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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2667.)
© 2005 American Heart Association, Inc.

Thrombosis

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

Anders Mälarstig; Taavo Tenno; Nina Johnston; Bo Lagerqvist; Tomas Axelsson; Ann-Christine Syvänen; Lars Wallentin; Agneta Siegbahn

From the Divisions of Clinical Chemistry (A.M., T.T., A.S.), Cardiology (N.J., B.L., L.W.), and Molecular Medicine (T.A., A-C.S.), Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Correspondence to Agneta Siegbahn, Department of Medical Sciences, Clinical Chemistry, Uppsala University, S-751 85 Uppsala, Sweden. E-mail agneta.siegbahn{at}akademiska.se

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 Coronary Artery Disease II (FRISC-II) study] and 376 controls, 13 SNPs were genotyped and plasma TF measured. Thereafter, the 5466 A>G and the –1812 C>T were genotyped among all of the FRISC-II participants (n=3143) 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 A>G SNP was associated with cardiovascular death (odds ratio, 1.8; P=0.025). The CG haplotype by –1812 C>T and 5466 A>G was associated with a 3-fold increased risk of death (P<0.001). 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 (P=0.04).

Conclusions— The 5466 AG genotype is a novel predictor of cardiovascular death in ACS and may act through a high TF response.

Polymorphisms in the tissue factor gene were investigated concerning association with risk and outcome in patients with acute coronary syndrome. The TF 5466 AG genotype was associated with cardiovascular death. In vitro endotoxin induced a relative increase in monocytic TF activity, which was significantly higher in AG compared with AA carriers.

Key Words: acute coronary syndrome • tissue factor • single nucleotide polymorphism • outcome • mRNA

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