Skip to main content
SpringerLink
Log in

Genetic Risk Factors for Deep Vein Thrombosis among Japanese: Importance of Protein S K196E Mutation

  • Review Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

There is mounting evidence that mutations associated with a given disease arise with different frequencies among ethnic groups, thus ethnicity-specific studies are needed to identify causative mutations and properly assess risk. In particular, ethnic differences in the genetic background of thrombophilia have been reported. We recently conducted a large-scale analysis of the plasma activities of proteins C, S, antithrombin, and plasminogen within the Japanese general population.We found age-and sex-related differences and estimated the prevalence of deficiencies of protein C (0.13%), antithrombin (0.15%), protein S (1.12%), and plasminogen (4.29%). We also evaluated the genetic contribution to deep vein thrombosis and found that protein S mutation K196E is a genetic risk factor in the Japanese population. We estimated allele frequency to be 0.009, suggesting that 1 of 12,000 Japanese may be homozygous for the E allele, thus possibly as many as 10,000 individuals. Accordingly, a substantial proportion of the Japanese population carries the protein S E allele and is at risk of developing deep vein thrombosis. Given the frequency of this mutation and its strong correlation with deep vein thrombosis, it may be valuable to conduct a large-scale screening for this allele and advise concerned persons to avoid environmental risk factors known to be associated with deep vein thrombosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Dahlback B. Progress in the understanding of the protein C anticoagulant pathway. Int J Hematol. 2004;79:109–116.

    Article  CAS  PubMed  Google Scholar 

  2. Dahlback B, Villoutreix BO. Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition. Arterioscler Thromb Vasc Biol. 2005;25:1311–1320.

    Article  CAS  PubMed  Google Scholar 

  3. Nicolaes GA, Dahlback B. Factor V and thrombotic disease: description of a janus-faced protein. Arterioscler Thromb Vasc Biol. 2002;22:530–538.

    Article  CAS  PubMed  Google Scholar 

  4. Cargill M, Altshuler D, Ireland J, et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet. 1999;22:231–238.

    Article  CAS  PubMed  Google Scholar 

  5. Stephens JC, Schneider JA, Tanguay DA, et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science. 2001;293:489–493.

    Article  CAS  PubMed  Google Scholar 

  6. Kalafatis M, Mann KG. Factor V Leiden and thrombophilia. Arterioscler Thromb Vasc Biol. 1997;17:620–627.

    Article  CAS  PubMed  Google Scholar 

  7. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A. 1993;90:1004–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bertina RM, Koeleman BP, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64–67.

    Article  CAS  PubMed  Google Scholar 

  9. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet. 1995;346:1133–1134.

    Article  CAS  PubMed  Google Scholar 

  10. Fujimura H, Kambayash J, Monden M, Kato H, Miyata T. Coagulation factor V Leiden mutation may have a racial background. Thromb Haemost. 1995;74:1381–1382.

    Article  PubMed  CAS  Google Scholar 

  11. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698–3703.

    PubMed  CAS  Google Scholar 

  12. Miyata T, Kawasaki T, Fujimura H, Uchida K, Tsushima M, Kato H. The prothrombin gene G20210A mutation is not found among Japanese patients with deep vein thrombosis and healthy individuals. Blood Coagul Fibrinolysis. 1998;9:451–452.

    Article  CAS  PubMed  Google Scholar 

  13. Kokubo Y, Inamoto N, Tomoike H, et al. Association of genetic polymorphisms of sodium-calcium exchanger 1 gene, NCX1, with hypertension in a Japanese general population. Hypertens Res. 2004;27:697–702.

    Article  CAS  PubMed  Google Scholar 

  14. Kamide K, Kokubo Y, Yang J, et al. Hypertension susceptibility genes on chromosome 2p24-p25 in a general Japanese population. J Hypertens. 2005;23:955–960.

    Article  CAS  PubMed  Google Scholar 

  15. Okamoto A, Sakata T, Mannami T, et al. Population-based distribution of plasminogen activity and estimated prevalence and relevance to thrombotic diseases of plasminogen deficiency in the Japanese: the Suita Study. J Thromb Haemost. 2003;1:2397–2403.

    Article  CAS  PubMed  Google Scholar 

  16. Sakata T, Okamoto A, Mannami T, Matsuo H, Miyata T. Protein C and antithrombin deficiency are important risk factors for deep vein thrombosis in Japanese. J Thromb Haemost. 2004;2:528–530.

    Article  CAS  PubMed  Google Scholar 

  17. Sakata T, Okamoto A, Mannami T, Tomoike H, Miyata T. Prevalence of protein S deficiency in the Japanese general population: the Suita Study. J Thromb Haemost. 2004;2:1012–1013.

