Polymorphisms in the 5 ' regulatory region of the tissue factor gene and the risk of myocardial infarction and venous thromboembolism - The ECTIM andPATHROS studies

Tissue factor (TF) is a transmembrane protein considered to be responsible for the initiation of coagulation. TF gene expression may be induced in mon ocytes and endothelial cells and is present in atherosclerotic plaque to in itiate thrombus formation. To investigate whether individual differences in TF gene expression could predispose subjects to thrombosis, we sequenced t he 5' domain of the gene up to nucleotide 2732 and found 6 different polymo rphisms: 4 of them were completely concordant and defined 2 haplotypes with similar frequencies, designated as 1208 D and 1208 I. Genotyping of patien ts with myocardial infarction in a case-control study involving 2354 subjec ts showed no association between the polymorphisms and nonfatal coronary th rombosis. In another study involving 255 patients with venous thromboemboli sm 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 homoz ygotes. 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 cor onary thrombosis but is associated with reduced plasma TF levels and a lowe r risk of venous thrombosis.