Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of von Willebrand disease and bleeding.
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Friedman Rachel K, Heath Adam S, Huffman Jennifer E, Baker James T, Hasbani Natalie R, Gagliano Taliun Sarah A, Chen Ming-Huei, Howard Tom E, Lewis Joshua P, Pankratz Nathan, Patil Snehal, Reiner Alex P, Thibord Florian, Yanek Lisa R, Yao Jie, Chen Hung-Hsin, Curran Joanne E, Faraday Nauder, Guo Xiuqing, Wheeler Marsha M, Ryan Kathleen A, Zhou Xiang, Cho Kelly, Almasy Laura, Auer Paul L, Becker Lewis C, Wilson Peter W F, Boerwinkle Eric, O'Connell Jeffrey R, Rich Stephen S, Samuels David C, National Heart, Lung and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Hematology & Hemostasis Working Group, VA Million Veteran Program, Blangero John, Fornage Myriam, Kooperberg Charles, Mathias Rasika A, Mitchell Braxton D, Rotter Jerome I, Johnson Andrew D, Smith Nicholas L, Coban-Akdemir Zeynep H, Below Jennifer E, Morrison Alanna C, Johnsen Jill M, de Vries Paul S
Аннотация
OBJECTIVES: To identify genetic variants influencing VWF:Ag levels ≤ 50 IU/dL.
METHODS: 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 Trans-Omics for Precision Medicine program. We then examined whether significant genome-wide 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 2 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 < .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 < .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: Although there are currently conflicting interpretations of pathogenicity p.Tyr1584Cys, our results suggest that it is a low penetrance pathogenic variant that contributes to VWF:Ag levels ≤ 50 IU/dL, bleeding, and VWD.