Genetic variations in the tissue factor gene are associated with clinical outcome in acute coronary syndrome and expression levels in human monocytes

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.