Effect of Genetic Variations in Syntaxin-Binding Protein-5 and Syntaxin-2 on von Willebrand Factor Concentration and Cardiovascular Risk

Abstract

Background 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]). Conclusion 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.

Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion

“…STXBP5 also promoted platelet secretion and thrombosis in mice. Thus, our present data provide strong functional evidence for the regulatory role on circulating vWF and thrombosis by a candidate gene previously identified by GWAS (45)(46)(47)(48)70).…”

“…We also tested the effect of genetic variation on STXBP5 function. We knocked down STXBP5 in ECs and then rescued STXBP5 expression with either WT STXBP5 or the N436S STXBP5 variant, which is associated with altered vWF levels in humans (47). N436S STXBP5 inhibited vWF secretion more effectively than did WT STXBP5 (Supplemenin murine brain, supporting studies identifying a role for Stxbp5 in neurovesicle release (49,54).…”

“…Recently, genome-wide association studies (GWAS) identified novel genetic variants that are associated with altered plasma vWF levels in humans (45)(46)(47). These genetic loci might indicate novel genes whose products regulate endothelial exocytosis.…”

Genome-wide association studies identify genetic loci for low von Willebrand factor levels

“…We have previously shown in a well-defined cohort of young patients with a first event of arterial thrombosis that genetic variation in STXBP5 is associated with VWF:Ag levels. 13,39 The LD between rs1221638:A4G and the SNP that had the highest significance in the previous meta-analysis is D′ = 0.90 and R 2 = 0.67. The fourth locus was marked by rs4981022:A4G, which is located in STAB2.…”

Transcriptomic profiling of peripheral blood nucleated cells in dogs with and without clinical signs of chronic mitral valve disease

“…Genetic studies in cardiology have shown an increase in syntax-binding protein and syntaxin 2, which are possibly involved in the secretion of von Willebrand factor (VWF). Increased concentrations of VWF are associated with a higher cardiovascular disease risk (24). The studies performed on rats have shown an increase in BNP GATA4 binding activity in the heart that was brought about by a pressure overload in vivo via the endothelin-1 signalling molecule (7).…”