A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels

Trans-Omics for Precision Medicine (TOPMed) program, The INVENT Consortium, Paul S. de Vries, Paula Reventun, Michael R. Brown, Adam S. Heath, Jennifer E. Huffman, Ngoc Quynh Le, Allison Bebo, Jennifer A. Brody, Gerard Temprano-Sagrera, Laura M. Raffield, Ayse Bilge Ozel, Florian Thibord, Deepti Jain, Joshua P. Lewis, Benjamin A.T. Rodriguez, Nathan Pankratz, Kent D. Taylor, Ozren PolasekMing Huei Chen, Lisa R. Yanek, German D. Carrasquilla, Riccardo E. Marioni, Marcus E. Kleber, David Alexandre Trégouët, Jie Yao, Ruifang Li-Gao, Peter K. Joshi, Stella Trompet, Angel Martinez-Perez, Mohsen Ghanbari, Tom E. Howard, Alex P. Reiner, Marios Arvanitis, Kathleen A. Ryan, Traci M. Bartz, Igor Rudan, Nauder Faraday, Allan Linneberg, Lynette Ekunwe, Gail Davies, Graciela E. Delgado, Pierre Suchon, Xiuqing Guo, Frits R. Rosendaal, Lucija Klaric, Raymond Noordam, Frank van Rooij, Joanne E. Curran, Marsha M. Wheeler, William O. Osburn, Jeffrey R. O'Connell, Eric Boerwinkle, Andrew Beswick, Bruce M. Psaty, Ivana Kolcic, Juan Carlos Souto, Lewis C. Becker, Torben Hansen, Margaret F. Doyle, Sarah E. Harris, Angela P. Moissl, Jean François Deleuze, Stephen S. Rich, Astrid van Hylckama Vlieg, Harry Campbell, David J. Stott, Jose Manuel Soria, Moniek P.M. de Maat, Laura Almasy, Lawrence C. Brody, Paul L. Auer, Namiko Abe, Gonçalo Abecasis, Francois Aguet, Christine Albert, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Kristin Ardlie, Dan Arking, Donna K. Arnett, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Paul Auer, Dimitrios Avramopoulos, Najib Ayas, Adithya Balasubramanian, John Barnard, Kathleen Barnes, R. Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Lewis Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Takis Benos, Marcos Bezerra, Larry Bielak, Joshua Bis, Thomas Blackwell, John Blangero, Nathan Blue, Donald W. Bowden, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Jai Broome, Deborah Brown, Karen Bunting, Esteban Burchard, Carlos Bustamante, Erin Buth, Brian Cade, Jonathan Cardwell, Vincent Carey, Julie Carrier, April P. Carson, Cara Carty, Richard Casaburi, Juan P. Casas Romero, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi Cheng Chang, Daniel Chasman, Sameer Chavan, Bo Juen Chen, Wei Min Chen, Yii Der Ida Chen, Michael Cho, Seung Hoan Choi, Lee Ming Chuang, Mina Chung, Ren Hua Chung, Clary Clish, Suzy Comhair, Matthew Conomos, Elaine Cornell, Adolfo Correa, Carolyn Crandall, James Crapo, L. Adrienne Cupples, Joanne Curran, Jeffrey Curtis, Brian Custer, Coleen Damcott, Dawood Darbar, Sean David, Colleen Davis, Michelle Daya, Mariza de Andrade, Lisa de las Fuentes, Paul de Vries, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Huyen Dinh, Harsha Doddapaneni, Qing Duan, Shannon Dugan-Perez, Ravi Duggirala, Jon Peter Durda, Susan K. Dutcher, Charles Eaton, Adel El Boueiz, Patrick Ellinor, Leslie Emery, Serpil Erzurum, Charles Farber, Jesse Farek, Tasha Fingerlin, Matthew Flickinger, Myriam Fornage, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M. Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Heather Geiger, Bruce Gelb, Mark Geraci, Soren Germer, Robert Gerszten, C. Charles Gu, D. C. Rao, Yun Ju Sung

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1845-1855
Number of pages11
JournalBlood
Volume143
Issue number18
DOIs
StatePublished - May 2 2024

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