Abstract Number: PB0502
Meeting: ISTH 2020 Congress
Theme: Diagnostics and OMICs » Epigenetics, OMICs and Bioinformatics
Background: Approximately 35% of patients with Type 1 von Willebrand Disease (VWD) do not have a known pathogenic variant in the VWF gene. While genome-wide association studies (GWAS) have successfully identified several non-VWF loci, they do not detect associations with rare variants.
Aims: Determine whether the number of rare (< 1%) variants and the predicted pathogenicity of those variants in low-VWF and VWD patients is associated with VWF levels and type of VWD.
Methods: 709 low-VWF and VWD subjects, as well as normal subjects were recruited from 35 centers across the United States. VWF sequencing was performed and VWF antigen levels (VWF:Ag) assayed at a central laboratory. All subtypes of Type 1 (except 1C), 2 and 3 were combined to increase power. CADD score >20 was used as a measure of predicted pathogenicity.
Results: The number of rare nonsynonymous VWF variants was a significant predictor of VWF levels, independent of VWD type (p=3.4×10-7). There was an association between average number of rare nonsynonymous VWF variants with VWD Type 1 (p=1.5×10-10) and to a much lesser extent low-VWF (p=0.01), with Type 1 subjects possessing on average a two-fold increase over those with low-VWF and three times as many as normal subjects (1.2 vs 0.67 vs 0.39). A variant with CADD score > 20 significantly predicted VWF:Ag levels even when controlling for number of rare nonsynonymous variants.
Conclusions: The number of rare nonsynonymous variants in VWF as well as the presence of a variant with CADD >20 are both significantly associated with VWF levels, even when number of rare nonsynonymous variants is included in the model. This suggests that differences in VWF levels in VWD are due in large part to the number of rare variants, as an increase in rare variants likely increases the probability that one of them is pathogenic.
[Relationship between VWD type, number of rare nonsynonymous variants and VWF:Ag levels]
To cite this abstract in AMA style:
Sadler B, Christopherson P, Montgomery R, Di Paola J, Zimmerman Program Investigators . Von Willebrand Disease Type 1 Is Associated with Number of Rare Nonsynonymous Variants in the VWF Gene [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/von-willebrand-disease-type-1-is-associated-with-number-of-rare-nonsynonymous-variants-in-the-vwf-gene/. Accessed January 27, 2022.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/von-willebrand-disease-type-1-is-associated-with-number-of-rare-nonsynonymous-variants-in-the-vwf-gene/