de Vries Paul S, Reventun Paula, Brown Michael R, Heath Adam S, Huffman Jennifer E, Le Ngoc-Quynh, Bebo Allison, Brody Jennifer A, Temprano-Sagrera Gerard, Raffield Laura M, Ozel Ayse Bilge, Thibord Florian, Jain Deepti, Lewis Joshua P, Rodriguez Benjamin A T, Pankratz Nathan, Taylor Kent D, Polasek Ozren, Chen Ming-Huei, Yanek Lisa R, Carrasquilla German D, Marioni Riccardo E, Kleber Marcus E, Trégouët David-Alexandre, Yao Jie, Li-Gao Ruifang, Joshi Peter K, Trompet Stella, Martinez-Perez Angel, Ghanbari Mohsen, Howard Tom E, Reiner Alex P, Arvanitis Marios, Ryan Kathleen A, Bartz Traci M, Rudan Igor, Faraday Nauder, Linneberg Allan, Ekunwe Lynette, Davies Gail, Delgado Graciela E, Suchon Pierre, Guo Xiuqing, Rosendaal Frits R, Klaric Lucija, Noordam Raymond, van Rooij Frank, Curran Joanne E, Wheeler Marsha M, Osburn William O, O'Connell Jeffrey R, Boerwinkle Eric, Beswick Andrew, Psaty Bruce M, Kolcic Ivana, Souto Juan Carlos, Becker Lewis C, Hansen Torben, Doyle Margaret F, Harris Sarah E, Moissl Angela P, Deleuze Jean-François, Rich Stephen S, van Hylckama Vlieg Astrid, Campbell Harry, Stott David J, Soria Jose Manuel, de Maat Moniek P M, Almasy Laura, Brody Lawrence C, Auer Paul L, Mitchell Braxton D, Ben-Shlomo Yoav, Fornage Myriam, Hayward Caroline, Mathias Rasika A, Kilpeläinen Tuomas O, Lange Leslie A, Cox Simon R, März Winfried, Morange Pierre-Emmanuel, Rotter Jerome I, Mook-Kanamori Dennis O, Wilson James F, van der Harst Pim, Jukema J Wouter, Ikram M Arfan, Blangero John, Kooperberg Charles, Desch Karl C, Johnson Andrew D, Sabater-Lleal Maria, Lowenstein Charles J, Smith Nicholas L, Morrison Alanna C
Department of Epidemiology, Human Genetics, and Environmental Sciences, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Blood. 2024 May 2;143(18):1845-1855. doi: 10.1182/blood.2023021452.
Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.
凝血因子 VIII（FVIII）及其载体蛋白血管性血友病因子（VWF）对凝血和血小板聚集至关重要。我们利用精准医学全基因组测序计划（TOPMed）的全基因组序列数据，以及基于TOPMed对其他样本进行的基因型推断，在一项单变量荟萃分析中确定与循环FVIII和VWF水平的遗传关联，该分析纳入了多达45289名参与者。在TOPMed中进行了基于基因的综合检验。我们鉴定出3个候选因果基因，并测试了它们对人肝内皮细胞（HLECs）释放FVIII以及人脐静脉内皮细胞释放VWF的功能影响。还进行了孟德尔随机化分析，以提供FVIII和VWF与血栓形成结局因果关联的证据。我们在7个新位点鉴定出与FVIII相关的关联（P < 5×10⁻⁹）（ST3GAL4、CLEC4M、B3GNT2、ASGR1、F12、KNG1和TREM1/NCR2），以及1个与VWF相关的新位点（B3GNT2）。在基于基因的分析中，VWF、ABO和STAB2与FVIII和VWF相关。对FVIII和VWF的多表型分析又鉴定出另外3个新位点，包括PDIA3。沉默B3GNT2和先前报道的CD36基因可减少HLECs释放FVIII，而沉默B3GNT2、CD36和PDIA3可减少人脐静脉内皮细胞释放VWF。孟德尔随机化分析支持较高的FVIII和VWF与血栓形成结局风险增加之间存在因果关联。鉴定出7个与FVIII相关的新位点和1个与VWF相关的新位点，有证据支持FVIII和VWF与血栓形成结局之间的因果关联。B3GNT2、CD36和PDIA3在体外调节FVIII和/或VWF的释放。
Zotero 插件