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

Abstract

a b s t r a c tObjective: 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.

The coagulation system in atherothrombosis: Implications for new therapeutic strategies

“…Furthermore, endogenous thrombin potential and thrombin‐antithrombin (TAT) complex values indicated a procoagulant profile of early atherosclerotic lesions as compared to stable advanced atherosclerotic lesions. Even in subclinical atherosclerotic disease, such as individuals with increased carotid intima media thickness (IMT), a relation between TF and IMT as marker of early atherosclerosis has been documented …”

“…Even in subclinical atherosclerotic disease, such as individuals with increased carotid intima media thickness (IMT), a relation between TF and IMT as marker of early atherosclerosis has been documented. 17 The presence of coagulation components in atherosclerotic lesions suggests at least a role of these coagulation proteins in plaque thrombogenicity. Taking it one step further, the question rises whether some of these coagulation proteases like thrombin and factor Xa really drive atherogenesis up to the point of atherothrombosis.…”

A 24-h Work Shift in Intensive Care Personnel: Biological Pathways between Work Stress and Ill Health

“…Moreover, the interpretation of TAT complexes is difficult without precisely analysing the balance between activated coagulation and fibrinolysis. Perhaps more importantly, accumulating evidence indicates a role for TF in atherosclerosis and inflammation 18 suggesting that, even if the magnitude of TF elevation observed in the present study was insufficient to induce a clinically relevant procoagulant state, it is plausible that increased TF production may *** Biological pathways between work stress and ill health contribute to the atherosclerotic process. This is supported, albeit indirectly, by a large epidemiological study demonstrating a significant association between job stress and plasma fibrinogen levels, 19 a marker reflecting two key pathways in atherosclerosis: inflammation and coagulation.…”

Circulating Tissue Factor Levels and Risk of Stroke

“…19 Moreover, TF gene promoter haplotypes were associated with carotid intima-media thickness, a condition predisposing to ischemic stroke. 44 According to the principle of Mendelian randomization, 45 circulating TF should be considered more a causal risk factor for stroke rather than a marker of unrecognized exogenous factors.…”