    Article  CAS  PubMed  Google Scholar 

  18. Sakata T, Mannami T, Baba S, et al. Potential of free-form TFPI and PA I-1 to be useful markers of early atherosclerosis in a Japanese general population (the Suita Study): association with the intimal-medial thickness of carotid arteries. Atherosclerosis. 2004;176:355–360.

    Article  CAS  PubMed  Google Scholar 

  19. De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood. 1996;87:3531–3544.

    PubMed  Google Scholar 

  20. Lane DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia: part 1. Thromb Haemost. 1996;76:651–662.

    Article  PubMed  CAS  Google Scholar 

  21. Tait RC, Walker ID, Reitsma PH, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost. 1995;73:87–93.

    Article  PubMed  CAS  Google Scholar 

  22. Miletich J, Sherman L, Broze G Jr. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med. 1987;317:991–996.

    Article  CAS  PubMed  Google Scholar 

  23. Tait RC, Walker ID, Perry DJ, et al. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol. 1994;87:106–112.

    Article  CAS  PubMed  Google Scholar 

  24. Suehisa E, Nomura T, Kawasaki T, Kanakura Y. Frequency of natural coagulation inhibitor (antithrombin III, protein C and protein S) deficiencies in Japanese patients with spontaneous deep vein thrombosis. Blood Coagul Fibrinolysis. 2001;12:95–99.

    Article  CAS  PubMed  Google Scholar 

  25. Aoki N, Moroi M, Sakata Y, Yoshida N, Matsuda M. Abnormal plasminogen. A hereditary molecular abnormality found in a patient with recurrent thrombosis. J Clin Invest. 1978;61:1186–1195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tait RC, Walker ID, Conkie JA, Islam SI, McCall F. Isolated familial plasminogen deficiency may not be a risk factor for thrombosis. Thromb Haemost. 1996;76:1004–1008.

    Article  PubMed  CAS  Google Scholar 

  27. Demarmels Biasiutti F, Sulzer I, Stucki B, Wuillemin WA, Furlan M, Lammle B. Is plasminogen deficiency a thrombotic risk factor? A study on 23 thrombophilic patients and their family members. Thromb Haemost. 1998;80:167–170.

    Article  CAS  PubMed  Google Scholar 

  28. Miyata T, Iwanaga S, Sakata Y, Aoki N. Plasminogen Tochigi: inactive plasmin resulting from replacement of alanine-600 by threonine in the active site. Proc Natl Acad Sci U S A. 1982;79:6132–6136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Antonarakis SE. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat. 1998;11:1–3.

    Article  CAS  PubMed  Google Scholar 

  30. Sakata Y, Aoki N. Molecular abnormality of plasminogen. J Biol Chem. 1980;255:5442–5447.

    PubMed  CAS  Google Scholar 

  31. Wang X, Lin X, Loy JA, Tang J, Zhang XC. Crystal structure of the catalytic domain of human plasmin complexed with streptokinase. Science. 1998;281:1662–1665.

    Article  CAS  PubMed  Google Scholar 

  32. Aoki N, Tateno K, Sakata Y. Differences of frequency distributions of plasminogen phenotypes between Japanese and American populations: new methods for the detection of plasminogen variants. Biochem Genet. 1984;22:871–881.

    Article  CAS  PubMed  Google Scholar 

  33. Ooe A, Kida M, Yamazaki T, et al. Common mutation of plasminogen detected in three Asian populations by an amplification refractory mutation system and rapid automated capillary electrophoresis. Thromb Haemost. 1999;82:1342–1346.

    Article  CAS  PubMed  Google Scholar 

  34. Sadler JE, Moake JL, Miyata T, George JN. Recent advances in thrombotic thrombocytopenic purpura. Hematology (Am Soc Hematol Educ Program). 2004;407–423.

    Article  Google Scholar 

  35. Kokame K, Matsumoto M, Soejima K, et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Wille-brand factor-cleaving protease activity. Proc Natl Acad Sci U S A. 2002;99:11902–11907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kokame K, Miyata T. Genetic defects leading to hereditary thrombotic thrombocytopenic purpura. Semin Hematol. 2004;41:34–40.

    Article  CAS  PubMed  Google Scholar 

  37. Ruan C, Dai L, Su J, Wang Z, Ruan C. The frequency of P475S polymorphism in von Willebrand factor-cleaving protease in the Chinese population and its relevance to arterial thrombotic disorders. Thromb Haemost. 2004;91:1257–1258.

