© 2000 American Heart Association, Inc.
Thrombosis |
Polymorphisms in the 5' Regulatory Region of the Tissue Factor Gene and the Risk of Myocardial Infarction and Venous Thromboembolism
The ECTIM and PATHROS Studies
From Laboratoire d’Hémostase and Service des Maladies Vasculaires, Hôpital Broussais—AP-HP, and Unité INSERM 428, Faculté de Pharmacie, Université René Descartes, Paris (E.A., J.E., J.-N.F., M.A.); Société bioMérieux, Marcy-l’Etoile (V.B.); and Unité INSERM 525, Paris (V.N., F.C.), France; and the MONICA Project: Belfast, Northern Ireland, UK (A.E.); Glasgow, Scotland, UK (C.M.); and Strasbourg (D.A.), Lille (G.L.), and Toulouse (J.-B.R.), France.
Correspondence to Dr Emmanuel Arnaud, Laboratoire d’Hémostase, Hôpital Broussais, 96 rue Didot, F-75674 Paris Cedex 14, France. E-mail emmanuel.arnaud{at}brs.ap-hop-paris.fr
Abstract—Tissue factor (TF) is a transmembrane protein considered to be responsible for the initiation of coagulation. TF gene expression may be induced in monocytes and endothelial cells and is present in atherosclerotic plaque to initiate thrombus formation. To investigate whether individual differences in TF gene expression could predispose subjects to thrombosis, we sequenced the 5' domain of the gene up to nucleotide 2732 and found 6 different polymorphisms: 4 of them were completely concordant and defined 2 haplotypes with similar frequencies, designated as 1208 D and 1208 I. Genotyping of patients with myocardial infarction in a case-control study involving 2354 subjects showed no association between the polymorphisms and nonfatal coronary thrombosis. In another study involving 255 patients with venous thromboembolism and 1204 controls, allele D was less common in the cases (P=0.022). The odds ratio associated with the presence of at least 1 D allele was 0.72 (P=0.031). Comparison of subgroups of control subjects who were homozygous for the D or I allele demonstrated a lower plasma TF concentration in DD homozygotes. These results indicate that the TF gene promoter exists in 2 major forms differing at 4 sites. The 1208 D haplotype is not associated with coronary thrombosis but is associated with reduced plasma TF levels and a lower risk of venous thrombosis.
Key Words: tissue factor • gene polymorphisms • venous thromboembolism • myocardial infarction
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