Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus
Authors
Stacey, David
Stanczyk, Paulina J
MacDonald, Stephen
Langdown, Jonathan
McKinney, Harriett
Downes, Kate
Farahi, Neda
Basu, Saonli
Tang, Weihong
de Vries, Paul S
Smith, Nicholas L
Dehghan, Abbas
Heath, Adam S
Morrison, Alanna C
Reiner, Alex P
Johnson, Andrew
Richmond, Anne
Peters, Annette
van Hylckama Vlieg, Astrid
McKnight, Barbara
Psaty, Bruce M
Hayward, Caroline
Ward-Caviness, Cavin
O’Donnell, Christopher
Chasman, Daniel
Strachan, David P
Tregouet, David A
Mook-Kanamori, Dennis
Gill, Dipender
Thibord, Florian
Asselbergs, Folkert W
Leebeek, Frank WG
Rosendaal, Frits R
Davies, Gail
Homuth, Georg
Temprano, Gerard
Campbell, Harry
Taylor, Herman A
Bressler, Jan
Huffman, Jennifer E
Rotter, Jerome I
Yao, Jie
Wilson, James F
Bis, Joshua C
Hahn, Julie M
Desch, Karl C
Wiggins, Kerri L
Raffield, Laura M
Bielak, Lawrence F
Yanek, Lisa R
Kleber, Marcus E
Mueller, Martina
Kavousi, Maryam
Mangino, Massimo
Conomos, Matthew P
Liu, Melissa
Brown, Michael R
Jhun, Min-A
Chen, Ming-Huei
de Maat, Moniek PM
Peyser, Patricia A
Elliot, Paul
Wei, Peng
Wild, Philipp S
Morange, Pierre E
van der Harst, Pim
Yang, Qiong
Le, Ngoc-Quynh
Marioni, Riccardo
Li, Ruifang
Damrauer, Scott M
Cox, Simon R
Trompet, Stella
Felix, Stephan B
Völker, Uwe
Koenig, Wolfgang
Jukema, J Wouter
Guo, Xiuqing
Gelinas, Amy D
Janjic, Nebojsa
Danesh, John
Publication Date
2022-12Journal Title
Nature Communications
Publisher
Springer Science and Business Media LLC
Volume
13
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Stacey, D., Chen, L., Stanczyk, P. J., Howson, J. M., Mason, A. M., Burgess, S., MacDonald, S., et al. (2022). Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus. Nature Communications, 13 (1) https://doi.org/10.1038/s41467-022-28729-3
Abstract
<jats:title>Abstract</jats:title><jats:p>Many 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 <jats:italic>PROCR</jats:italic> locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify <jats:italic>PROCR</jats:italic>-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 <jats:italic>PROCR</jats:italic>-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 <jats:italic>PROCR</jats:italic>-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links <jats:italic>PROCR</jats:italic>-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.</jats:p>
Keywords
Article, /631/208/212/2301, /692/4019/592/2727, /45/43, /45/88, /13/31, /13/106, /13/1, article
Sponsorship
British Heart Foundation (BHF) (RE/13/6/30180)
Identifiers
s41467-022-28729-3, 28729
External DOI: https://doi.org/10.1038/s41467-022-28729-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334809
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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