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Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus
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 PROCR locus, associated with lower coronary artery di...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8907312/ https://www.ncbi.nlm.nih.gov/pubmed/35264566 http://dx.doi.org/10.1038/s41467-022-28729-3 |
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author | Stacey, David Chen, Lingyan Stanczyk, Paulina J. Howson, Joanna M. M. Mason, Amy M. Burgess, Stephen MacDonald, Stephen Langdown, Jonathan McKinney, Harriett Downes, Kate Farahi, Neda Peters, James E. Basu, Saonli Pankow, James S. Tang, Weihong Pankratz, Nathan Sabater-Lleal, Maria de Vries, Paul S. Smith, Nicholas L. Gelinas, Amy D. Schneider, Daniel J. Janjic, Nebojsa Samani, Nilesh J. Ye, Shu Summers, Charlotte Chilvers, Edwin R. Danesh, John Paul, Dirk S. |
author_facet | Stacey, David Chen, Lingyan Stanczyk, Paulina J. Howson, Joanna M. M. Mason, Amy M. Burgess, Stephen MacDonald, Stephen Langdown, Jonathan McKinney, Harriett Downes, Kate Farahi, Neda Peters, James E. Basu, Saonli Pankow, James S. Tang, Weihong Pankratz, Nathan Sabater-Lleal, Maria de Vries, Paul S. Smith, Nicholas L. Gelinas, Amy D. Schneider, Daniel J. Janjic, Nebojsa Samani, Nilesh J. Ye, Shu Summers, Charlotte Chilvers, Edwin R. Danesh, John Paul, Dirk S. |
author_sort | Stacey, David |
collection | PubMed |
description | 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 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. |
format | Online Article Text |
id | pubmed-8907312 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-89073122022-03-23 Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus Stacey, David Chen, Lingyan Stanczyk, Paulina J. Howson, Joanna M. M. Mason, Amy M. Burgess, Stephen MacDonald, Stephen Langdown, Jonathan McKinney, Harriett Downes, Kate Farahi, Neda Peters, James E. Basu, Saonli Pankow, James S. Tang, Weihong Pankratz, Nathan Sabater-Lleal, Maria de Vries, Paul S. Smith, Nicholas L. Gelinas, Amy D. Schneider, Daniel J. Janjic, Nebojsa Samani, Nilesh J. Ye, Shu Summers, Charlotte Chilvers, Edwin R. Danesh, John Paul, Dirk S. Nat Commun Article 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 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. Nature Publishing Group UK 2022-03-09 /pmc/articles/PMC8907312/ /pubmed/35264566 http://dx.doi.org/10.1038/s41467-022-28729-3 Text en © The Author(s) 2022, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Stacey, David Chen, Lingyan Stanczyk, Paulina J. Howson, Joanna M. M. Mason, Amy M. Burgess, Stephen MacDonald, Stephen Langdown, Jonathan McKinney, Harriett Downes, Kate Farahi, Neda Peters, James E. Basu, Saonli Pankow, James S. Tang, Weihong Pankratz, Nathan Sabater-Lleal, Maria de Vries, Paul S. Smith, Nicholas L. Gelinas, Amy D. Schneider, Daniel J. Janjic, Nebojsa Samani, Nilesh J. Ye, Shu Summers, Charlotte Chilvers, Edwin R. Danesh, John Paul, Dirk S. Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus |
title | Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus |
title_full | Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus |
title_fullStr | Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus |
title_full_unstemmed | Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus |
title_short | Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus |
title_sort | elucidating mechanisms of genetic cross-disease associations at the procr vascular disease locus |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8907312/ https://www.ncbi.nlm.nih.gov/pubmed/35264566 http://dx.doi.org/10.1038/s41467-022-28729-3 |
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