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Get Free AccessMany individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR -p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR -219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation. We also associate PROCR -219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR -219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.
David Stacey, Lingyan Chen, Paulina J. Stanczyk, Joanna M. M. Howson, Amy M. Mason, Stephen Burgess, Stephen MacDonald, Jonathan Langdown, Harriett McKinney, Kate Downes, Neda Farahi, James E. Peters, Saonli Basu, James S. Pankow, Weihong Tang, Nathan Pankratz, Maria Sabater‐Lleal, Paul S. de Vries, Nicholas L. Smith, Abbas Dehghan, Adam S. Heath, Alanna C. Morrison, Alex P. Reiner, Andrew D. Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M. Psaty, Caroline Hayward, Cavin Ward‐Caviness, Christopher J. O’Donnell, Daniel I. Chasman, David P. Strachan, David‐Alexandre Trégouët, Dennis O. Mook‐Kanamori, Dipender Gill, Florian Thibord, Folkert W. Asselbergs, Frank W.G. Leebeek, Frits R. Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano, Harry Campbell, Herman A. Taylor, Jan Bressler, Jennifer E. Huffman, Jerome I. Rotter, Jie Yao, James F. Wilson, Joshua C. Bis, Julie Hahn, Karl C. Desch, Kerri L. Wiggins, Laura M. Raffield, Lawrence F. Bielak, Lisa R. Yanek, Marcus E. Kleber, Martina Mueller, Maryam Kavousi, Massimo Mangino, Matthew P. Conomos, Melissa Liu, Michael R. Brown, Min-A Jhun, Ming‐Huei Chen, Moniek P.M. de Maat, Patricia A. Peyser, Paul Elliot, Peng Wei, Philipp S. Wild, Pierre‐Emmanuel Morange, Pim van der Harst, Qiong Yang, Ngoc‐Quynh Le, Riccardo E. Marioni, Ruifang Li, Scott M. Damrauer, Simon R. Cox, Stella Trompet, Stephan B. Felix, Uwe Völker, Wolfgang Köenig, J. Wouter Jukema, Xiuqing Guo, Amy D. Gelinas, Daniel J. Schneider, Nebojša Janjić, Nilesh J. Samani, Shu Ye, Charlotte Summers, Edwin R. Chilvers, John Danesh, Dirk S. Paul (2022). Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus. Nature Communications, 13(1), DOI: 10.1038/s41467-022-28729-3.
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Type
Article
Year
2022
Authors
95
Datasets
0
Total Files
0
Language
English
Journal
Nature Communications
DOI
10.1038/s41467-022-28729-3
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