Abstract
Deep vein thrombosis (DVT) is a multifactorial disease caused by acquired risk factors such as a bed rest, surgery and malignancies. Although the factor V Leiden and the prothrombin-20210G>A mutation do not exist in Japanese populations, a mutation in protein S (PS) Tokushima (K196E) has been attracting attention in Japan. In this study, the genetic contribution of PS Tokushima (K196E) was evaluated in 60 Japanese patients with thrombosis in comparison to 234 healthy volunteers and 88 patients without thrombosis. Genes associated with the response to warfarin, cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and γ-glutamyl carboxylase (GGCX) were also investigated simultaneously. PS Tokushima (K196E) was detected in 6 patients with thrombosis, in 3 without thrombosis and in 3 healthy volunteers, indicating that there is a high frequency of the PS Tokushima (K196E). There were no significant differences of CYP2C9, VKORC1 or GGCX between the patients with and without DVT. Therefore, PS Tokushima (K196E) is an important genetic risk factor for DVT in the Japanese population.
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References
Dahlbäck B. The protein C anticoagulant system: inherited defects as basis for venous thrombosis. Thromb Res. 1995;77:1–43.
Dahlbäck B. Protein S and C4b-binding protein: components involved n the regulation of the protein C anticoagulant system. Thromb Haemost. 1991;66:49–61.
Makris M, Leach M, Beauchamp NJ, Daly ME, Cooper PC, Hampton KK, et al. Gene analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S. Blood. 2000;95:1935–44.
Beauchamp NJ, Dykes AC, Parikh N, Campbell Tait R, Daly ME. The prevalence of, and molecular defects underlying, inherited protein S deficiency in the general population. Br J Haematol. 2004;125:647–54.
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;2:1012–3.
Nomura T, Suehisa E, Kawasaki T, Okada A. Frequency of protein S deficiency in general Japanese population. Thromb Res. 2000;100:367–71.
Tsuda H, Hattori S, Tanabe S, Iida H, Nakahara M, Nishioka S, et al. Screening for aetiology of thrombophilia: a high prevalence of protein S abnormality. Ann Clin Biochem. 1999;36:423–32.
Hamasaki N, Kanaji T. Clinical role of protein S deficiency in Asian population. In: Tanaka K, Davie EW, editors. Recent advance in thrombosis and hemostasis. Japan: Springer; 2008. p. 597–613.
Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64–7.
Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med. 1995;332:912–7.
Kinoshita S, Iida H, Inoue S, Watanabe K, Kurihara M, Wada Y, et al. Protein S and protein C gene mutations in Japanese deep vein thrombosis patient. Clin Biochem. 2005;38:908–15.
Gandrille S, Borgel D, Sala N, Espinosa-Parrilla Y, Simmonds R, Rezende S, et al. Protein S deficiency; a database of mutations—summary of the first update. Thromb Haemost. 2000;84:918.
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;83:683–90.
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;1272:159–67.
Kimura R, Honda S, Kawasaki T, Tsuji H, Madoiwa S, Sakata Y, et al. Protein S-K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients. Blood. 2006;107:1737–8.
Mushiroda T, Ohnishi Y, Saito S, Takahashi A, Kikuchi Y, Saito S, et al. Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients. J Hum Genet. 2006;51:249–53.
Takahashi H, Wilkinson GR, Nutescu EA, Morita T, Ritchie MD, Scordo MG, et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics. 2006;16:101–10.
Kimura R, Miyashita K, Kokubo Y, Akaiwa Y, Otsubo R, Nagatsuka K, et al. Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb Res. 2007;120(2):181–6.
Okada H, Takagi A, Adachi T, Yamamoto K, Matsushita T, Takamatsu J, et al. Identification of protein Sa gene mutations including four novel mutations in eight unrelated patients with protein S deficiency. Br J Haematol. 2004;126:219–25.
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;12:95–9.
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Ikejiri, M., Wada, H., Sakamoto, Y. et al. The association of protein S Tokushima-K196E with a risk of deep vein thrombosis. Int J Hematol 92, 302–305 (2010). https://doi.org/10.1007/s12185-010-0671-0
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DOI: https://doi.org/10.1007/s12185-010-0671-0