title: Haplotype of thrombomodulin gene associated with plasma thrombomodulin level and deep vein thrombosis in the Japanese population.
abstract: BACKGROUND
  Thrombomodulin (TM) is an essential cofactor in protein C activation by thrombin. Here, we evaluated the contribution of genetic variations in the TM gene to soluble TM (sTM) level and deep vein thrombosis (DVT) in Japanese.
  
  
  METHODS
  We sequenced the TM putative promoter, exon, and 3'-untranslated region in DVT patients (n=118). Among 17 genetic variations we identified, two missense mutations (R385K, D468Y) and three common single nucleotide polymorphisms (-202G>A, 2487A>T, 2729A>C) were genotyped in a general population of 2247 subjects (1032 men and 1215 women) whose sTM levels were measured. We then compared the frequency of these mutations in DVT patients with that in the age, body mass index-adjusted population-based controls.
  
  
  RESULTS
  We identified one neutral mutation (H381) and three missense mutations (R385K; n=2, A455V; n=53 heterozygous, n=14 homozygous, D468Y; n=2) of TM in the DVT patients. Age-adjusted mean values of sTM were lower in C-allele carriers of 2729A>C than in noncarriers in the Japanese general population (women: 16.7+/-0.3 U/ml vs. 17.9+/-0.2 U/ml, p<0.01, men: 19.4+/-0.3 U/ml vs. 20.4+/-0.3 U/ml, p=0.03). Additionally, the CC genotype of this mutation was more common in the male DVT patients than in the male individuals of the general population (odds ratio=2.76, 95% confidence interval=1.14-6.67; p=0.02). This mutation was in linkage disequilibrium (r-square>0.9) with A455V mutation.
  
  
  CONCLUSIONS
  TM mutations, especially those with a haplotype consisting of 2729A>C and A455V missense mutation, affect sTM levels, and may be associated with DVT in Japanese.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Sugiyama
authors.forename: Hisao
authors.initials: H
authors.lastname: Hirota
authors.forename: Rina
authors.initials: R
authors.lastname: Kimura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kokubo
authors.forename: Tomio
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Etsuji
authors.initials: E
authors.lastname: Suehisa
authors.forename: Akira
authors.initials: A
authors.lastname: Okayama
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
authors.forename: Tokio
authors.initials: T
authors.lastname: Hayashi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nishigami
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018180:Thrombomodulin / Q000097:blood* / Q000235:genetics*; D020246:Venous Thrombosis / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D018180:Thrombomodulin