    Article  PubMed  Google Scholar 

  38. Bongers TN, De Maat MP, Dippel DW, Uitterlinden AG, Leebeek FW. Absence of Pro475Ser polymorphism in ADAMTS-13 in Caucasians. J Thromb Haemost. 2005;3:805.

    Article  CAS  PubMed  Google Scholar 

  39. Yamazaki T, Sugiura I, Matsushita T, et al. A phenotypically neutral dimorphism of protein S: the substitution of Lys155 by Glu in the second EGF domain predicted by an A to G base exchange in the gene. Thromb Res. 1993;70:395–403.

    Article  CAS  PubMed  Google Scholar 

  40. Hayashi T, Nishioka J, Shigekiyo T, Saito S, Suzuki K. Protein S Tokushima: abnormal molecule with a substitution of Glu for Lys-155 in the second epidermal growth factor-like domain of protein S. Blood. 1994;83:683–690.

    PubMed  CAS  Google Scholar 

  41. Shigekiyo T, Uno Y, Kawauchi S, et al. Protein S Tokushima: an abnormal protein S found in a Japanese family with thrombosis. Thromb Haemost. 1993;70:244–246.

    Article  PubMed  CAS  Google Scholar 

  42. Hayashi T, Nishioka J, Suzuki K. Characterization of dysfunctional protein S-Tokushima (K155→E) in relation to the molecular interactions required for the regulation of blood coagulation. Pol J Pharmacol. 1996;48:221–223.

    PubMed  CAS  Google Scholar 

  43. Kanaji T, Okamura T, Osaki K, et al. A common genetic polymorphism (46 C to T substitution) in the 5′-untranslated region of the coagulation factor XII gene is associated with low translation efficiency and decrease in plasma factor XII level. Blood. 1998;91:2010–2014.

    PubMed  CAS  Google Scholar 

  44. Bertina RM, Poort SR, Vos HL, Rosendaal FR. The 46C→T polymorphism in the factor XII gene (F12) and the risk of venous thrombosis. J Thromb Haemost. 2005;3:597–599.

    Article  CAS  PubMed  Google Scholar 

  45. Eriksson P, Kallin B, van ‘t Hooft FM, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A. 1995;92:1851–1855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Miletich JP. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation. 1997;95:59–62.

    Article  CAS  PubMed  Google Scholar 

  47. Matsubara Y, Murata M, Isshiki I, et al. Genotype frequency of plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism in healthy Japanese males and its relation to PAI-1 levels. Int J Hematol. 1999;69:43–47.

    PubMed  CAS  Google Scholar 

  48. Kimura R, Honda S, Kawasaki T, et al. Protein S-K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients. Blood. 2006;107:1737–1738.

    Article  CAS  PubMed  Google Scholar 

  49. Kinoshita S, Iida H, Inoue S, et al. Protein S and protein C gene mutations in Japanese deep vein thrombosis patients. Clin Biochem. 2005;38:908–915.

    Article  CAS  PubMed  Google Scholar 

  50. Hayashi T, Nishioka J, Suzuki K. Molecular mechanism of the dysfunction of protein S(Tokushima) (Lys155→ Glu) for the regulation of the blood coagulation system. Biochim Biophys Acta. 1995;1272:159–167.

    Article  PubMed  Google Scholar 

  51. Cox DW, Woo SL, Mansfield T. DNA restriction fragments associated with alpha 1-antitrypsin indicate a single origin for deficiency allele PI Z. Nature. 1985;316:79–81.

    Article  CAS  PubMed  Google Scholar 

  52. Zivelin A, Griffin JH, Xu X, et al. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood. 1997;89:397–402.

    PubMed  CAS  Google Scholar 

  53. Dykes AC, Walker ID, McMahon AD, Islam SI, Tait RC. A study of protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br J Haematol. 2001;113:636–641.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Research Institute, National Cardiovascular Center, Osaka, Suita, Japan

    Toshiyuki Miyata & Rina Kimura

  2. Department of Preventive Cardiology, National Cardiovascular Center, Osaka, Suita, Japan

    Yoshihiro Kokubo

  3. Laboratory of Clinical Chemistry, National Cardiovascular Center, Osaka, Suita, Japan

    Toshiyuki Sakata

Authors
  1. Toshiyuki Miyata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rina Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshihiro Kokubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshiyuki Sakata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshiyuki Miyata.

About this article

Cite this article

Miyata, T., Kimura, R., Kokubo, Y. et al. Genetic Risk Factors for Deep Vein Thrombosis among Japanese: Importance of Protein S K196E Mutation. Int J Hematol 83, 217–223 (2006). https://doi.org/10.1532/IJH97.A20514

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1532/IJH97.A20514

Key words

Search

Navigation