Tissue factor gene promoter haplotype associates with carotid intima-media thickness in subjects in cardiovascular risk prevention

Objective: Tissue factor (TF), key initiator of coagulation, has been ascribed roles not only in thrombosis but also in atherosclerosis. TF gene promoter haplotypes modulate TF expression, thereby potentially affecting atherosclerosis. The objective of this study was to evaluate functionally relevant TF promoter haplotypes as determinants of carotid intima-media thickness (C-IMT), a marker of atherosclerosis. Methods: The haplotype-tagging TF A-603G polymorphism and C-IMT were determined in 611 subjects referred to cardiovascular risk prevention. Subjects were aged 59.7 (58.1-61.1) years (mean (95% C.I.)), 79% were male, and 74% in secondary prevention with a history of coronary, cerebrovascular, or peripheral atherosclerotic disease. TF plasma levels were measured in 120 subjects. Results: Significant dose-dependent associations were found between A-603G genotype and both IMT_max and IMT_mean-max after adjusting for potential confounders. IMT values were highest in A/A (n = 173), intermediate in A/G (n = 312) and lowest in G/G (n = 126). IMT_max values (average and 95% C.I., in mm) for A/A, A/G and G/G, were 2.22 (2.11-2.34), 2.09 (2.01-2.18) and 2.02 (1.90-2.15), respectively (p_trend = 0.019), and IMT_mean-max values were 1.28 (1.23-1.32), 1.25 (1.22-1.28) and 1.21 (1.16-1.26), respectively (p_trend = 0.041). A significant interaction between A-603G genotype and prevention status was found (p = 0.046 and p = 0.042 for IMT_max and IMT_mean-max, respectively). TF plasma levels did not differ between genotypes and were not determinants of C-IMT. Conclusion: The haplotype-tagging TF A-603G polymorphism is associated with C-IMT, independently of TF levels in plasma. These findings provide clinical evidence of an involvement of TF in atherosclerosis, in addition to its well-known roles in hemostasis and thrombosis.