, and L. Le Marchand. 2010. Serum CRP and IL-6, genetic variants and risk of colorectal adenoma in a multiethnic population. Cancer Causes and Control 21: 1131–1138.PubMedCrossRefGoogle Scholar
  35. Olivieri, F., R. Antonicelli, M. Cardelli, F. Marchegiani, L. Cavallone, E. Mocchegiani, and C. Franceschi. 2006. Genetic polymorphisms of inflammatory cytokines and myocardial infarction in the elderly. Mechanisms of Ageing and Development 127: 552–559.PubMedCrossRefGoogle Scholar
  36. Opal, S.M., and C.T. Esmon. 2003. Bench-to-bed-side review: Functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis. Critical Care 7: 23–38.PubMedCentralPubMedCrossRefGoogle Scholar
  37. Orbe, J., C. Chorda, R. Montes, and J.A. Paramo. 1999. Changes in the fibrinolytic components of cultured human umbilical vein endothelial cells induced by endotoxin, tumor necrosis factor-alpha and interleukin-1 alpha. Haematologica 84: 306–311.PubMedGoogle Scholar
  38. Pravica, V., C. Perrey, A. Stevenes, J.H. Lee, and I.V. Hutchinson. 2000. A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: Absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Human Immunology 61: 863–866.PubMedCrossRefGoogle Scholar
  39. PRIME Study Group. 2003. C-reactive protein, interleukin-6, and fibrinogen as predictors of coronary heart disease: The PRIME Study. Arteriosclerosis Thrombosis and Vascular Biology 23: 1255–1261.CrossRefGoogle Scholar
  40. Real, J.M.F., F. Vendrell, C. Richart, C. Gutierrez, and W. Ricart. 2001. Platelet account and interleukin-6 gene polymorphism in healthy subjects. BMC Medical Genetics 2: 6–11.CrossRefGoogle Scholar
  41. Shah, P.K. 2007. Molecular mechanisms of plaque instability. Current Opinion in Lipidology 18: 492–499.PubMedCrossRefGoogle Scholar
  42. Tumor, D.M., D.M. Williams, D. Sankaran, M. Lazarus, P.J. Sinnott, and I.V. Hutchinson. 1997. An investigation of polymorphism in the interleukin-10 gene. European Journal of Immunogenetics 24: 1–8.CrossRefGoogle Scholar
  43. Wilson, A.G., J.A. Symon, T. McDowell, H.O. McDevitt, and G.W. Duff. 1997. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proceedings of the National Academy of Sciences of the United States of America 94: 3195–3199.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2013

Authors and Affiliations

  • In Kyung Yoon
    • 1
  • Yun Jung Choi
    • 1
  • Byung Chul Chang
    • 2
  • Kyung Eun Lee
    • 1
  • Jeong Yeon Rhie
    • 1
  • Byung Koo Lee
    • 1
  • Hye Sun Gwak
    • 1
    Email author
  1. 1.Division of Life and Pharmaceutical Sciences, College of PharmacyEwha Womans UniversitySeoulKorea
  2. 2.Department of Thoracic & Cardiovascular SurgeryYonsei University Health SystemSeoulKorea

Personalised recommendations