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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1737-1738. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kimura, R. Articles by Miyata, T. Search for Related Content PubMed PubMed Citation Articles by Kimura, R. Articles by Miyata, T. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents CORRESPONDENCE To the editor: Protein S–K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients Deep vein thrombosis (DVT) is a multifactorial disease caused by interactions between acquired risk factors and coagulation abnormalities.1 In whites, the factor V–Leiden and the prothrombin-20210G>A are widely recognized as genetic risk factors for DVT. However, these 2 mutations are not present in Japanese populations, and little is known about the genetic risk factors for DVT in these populations. In this study, we evaluated the genetic contributions of 5 polymorphisms in Japanese DVT patients. The plasminogen-A620T mutation, formerly referred to as plasminogen-Tochigi, and the protein S–K196E mutation, formerly referred to as protein S–Tokushima, exhibited decreased activities of plasminogen and protein S despite normal antigen levels.2-4 The ADAMTS13-P475S mutation exhibited low von Willebrand factor–cleaving activity in vitro.5 The factor XII–4C>T substitution in the 5'-untranslated region, formerly referred to as 46C>T, showed decreased plasma levels of both antigen and activity.6 The plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism is related to in vitro differences in transcription activity.7 We genotyped subjects for these 5 polymorphisms and compared their genotypic frequencies between 161 DVT patients and 3655 population-based controls. The protocol for this study was approved by the ethical review committee, and only those subjects who provided written informed consent for genetic analyses were included in this study. All participants of this study were Japanese. The controls were from a general population randomly selected from the residents of Suita City located in the second largest urban area in Japan (the Suita Study).8 One hundred sixty-one DVT patients, 78 men and 83 women, were registered by the Study Group of Research on Measures for Intractable Diseases, working under the auspices of the Ministry of Health, Labor, and Welfare of Japan. Six centers (Tochigi, Tokyo, Nagoya, Kyoto, and 2 in Osaka) participated in this study. The patients' mean age was 49.5 years (range, 12-87 years) and their mean body mass index was 23.6 ± 3.3. Thirteen percent of patients had a family history of thrombosis, and 16% of the patients had recurrent thrombosis. Of all the polymorphisms tested, only the frequency of protein S–K196E was statistically different between the 2 groups (2 = 38.3, P < .001) (Table 1). No other frequency differences were statistically significant. Two DVT patients were homozygous for the protein S–196E allele; however, no homozygotes were identified in the control group. One patient with the 196EE genotype first developed DVT following surgery at age 47, while the other patient developed DVT during pregnancy at age 32. View this table: [in this window] [in a new window]   Table 1.. Numbers and genotypic frequencies of protein S–K196E mutation in the DVT and control groups   The mutant protein S with the E allele has already been intensively studied as protein S–Tokushima.11 The protein S mutant showed the reduced activated protein C cofactor activity compared with wild-type protein S, suggesting a direct link between the protein S–K196E mutation and the development of DVT. By the genotyping of the general population, the protein S–196E allele frequency was estimated as 0.009. Thus, a substantial portion of the Japanese population harbors this mutant allele and is at higher risk for DVT. Rina Kimura, Shigenori Honda, Tomio Kawasaki, Hajime Tsuji, Seiji Madoiwa, Yoichi Sakata, Tetsuhito Kojima, Mitsuru Murata, Kazuhiro Nishigami, Masaaki Chiku, Tokio Hayashi, Yoshihiro Kokubo, Akira Okayama, Hitonobu Tomoike, Yasuo Ikeda, and Toshiyuki Miyata Correspondence: Toshiyuki Miyata, Research Institute, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan; e-mail: miyata{at}ri.ncvc.go.jp. References Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood. 2000;95: 1517-1532.[Free Full Text] 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.[Abstract/Free Full Text] 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.[CrossRef][Medline] [Order article via Infotrieve] 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.[Medline] [Order article via Infotrieve] Kokame K, Matsumoto M, Soejima K, et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci U S A. 2002;99: 11902-11907.[Abstract/Free Full Text] 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.[Abstract/Free Full Text] 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.[Abstract/Free Full Text] Mannami T, Baba S, Ogata J. Potential of carotid enlargement as a useful indicator affected by high blood pressure in a large general population of a Japanese city: the Suita study. Stroke. 2000;31: 2958-2965.[Abstract/Free Full Text] Kokubo Y, Kamide K, Inamoto N, et al. Identification of 108 SNPs in TSC, WNK1, and WNK4 and their association with hypertension in a Japanese general population. J Hum Genet. 2004;49: 507-515.[Medline] [Order article via Infotrieve] Antonarakis SE. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat. 1998;11: 1-3.[CrossRef][Medline] [Order article via Infotrieve] 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.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kimura, R. Articles by Miyata, T. Search for Related Content PubMed PubMed Citation Articles by Kimura, R. Articles by Miyata, T. Social Bookmarking                   What's this?

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