Background and Purpose-Many studies have investigated the role of plasma von Willebrand factor level in coronary heart disease, but few have investigated its role in stroke. The aim of this study was to determine if von Willebrand factor levels are associated with the risk of stroke. Methods-The study was part of the Rotterdam Study, a large population-based cohort study among subjects aged Ն55 years. We included 6 250 participants who were free from stroke at baseline (1997 to 2001) and for whom blood samples were available. Follow-up for incident stroke was complete up to January 1, 2005. Data were analyzed with Cox proportional hazards models adjusted for age and sex and additionally with models adjusted for other potential confounders including ABO blood group. A subgroup analysis was performed in participants without atrial fibrillation.Effect modification by sex was tested on a multiplicative and on an additive scale. Results-During an average follow-up time of 5.0 years, 290 first-ever strokes occurred, of which 197 were classified as ischemic. The risk of stroke increased with increasing von Willebrand factor levels (age-and sex-adjusted hazard ratios per SD increase in von Willebrand factor level:

High levels of von Willebrand factor (VWF) are associated with an increased risk for cardiovascular disease (CVD). Although VWF levels are strongly heritable and genetic susceptibility is an important risk factor for CVD, information on the contribution of common VWF gene variants to VWF levels and CVD risk is limited. In a case-control study of 421 young patients with a first event of acute coronary heart disease (CHD) or ischemic stroke (

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.

Summary. Background: High von Willebrand factor (VWF) plasma levels are associated with an increased risk of stroke. VWF levels are strongly heritable. A previous meta-analysis of five large genome-wide association studies identified singlenucleotide polymorphisms (SNPs) within eight genetic loci as determinants of VWF levels. Whether these SNPs are associated with stroke risk is not known. The aim of our study was to investigate the association between genetic determinants of VWF levels and stroke risk. Methods: The study was part of the Rotterdam Study, a large population-based cohort study among subjects aged ‡ 55 years. A total of 5763 participants for whom DNA was available, and who were free of stroke at baseline, were eligible for analysis. VWF antigen (VWF:Ag) levels were measured in 3379 eligible participants. Within each of the eight loci, one top SNP was defined. The association between the eight SNPs and the risk of stroke was analyzed. Then, a genetic score, based on these eight SNPs, was constructed, and its total contribution to VWF plasma levels and stroke risk was investigated. Results: None of the eight SNPs was individually associated with stroke risk. A higher genetic score was significantly associated with a higher VWF:Ag level, but was not associated with an increased risk of stroke. Conclusion: Eight SNPs that strongly determine VWF levels are not associated with stroke risk, either individually, or combined in a genetic score.

von Willebrand factor propeptide and the occurrence of a first ischemic stroke propeptide and the occurrence of a first ischemic stroke.