Genetic Variations in the Tissue Factor Gene Are Associated With Clinical Outcome in Acute Coronary Syndrome and Expression Levels in Human Monocytes

Abstract

Objective-Tissue factor (TF) has, among other factors, a prominent role in acute coronary syndrome (ACS). Our goal was to investigate whether single nucleotide polymorphisms (SNP) in the TF gene (F3) are associated with plasma TF, risk, and outcome in patients with ACS. Moreover, we wanted to investigate the impact of associated TF SNPs on mRNA production in human monocytes. Methods and Results-In 725 patients with ACS [Fragmin and Fast Revascularization during Instability in CoronaryArtery Disease II (FRISC-II) study] and 376 controls, 13 SNPs were genotyped and plasma TF measured. Thereafter, the 5466 AϾG and the Ϫ1812 CϾT were genotyped among all of the FRISC-II participants (nϭ3143) and assessed concerning clinical outcome. Associated SNPs were genotyped in 92 healthy blood donors for comparison of TF activity and TF mRNA expression. None of the SNPs were associated with patient/control status. The 5466 AϾG SNP was associated with cardiovascular death (odds ratio, 1.8; Pϭ0.025). The CG haplotype by Ϫ1812 CϾT and 5466 AϾG was associated with a 3-fold increased risk of death (PϽ0.001). TF mRNA and basal TF activity was significantly lower among 5466 AG carriers, whereas the increase in monocyte TF activity on lipopolysaccharide stimulation was significantly stronger (Pϭ0.04). Key Words: acute coronary syndrome Ⅲ tissue factor Ⅲ single nucleotide polymorphism Ⅲ outcome Ⅲ mRNA A cute coronary syndrome (ACS) is a multifactorial disease in which a multitude of lifestyle and genetic factors contribute to the development and outcome of the disease. 1 The genetic component of ACS seems to be relatively high, because family history is a strong risk factor, and heritability studies have shown a large genetic contribution to cardiac disease. 2,3 Single nucleotide polymorphisms (SNPs) are the most common genetic variations in the genome and may influence factors involved in atherosclerosis, plaque destabilization, and thrombosis, all of which are fundamental aspects of ACS etiology. 3 Variations in genes that encode for hemostatic factors are considered to be likely candidates for modifiers of the procoagulant phenotype, usually observed in patients with myocardial infarction (MI). 4 A procoagulant phenotype may have a substantial effect on ACS outcome, because a larger sized superimposed thrombus is directly related to the severity of myocardial ischemia. 5 A major player in this respect is tissue factor (TF), which rapidly initiates blood coagulation and is generally recognized as an important thrombogenic factor in atherosclerotic lesions. 6 TF is present as a membrane-bound molecule in different cell types in the vessel wall and within plaques, including endothelial cells, smooth muscle cells monocytes/macrophages, and foam cells. 7 Proteolytic cleavage of TF results in a soluble form of TF (plasma TF), which only contains the extracellular part of the protein and does not show significant procoagulant activity. 8 Moreover, the presence of an alternatively spliced form of TF has been reported recently. 9 Intravascula...

Sex Is Associated With the Presence of Atherosclerotic Plaque Hemorrhage and Modifies the Relation Between Plaque Hemorrhage and Cardiovascular Outcome

“…26 In another study, this single-nucleotide polymorphism was associated with an increase of tissue factor activity in monocytes from healthy donors after stimulation with lipopolysaccharide through higher expression of mRNA levels. 27 This may also be a mechanism resulting in a hypercoagulable state in women, which could be independent of plaque-related mechanisms. Relating to this hypercoagulability in a clinical setting, women show a higher embolic rate after CEA, 28,29 which is associated with cardiovascular complications after this surgical procedure.…”

Lack of association between potential prothrombotic genetic risk factors and arterial and venous thrombosis

“…Some studies have described the role of the polymorphism +5466 A/G of the TF gene, showing that it is associated with the risk of thrombosis (Reny et al, 2004;Mälarstig et al, 2005;Morange et al, 2007;Davis and Erlich, 2008;Boles and Mackman, 2010) and a threefold increase in the risk of thrombosis in individuals that possess this polymorphism (Opstad et al, 2010a). Thus, several studies have reported the relationship between this polymorphism and regulation of TF expression and high levels of TF in cardiovascular disease (Campo et al, 2006;Undas et al, 2009;Opstad et al, 2010b).…”

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

“…With regard to clinical data, controversial results were reported about the contribution of TF promoter A/G haplotype on risk of cardiovascular events [11][12][13]15], with studies indicating lower [15], null [11,12] or higher [13] risk in carriers of the A promoter haplotype. It is worth to point out that the endpoint of these studies (i.e.…”

“…The involvement of TF in pathological processes may be modulated by genetic factors influencing TF expression and activity [11][12][13][14][15][16][17]. Common variants of the TF gene have been described, such as two haplotypes formed by the four completely concordant promoter polymorphisms C-1812T (rs958587), C-1322T (rs3761955), Del-1208Ins (rs ID not available), and A-603G (rs1361600), as reported by Arnaud [11].…”

“…Common variants of the TF gene have been described, such as two haplotypes formed by the four completely concordant promoter polymorphisms C-1812T (rs958587), C-1322T (rs3761955), Del-1208Ins (rs ID not available), and A-603G (rs1361600), as reported by Arnaud [11]. Although not in a fully conclusive manner, these promoter haplotypes have been associated with TF expression levels and/or activity as well as to thrombotic risk in several studies [11][12][13][14][15][16][17]. However, to our knowledge, no studies of possible associations between functionally relevant variants of the TF gene and measures of atherosclerosis were reported so far.…”