A common variant in the Von Willebrand factor gene is associated with multiple functional consequences

Von Willebrand Factor (vWF) is a plasma protein involved in thrombosis and hemostasis [Sadler JE, Annu Rev Biochem 1998;67:395-424]. We examined whether common single nucleotide polymorphisms (SNPs) in the vWF gene were associated with vWF levels and platelet aggregation-related functional consequences in 1,230 Whites and 837 African Americans in a cross-sectional family-based genetic study of platelet function. From a high-density scan, 28 SNPs with a minor allele frequency >5% in both races were tested for association using age and sex adjusted variance components analysis in MERLIN. SNP rs216321, with the strongest association with vWF levels in biracial metaanalysis (P = 9.5 x 10(-6), Whites - P = 8.1 x 10(-4), African Americans - P = 3.6 x 10(-3)), encoding a R852Q substitution in the D'D3 protein domain, demonstrated negative association with plasma vWF. The R8520 variant was recessively associated with 15.5% lower collagen-induced platelet aggregation adjusting for dose-response relationship (P = 0.010, vWF-level adjusted P = 0.003). Each copy of the R8520 variant was additively associated with 31% higher FVIII levels (P = 0.039, vWF-adjusted P = 0.033). In conclusion, this common missense polymorphism appears to have pleiotropic functional consequences.