Thrombomodulin gene polymorphisms or haplotypes as potential risk factors for venous thromboembolism: A population-based case-control study

John A. Heit, Tanya M. Petterson, Whyte G. Owen, James P. Burke, Mariza De Andrade, L. Joseph Melton

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Dysfunction of the protein C anticoagulant system is associated with venous thromboembolism (VTE) and thrombomodulin (TM) is a critical cofactor within the protein C system. The aim of this study was to test the hypotheses that polymorphisms or haplotypes within the TM gene are common risk factors for VTE. We screened the TM putative promoter, exon and 3′-untranslated region for sequence variations in a random sample (n = 266) of consecutive idiopathic, objectively confirmed non-Olmsted County VTE patients referred to the Mayo Clinic. We then genotyped a sample of Olmsted County, MN residents with a first lifetime, objectively confirmed VTE in the 25-year period, 1966-90 (n = 223), and a sample of Olmsted County residents without VTE (n = 237) for polymorphisms either discovered in the screening population or previously published, and tested for an association of VTE with TM genotype or haplotypes using unconditional logistic regression and generalized linear models, respectively. We also genotyped these Olmsted County cases and controls at 20 'null' genetic maker loci and tested for population admixture. Nine novel and three previously described mutations were identified in the screening population. Mutations within the TM promoter, EGF1-5, serine/threonine-rich, transmembrane, and cytoplasm regions were absent or uncommon. TM845G → A (Ala25Thr; lectin region), TM2136T → C (Ala455Val; EGF6 region), TM2470C deletion (3′-untranslated region), and 4363A → G (3′-flanking region) were more common, but were not associated with VTE by genotype or haplotype. Null genetic marker allele frequencies did not differ significantly among cases and controls. We conclude that polymorphisms or haplotypes within the TM gene are not common risk factors for incident VTE.

Original languageEnglish (US)
Pages (from-to)710-717
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume3
Issue number4
DOIs
StatePublished - Apr 2005

Keywords

  • Mutation
  • Thrombomodulin gene
  • Venous thromboembolism

ASJC Scopus subject areas

  • Hematology

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