Genetic regulation of plasma von Willebrand factor levels in health and disease

Abstract

Plasma levels of the multimeric glycoprotein von Willebrand factor (VWF) constitute a complex quantitative trait with a continuous distribution and wide range in the normal population (50-200%). Quantitative deficiencies of VWF (< 50%) are associated with an increased risk of bleeding, whereas high plasma levels of VWF (> 150%) influence the risk of arterial and venous thromboembolism. Although environmental factors can strongly influence plasma VWF levels, it is estimated that approximately 65% of this variability is heritable. Interestingly, although variability in VWF can account for ~ 5% of the genetic influence on plasma VWF levels, other genetic loci also strongly modify plasma VWF levels. The identification of the additional sources of VWF heritability has been the focus of recent observational trait-mapping studies, including genome-wide association studies or linkage analyses, as well as hypothesis-driven research studies. Quantitative trait loci influencing VWF glycosylation, secretion and clearance have been associated with plasma VWF antigen levels in normal individuals, and may contribute to quantitative VWF abnormalities in patients with a thrombotic tendency or type 1 von Willebrand disease (VWD). The identification of genetic modifiers of plasma VWF levels may allow for better molecular diagnosis of type 1 VWD, and enable the identification of individuals at increased risk for thrombosis. Validation of trait-mapping studies with in vitro and in vivo methodologies has led to novel insights into the life cycle of VWF and the pathogenesis of quantitative VWF abnormalities.

Keywords: ABO blood group; factor VIII; genome-wide association study; quantitative trait loci; von Willebrand factor.

Figure 1.. VWF:Ag is a complex quantitative trait.

(A) Distribution of VWF:Ag levels in Canadian type 1 VWD patients and their unaffected (normal) family members [40,111]. (B) Heritability estimates of VWF:Ag [19-23]. (C) 65% of plasma VWF levels are heritable with variability at the VWF gene, ABO blood group locus, and others contributing to this phenotype [20,70]. (D) The VWF gene is comprised of 52 exons encoding a ~370 kDA mature protein that is comprised of multi-functional domains.

Figure 2.. Rare and common genetic variants influence VWF levels.

VWF plasma levels are influenced by both rare and common variants in the VWF gene, ABO blood group locus, and additional loci. LOF = loss of function.

Figure 3.. VWF:Ag levels are influenced by VWF glycosylation.

(A) Post-translational modification of VWF includes the addition of 16 putative N-linked and 10 putative O-linked glycans. (B) ABO(H) blood group antigens are added to the VWF N- and O-linked glycans. (C) Dysfunction of FUT1/2 and ABO blood group status can influence VWF plasma levels. Bombay = FUT1 and FUT1/FUT2 null, Se=FUT2, se=FUT2 null.

Figure 4.. VWF:Ag levels are influenced by processes that regulate VWF synthesis/secretion and mechanisms that regulate VWF clearance.

(A) VWF synthesis/secretion can be influenced by variants in or adjacent to the VWF gene that regulate VWF transcriptional activity, mRNA stability, codon use, protein folding, and Weibel Palade Body packaging and secretion. Variants at additional loci including SNARE proteins can influence the secretion of VWF from endothelial WPB or platelet α-granules. (B) VWF clearance can be influenced by variants in the VWF amino acid sequence and/or glycome that modify the affinity of VWF for one or more clearance receptors. Additionally, variants in the clearance receptors for VWF that alter ligand binding or expression can modify VWF plasma levels. HL = hepatic lectin, CBD = carbohydrate binding domain, EGF = endothelial growth factor, VNTR = variable number of tandem repeats, SRCR = scavenger receptor cysteine-rich.

Figure 4.. VWF:Ag levels are influenced by processes that regulate VWF synthesis/secretion and mechanisms that regulate VWF clearance.

(A) VWF synthesis/secretion can be influenced by variants in or adjacent to the VWF gene that regulate VWF transcriptional activity, mRNA stability, codon use, protein folding, and Weibel Palade Body packaging and secretion. Variants at additional loci including SNARE proteins can influence the secretion of VWF from endothelial WPB or platelet α-granules. (B) VWF clearance can be influenced by variants in the VWF amino acid sequence and/or glycome that modify the affinity of VWF for one or more clearance receptors. Additionally, variants in the clearance receptors for VWF that alter ligand binding or expression can modify VWF plasma levels. HL = hepatic lectin, CBD = carbohydrate binding domain, EGF = endothelial growth factor, VNTR = variable number of tandem repeats, SRCR = scavenger receptor cysteine-rich.