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Elucidating mechani...
Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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2022-03-09
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Springer Science and Business Media LLC,2022
Numbers
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LIBRIS-ID:oai:prod.swepub.kib.ki.se:149032987
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http://kipublications.ki.se/Default.aspx?queryparsed=id:149032987URI
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https://doi.org/10.1038/s41467-022-28729-3DOI
Supplementary language notes
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Language:English
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Summary in:English
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Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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.
Added entries (persons, corporate bodies, meetings, titles ...)
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Chen, LY
(author)
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Stanczyk, PJ
(author)
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Howson, JMM
(author)
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Mason, AM
(author)
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Burgess, S
(author)
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MacDonald, S
(author)
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Langdown, J
(author)
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McKinney, H
(author)
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Downes, K
(author)
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Farahi, N
(author)
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Peters, JE
(author)
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Bas, S
(author)
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Pankowf, JS
(author)
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Tang, WH
(author)
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Pankratz, N
(author)
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Sabater-Llear, M
(author)
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de Vries, PS
(author)
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Smith, NL
(author)
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Gelinas, AD
(author)
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Schneider, DJ
(author)
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Janjic, N
(author)
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Samani, NJ
(author)
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Ye, S
(author)
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Summers, C
(author)
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Chilvers, ER
(author)
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Danesh, J
(author)
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Paul, DS
(author)
Related titles
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In:Nature communications: Springer Science and Business Media LLC13:1, s. 1222-2041-1723
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Find in a library
To the university's database
- By the author/editor
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Stacey, D
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Chen, LY
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Stanczyk, PJ
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Howson, JMM
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Mason, AM
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Burgess, S
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show more...
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MacDonald, S
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Langdown, J
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McKinney, H
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Downes, K
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Farahi, N
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Peters, JE
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Bas, S
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Pankowf, JS
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Tang, WH
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Pankratz, N
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Sabater-Llear, M
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de Vries, PS
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Smith, NL
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Gelinas, AD
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Schneider, DJ
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Janjic, N
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Samani, NJ
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Ye, S
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Summers, C
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Chilvers, ER
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Danesh, J
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Paul, DS
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- Articles in the publication
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Nature communica ...
- By the university
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Karolinska Institutet