Single nucleotide gene polymorphisms differentially associate with plasma levels of von Willebrand factor in European and African Americans: An ARIC study

Abstract

von Willebrand factor (VWF) tethers platelets to subendothelium at sites of vessel injury and mediates shear-induced platelet aggregation. Hemostatic function of VWF is determined by its multimer size and the amount in circulation. We have recently identified a cluster of VWF gene single nucleotide polymorphisms (SNPs) that is strongly associated with VWF antigen levels in 7856 subjects of European decent (EA) in the Atherosclerosis Risk in Communities (ARIC) cohort. Among 78 available SNPs that distributed throughout the VWF gene, the cluster of 18 intronic (89%) and silent exonic (11%) SNPs associated with VWF levels is located in a 50 kilobase region of the VWF gene on chromosome 12 that encodes for the D2, D' and D3 domains, which are known to regulate VWF. In the present study, we expanded the study to determine a differential association of VWF SNPs between European Americans (EA, 9301) and African Americans (AA, 3032) in the ARIC cohort. The mean ages for EA and AA were 54.3 and 53.4, respectively. VWF antigen varied from 22% to 456% (median at 109%). AA had a significantly higher level VWF antigen as compared to EA (133.2% vs. 112.1, P < 0.01). Seventy-five VWF SNPs were included in data analysis and the majority was in Hardy-Weinberg Equilibrium. The associations with SNPs were adjusted for sex, body mass index, smoking status, diabetes, and hypertension. Among SNPs analyzed, 71 (94.7%) had a significant difference in allele frequencies between EA and AA subjects (P < 0.001). Among 18 SNPs that associate with VWF antigen in EA subjects, 10 (58.8%) had significant different genotype frequencies as compared to EA subjects. None of the 18 SNPs associated with VWF antigen levels in AA males and only one (RS1063857) with AA females. These results suggest a strong race-dependent association of VWF SNPs with VWF antigen between Americans of European and African decent.