To cite this article: van Schie MC, van Loon JE, de Maat MPM, Leebeek FWG. Genetic determinants of von Willebrand factor levels and activity in relation to the risk of cardiovascular disease. A review. J Thromb Haemost 2011; 9: 899-908.

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.

BackgroundIn type 1 von Willebrand Disease (VWD) patients, von Willebrand Factor (VWF) levels and bleeding symptoms are highly variable. Recently, the association between genetic variations in STXBP5 and STX2 with VWF levels has been discovered in the general population. We assessed the relationship between genetic variations in STXBP5 and STX2, VWF levels, and bleeding phenotype in type 1 VWD patients.MethodsIn 158 patients diagnosed with type 1 VWD according to the current ISTH guidelines, we genotyped three tagging-SNPs in STXBP5 and STX2 and analyzed their relationship with VWF:Ag levels and the severity of the bleeding phenotype, as assessed by the Tosetto bleeding score.ResultsIn STX2, rs7978987 was significantly associated with VWF:Ag levels (bèta-coefficient (β) = −0.04 IU/mL per allele, [95%CI −0.07;−0.001], p = 0.04) and VWF:CB activity (β = −0.12 IU/mL per allele, [95%CI −0.17;−0.06], p<0.0001). For rs1039084 in STXBP5 a similar trend with VWF:Ag levels was observed: (β = −0.03 IU/mL per allele [95% CI −0.06;0.003], p = 0.07). In women, homozygous carriers of the minor alleles of both SNPs in STXBP5 had a significantly higher bleeding score than homozygous carriers of the major alleles. (Rs1039084 p = 0.01 and rs9399599 p = 0.02).ConclusionsGenetic variation in STX2 is associated with VWF:Ag levels in patients diagnosed with type 1 VWD. In addition, genetic variation in STXBP5 is associated with bleeding phenotype in female VWD patients. Our findings may partly explain the variable VWF levels and bleeding phenotype in type 1 VWD patients.

To cite this article: van Loon JE, Kavousi M, Leebeek FWG, Felix JF, Hofman A, Witteman JCM, de Maat MPM. von Willebrand factor plasma levels, genetic variations and coronary heart disease in an older population. J Thromb Haemost 2012; 10: 1262-9.Summary. Background: High von Willebrand factor (VWF) levels are associated with an increased risk of coronary heart disease (CHD). However, it remains unclear whether VWF is causally related to the occurrence of CHD or primarily mirrors endothelial dysfunction, which predisposes to atherosclerosis and subsequent CHD. Objectives: Because VWF is largely determined by genetic factors, we investigated whether VWF antigen levels (VWF:Ag) and the risk of CHD are affected by common variations in the VWF gene. Methods: We included 7002 participants ( ‡ 55 years) from the large prospective population-based Rotterdam Study in the discovery cohort. The extension cohort of the Rotterdam Study, consisting of 3011 participants, was used as a replication cohort. We determined VWF:Ag levels and genotype data of 38 singlenucleotide polymorphisms (SNPs) in VWF. Subsequently, hazard ratios for CHD were calculated and genetic analyses were performed to assess the relationship between SNPs, VWF:Ag levels and CHD risk. Results: We identified and replicated three SNPs that were associated with VWF:Ag: rs216321 (b = 0.10 [95% confidence interval, CI, 0.06;0.13]) (Ala852Gln), rs1063856 (b = 0.05 [95% CI 0.03;0.07]) (Thr789Ala) and rs2283333 (b = 0.09 [95% CI 0.05;0.21]) (intron 15). However, genetic polymorphisms in the VWF gene were not associated with the risk of CHD. Conclusions: In this study we have shown that genetic variations in VWF strongly affect VWF plasma levels, but are not associated with the risk of CHD. Our findings therefore do not support a strong causal relationship between VWF and CHD in elderly individuals of ‡ 55 years, but suggest that VWF is primarily a marker of CHD.