Genome-wide association studies identify genetic loci for low von Willebrand factor levels

Abstract

Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels. For this meta-analysis, we included 31 149 participants of European ancestry from 11 community-based studies. From all participants, VWF antigen (VWF:Ag) measurements and genome-wide single-nucleotide polymorphism (SNP) scans were available. Each study conducted analyses using logistic regression of SNPs on dichotomized VWF:Ag measures (lowest 5% for blood group O and non-O) with an additive genetic model adjusted for age and sex. An inverse-variance weighted meta-analysis was performed for VWF:Ag levels. A total of 97 SNPs exceeded the genome-wide significance threshold of 5 × 10 − 8 and comprised five loci on four different chromosomes: 6q24 (smallest P-value 5.8 × 10 − 10 ), 9q34 (2.4 × 10 − 64 ), 12p13 (5.3 × 10 − 22 ), 12q23 (1.2 × 10 − 8 ) and 13q13 (2.6 × 10 − 8 ). All loci were within or close to genes, including STXBP5 (Syntaxin Binding Protein 5) (6q24), STAB5 (stabilin-5) (12q23), ABO (9q34), VWF (12p13) and UFM1 (ubiquitin-fold modifier 1) (13q13). Of these, UFM1 has not been previously associated with VWF:Ag levels. Four genes that were previously associated with VWF levels (VWF, ABO, STXBP5 and STAB2) were also associated with low VWF levels, and, in addition, we identified a new gene, UFM1, that is associated with low VWF levels. These findings point to novel mechanisms for the occurrence of low VWF levels.

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

“…An increased median patient age, differences in ethnicity, inclusion/ exclusion criteria related to VWF:Ag levels, and a lower proportion of VWF mutation-negative patients in the Dutch population may explain these differences. Consistent with our results, however, a GWAS found that the STAB2 SNV rs4981022 associates with low VWF plasma levels (24). Further studies on the influence of rare and common STAB2 variants on the type 1 VWD phenotype are required to better understand this relationship.…”

“…While the exact mechanistic basis by which this variant modifies stabilin-2 expression is not yet known, in silico CentroidFold (http://rtools.cbrc.jp/centroidfold/) analysis predicts LSECs have the highest endocytic capacity of any cell in the body, and are reported to express a series of endocytic receptors including stabilin-2, CLEC4M, the mannose receptor, SR-A1, SR-B1, CD36, stabilin-1, FcγRIIb2, LSECtin, LRP-1, and LYVE-1. Both stabilin-2 and CLEC4M have been identified by GWAS as associating with plasma VWF or FVIII levels in normal individuals (18,24,25). In these studies, we characterize the scavenger receptor stabilin-2 as a novel clearance and immunomodulatory receptor for the human VWF-FVIII complex.…”

Novel Thrombotic Function of a Human SNP in STXBP5 Revealed by CRISPR/Cas9 Gene Editing in Mice

“…2–6 These loci may contain novel genes whose products regulate endothelial or platelet exocytosis. 7 For example, the CHARGE Consortium identified over 50 single nucleotide polymorphisms (SNPs) linked to altered VWF levels that are located within or near the gene encoding syntaxin-binding protein 5 ( STXBP5 ).…”

Preoperative Detection of Low Von Willebrand Factor Activity and Operative Blood Loss in Pediatric Scoliosis Patients Undergoing Posterior Spinal Fusion

“…In the next decade, our understanding of inherited bleeding disorders and the appropriate use of pro-coagulant therapy will evolve as high throughput gene sequencing tests are being developed to assess bleeding disorders in a highly specific manner [27]. Indeed there are new genomic loci for VWD being determined and our understanding of the downstream disruption of the coagulation pathway from having a low VWF: RCo levels will become better characterized and even potentially personalized [28].…”