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

8-2025

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., Taliun, S. A. G., ... & Hemostasis Working Group. (2025). Genetic study of von Willebrand factor antigen levels≤ 50 IU/dL identifies variants associated with increased risk of von Willebrand disease and bleeding. Journal of Thrombosis and Haemostasis, 23(8), 2410-2421. 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