Previous studies identified common variants at the ABO and VWF loci and unknown variants in a chromosome 2q12 linkage interval that contributed to the variation of plasma von Willebrand factor levels (VWF). While the association with ABO haplotypes can be explained by differential VWF clearance, little is known about the mechanisms underlying the association with VWF SNPs or with variants in the chromosome 2 linkage interval. VWF propeptide (VWFpp) and mature VWF are synthesized from the VWF gene and secreted at the same rate but have different plasma half-lives. Therefore, comparison of VWFpp and VWF association signals can be used to assess if the variants are primarily affecting synthesis/secretion or clearance.
We measured plasma VWFpp levels and performed genome-wide linkage and association studies in 3,238 young and healthy individuals for whom VWF levels have been analyzed previously.
RESULTS AND CONCLUSIONS:
Common variants in an intergenic region on 7q11 were associated with VWFpp. We demonstrate ABO serotype specific SNPs were associated with VWFpp levels in the same direction as VWF but with a much lower effect size. Neither the association at VWF nor the linkage on chromosome 2 previously reported for VWF was observed for VWFpp. Taken together, these results suggest that the major genetic factors affecting plasma VWF levels: variants at ABO, VWF and a locus on chromosome 2, operate primarily through their effects on VWF clearance.