Elevated von Willebrand Factor (VWF) plasma levels are associated with an increased risk of cardiovascular disease. A meta-analysis of genome wide association studies on VWF identified novel candidate genes, i.e. syntaxin-binding protein 5 (STXBP5) and syntaxin 2 (STX2), which are possibly involved in the secretion of VWF. We investigated whether VWF antigen levels (VWF:Ag), VWF collagen-binding activity (VWF:CB), and the risk of arterial thrombosis are affected by common genetic variations in these genes.
Methods and Results
In 463 young Caucasian subjects (males ≤ 45 years, females ≤ 55 years), who were included one to three months after a first event of arterial thrombosis, and 406 controls, we measured VWF:Ag and VWF:CB. Nine haplotype tagging SNPs of STXBP5 and STX2 were selected and subsequently analysed using linear regression with additive genetic models adjusted for age, sex and ABO blood group. The minor alleles of rs9399599 and rs1039084 in STXBP5 were associated with lower VWF plasma levels and activity, whereas the minor allele of rs7978987 in STX2 was associated with higher VWF plasma levels and activity. The minor alleles of the SNPs in STX2 were associated with a reduced risk of arterial thrombosis (rs1236:OR 0.73 [95%CI 0.59, 0.89], rs7978987:OR 0.81 [95%CI 0.65, 1.00], rs11061158:OR 0.69 [95%CI 0.55, 0.88]).
Genetic variability in STXBP5 and STX2 affects both VWF concentration and activity in young individuals with premature arterial thrombosis. Furthermore, in our study genetic variability in STX2 is associated with the risk of arterial thrombosis. However, at this point the underlying mechanism remains unclear.