Abstract 3140: A Variant in the von Willebrand Factor Gene is Associated with Differences in Circulating Protein Levels and Platelet Function
Platelets are recruited to the site of vascular injury by von Willebrand factor (vWF) immobilized on exposed collagen. High circulating vWF levels are associated with myocardial infarction, while low levels are seen in the bleeding disorder von Willebrand’s disease (VWD). We examined the association of single nucleotide polymorphisms (SNPs) in the vWF gene with circulating vWF levels and with collagen-induced aggregation of ex vivo platelets in plasma. We genotyped 51 SNPs (with minor allele frequency >5%, constituting 25 linkage disequilibrium blocks) in the vWF gene in 2077 apparently healthy individuals with a family history of coronary disease (40% Black, 58% female), measured serum vWF levels, and ex vivo platelet aggregation to 10 mM collagen using optical aggregometry. Family-based additive genetic associations for age and sex adjusted vWF levels were assessed using the SAGE software package. Combined p-values for race-stratified analyses using meta-analysis were considered significant at p=0.002 (Bonferroni-corrected). Effect sizes were estimated using generalized estimating equations regression accounting for family structure. SNP rs216321 encoding the missense variant Q852R (minor allele frequency Whites 8%, Blacks 6%) was associated with vWF levels (p=0.003 [Whites], 0.077[Blacks], 0.002 [combined]). The variant Q852R neighbors a known VWD locus (R854Q). Each copy of Q852R was additively associated with a 13% lower level of vWF (adjusted for age, sex, and race, p=0.0003). However, this variant was recessive in association with collagen-induced aggregation, which was profoundly lower by 23% in minor allele homozygotes as compared to the other two genotypes (p=0.000004). We have discovered a novel association of a missense variant in the vWF gene with vWF blood levels and vWF-mediated platelet function. Whether this variant is adaptive (protecting from cardiovascular disease) or maladaptive (promoting inappropriate bleeding) remains to be determined.