Combined Analysis of Three Genome-Wide Association Studies on vWF and FVIII Plasma Levels

Abstract

Background: Elevated levels of factor VIII (FVIII) and von Willebrand Factor (vWF) are well-established risk factors for cardiovascular diseases, in particular venous thrombosis. Although high, the heritability of these traits is poorly explained by the genetic factors known so far. The aim of this work was to identify novel single nucleotide polymorphisms (SNPs) that could influence the variability of these traits. Methods: Three independent genome-wide association studies for vWF plasma levels and FVIII activity were conducted and their results were combined into a meta-analysis totalling 1,624 subjects.

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).…”

“…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.…”

“…Human GWAS show that multiple genetic variants associated with altered vWF levels lie within the STXBP5 allele (45)(46)(47). One SNP highly correlated with altered vWF levels in humans, rs1039084, is located in exon 13 of STXBP5 (47).…”

Platelet secretion and hemostasis require syntaxin-binding protein STXBP5

“…As might be predicted from GWAS analysis (14)(15)(16)(17)(18)(19), plasma vWF levels were increased in these mice, although plasma IgG was unaffected, as indicated by light chain levels (Supplemental Figure 1). Platelet extracts from Stxbp5 KO and littermate WT mice were prepared Figure 3.…”

“…Deletions in the Stxbp5 gene are linked to autism (36). GWAS show genetic variations in Stxbp5 are linked with increased plasma levels of vWF (14)(15)(16)(17)(18)(19), alterations in tissue plasminogen activator (tPA) levels (20), venous thrombosis (16), and arterial thrombosis (19). Specifically, 1 SNP that produces a nonsynonymous mutation (N436S) was associated with increased bleeding (18).…”