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Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus.

TitleElucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus.
Publication TypeJournal Article
Year of Publication2022
AuthorsStacey D, Chen L, Stanczyk PJ, Howson JMM, Mason AM, Burgess S, MacDonald S, Langdown J, McKinney H, Downes K, Farahi N, Peters JE, Basu S, Pankow JS, Tang W, Pankratz N, Sabater-Lleal M, de Vries PS, Smith NL, Gelinas AD, Schneider DJ, Janjic N, Samani NJ, Ye S, Summers C, Chilvers ER, Danesh J, Paul DS
Corporate AuthorsCHARGE Hemostasis Working Group
JournalNat Commun
Volume13
Issue1
Pagination1222
Date Published2022 03 09
ISSN2041-1723
KeywordsAntigens, CD, Crosses, Genetic, Endothelial Cells, Endothelial Protein C Receptor, Humans, Protein C, Receptors, Cell Surface, Thrombosis, Venous Thromboembolism
Abstract

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.

DOI10.1038/s41467-022-28729-3
Alternate JournalNat Commun
PubMed ID35264566
PubMed Central IDPMC8907312
Grant ListMR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
BRC-1215-20014 / DH_ / Department of Health / United Kingdom
MR/P502091/1 / MRC_ / Medical Research Council / United Kingdom
UL1 RR025005 / RR / NCRR NIH HHS / United States
NIHR133788 / DH_ / Department of Health / United Kingdom
R01 HL059367 / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
RG/18/13/33946 / BHF_ / British Heart Foundation / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
RG/19/9/34655 / BHF_ / British Heart Foundation / United Kingdom
HHSN268201700002C / HL / NHLBI NIH HHS / United States
HHSN268201700001I / HL / NHLBI NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
RG/16/4/32218 / BHF_ / British Heart Foundation / United Kingdom
R01 HL134894 / HL / NHLBI NIH HHS / United States
MR/S004068/2 / MRC_ / Medical Research Council / United Kingdom
RE/13/6/30180 / BHF_ / British Heart Foundation / United Kingdom
U01 HG004402 / HG / NHGRI NIH HHS / United States
HHSN268201700005C / HL / NHLBI NIH HHS / United States
HHSN268201700001C / HL / NHLBI NIH HHS / United States
HHSN268201700003C / HL / NHLBI NIH HHS / United States
HHSN268201700004C / HL / NHLBI NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
HHSN268201700002I / HL / NHLBI NIH HHS / United States
HHSN268201700005I / HL / NHLBI NIH HHS / United States
/ CSO_ / Chief Scientist Office / United Kingdom
R01 HL087641 / HL / NHLBI NIH HHS / United States
HHSN268201700003I / HL / NHLBI NIH HHS / United States
RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
SP/19/2/344612 / BHF_ / British Heart Foundation / United Kingdom