Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of VWD and bleeding

Authors

Rachel K. Friedman
Adam S. Heath
Jennifer E. Huffman
James T. Baker
Natalie R. Hasbani
Sarah A. Gagliano Taliun
Ming-Huei Chen
Tom Howard, The University of Texas Rio Grande ValleyFollow
Joanne E. Curran, The University of Texas Rio Grande ValleyFollow
John Blangero, The University of Texas Rio Grande ValleyFollow

Document Type

Article

Publication Date

5-12-2025

Abstract

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (≤50 IU/dL) in the general population is underexplored.

Methods: To identify genetic variants influencing VWF:Ag levels ≤50 IU/dL, we performed a genome-wide association study in 926 cases with VWF:Ag levels ≤50 IU/dL and 12,846 controls from 7 studies from the TOPMed program. We then examined whether genome-wide significant findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1,286,069 controls, and with 6 bleeding and thrombotic disorders in FinnGen.

Results: Variants at two loci were associated (P< 5×10-9) with VWF:Ag levels ≤50 IU/dL: ABO and VWF. The VWF index variant, p.Tyr1584Cys, is a rare (0.22%) missense variant with odds ratio (OR) of 78.58, while the ABO index variant is a common intronic variant with a smaller effect (OR=2.52). Notably, both VWF (OR=7.16) and ABO (OR=1.57) variants were also associated (P< 0.025) with diagnosed VWD. Among p.Tyr1584Cys heterozygotes, the penetrance of VWF:Ag levels ≤50 IU/dL was 24.2% and the penetrance of diagnosed VWD was 0.3%. p.Tyr1584Cys was associated (P< 0.0042) with increased odds of heavy menstrual bleeding (OR=1.27), iron deficiency anemia (OR=1.55), and intrapartum hemorrhage (OR=2.20), but decreased odds of deep vein thrombosis (OR=0.54).

Conclusions: While p.Tyr1584Cys currently has conflicting interpretations of pathogenicity, our results suggest that it is a low penetrance pathogenic variant that contributes to VWF:Ag levels ≤50 IU/dL, bleeding, and VWD.

Comments

Original published version available at https://doi.org/10.1016/j.jtha.2025.04.029

Recommended Citation

Friedman, R. K., Heath, A. S., Huffman, J. E., Baker, J. T., Hasbani, N. R., Gagliano Taliun, S. A., Chen, M. H., Howard, T. E., Lewis, J. P., Pankratz, N., Patil, S., Reiner, A. P., Thibord, F., Yanek, L. R., Yao, J., Chen, H. H., Curran, J. E., Faraday, N., Guo, X., Wheeler, M. M., … de Vries, P. S. (2025). Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of VWD and bleeding. Journal of thrombosis and haemostasis : JTH, S1538-7836(25)00311-3. Advance online publication. https://doi.org/10.1016/j.jtha.2025.04.029

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Publication Title

Journal of Thrombosis and Haemostasis

DOI

10.1016/j.jtha.2025.04.029

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics