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, 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
Human Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Veteran Affairs Boston Healthcare System, Boston, Massachusetts, USA; Palo Alto Veterans Institute for Research (PAVIR), Veteran Affairs Palo Alto Health Care System, Palo Alto, California, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
J Thromb Haemost. 2025 Aug;23(8):2410-2421. doi: 10.1016/j.jtha.2025.04.029. Epub 2025 May 12.
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.
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 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.
Variants at 2 loci were associated (P < 5 × 10) 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).
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.
血管性血友病（VWD）是一种常见的遗传性出血性疾病，由循环中的血管性血友病因子（VWF）水平或活性降低引起。普通人群中血管性血友病因子抗原（VWF:Ag）低于正常水平（≤50 IU/dL）的遗传易感性尚未得到充分研究。
确定影响VWF:Ag水平≤50 IU/dL的基因变异。
我们对精准医学跨组学计划7项研究中的926例VWF:Ag水平≤50 IU/dL的病例和12846例对照进行了全基因组关联研究。然后，我们在5个生物样本库中检查了全基因组显著发现是否也与708例VWD病例和1286069例对照的VWD临床诊断相关，以及与芬兰基因研究中的6种出血和血栓形成性疾病相关。
2个基因座的变异与VWF:Ag水平≤50 IU/dL相关（P < 5×10）：ABO和VWF。VWF指数变异p.Tyr1584Cys是一种罕见的（0.22%）错义变异，优势比（OR）为78.58，而ABO指数变异是一种常见的内含子变异，效应较小（OR = 2.52）。值得注意的是，VWF（OR = 7.16）和ABO（OR = 1.57）变异也与确诊的VWD相关（P < 0.025）。在p.Tyr1584Cys杂合子中，VWF:Ag水平≤50 IU/dL的外显率为24.2%，确诊VWD的外显率为0.3%。p.Tyr1584Cys与月经过多（OR = 1.27）、缺铁性贫血（OR = 1.55）和分娩期出血（OR = 2.20）的几率增加相关（P < 0.0042），但与深静脉血栓形成的几率降低相关（OR = 0.54）。
尽管目前对p.Tyr1584Cys的致病性存在相互矛盾的解释，但我们的结果表明它是一种低外显率的致病变异，导致VWF:Ag水平≤50 IU/dL、出血和VWD。
