Genetic determinants of von Willebrand factor plasma levels and the risk of stroke: the Rotterdam Study

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 single-nucleotide 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. Atotal 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.