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.
| Original language | English (US) |
|---|---|
| Article number | 1222 |
| Journal | Nature communications |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2022 |
Bibliographical note
Funding Information:During the drafting of the manuscript, L.C. and J.M.M.H. became full-time employees of Novo Nordisk and D.S.P. became a full-time employee of AstraZeneca. J.E.P. has received travel and accommodation expenses and hospitality from Olink to speak at Olink-sponsored academic meetings. A.D.G., D.J.S. and N.J. are employees and stakeholders of SomaLogic. J.D. reports grants, personal fees and non-financial support from Merck Sharp & Dohme (MSD); grants, personal fees and non-financial support from Novartis; grants from Pfizer; and grants from AstraZeneca outside the submitted work. J.D. sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010); the Steering Committee of UK Biobank (since 2011); the MRC International Advisory Group (ING) member, London (since 2013); the MRC High Throughput Science ‘Omics Panel Member, London (since 2013); the Scientific Advisory Committee for Sanofi (since 2013); the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis; and the AstraZeneca Genomics Advisory Board (2018). The remaining authors declare no competing interests.
Funding Information:
We gratefully acknowledge the participation of all National Institute for Health Research (NIHR) BioResource Center Cambridge volunteers and thank the NIHR BioResource Center Cambridge and staff for their contribution. We thank the NIHR and NHS Blood and Transplant. We acknowledge Dr Honglin Song for her technical support. This work was supported by the British Heart Foundation (BHF) Cambridge Center of Excellence [RE/13/6/30180]. The Cardiovascular Epidemiology Unit is supported by core funding from the: UK Medical Research Council [MR/L003120/1], BHF [RG/13/13/30194; RG/18/13/33946] and NIHR Cambridge Biomedical Research Center [BRC-1215-20014]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This work was further supported by BHF-DZHK VIAgenomics [SP/19/2/344612], a BHF Program Grant [RG/19/9/34655], the Van Geest Heart and Cardiovascular Diseases Research Fund and Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), BHF and Wellcome. D.S. is supported by a BHF Program Grant [RG/18/13/33946].
Funding Information:
We gratefully acknowledge the participation of all National Institute for Health Research (NIHR) BioResource Center Cambridge volunteers and thank the NIHR BioResource Center Cambridge and staff for their contribution. We thank the NIHR and NHS Blood and Transplant. We acknowledge Dr Honglin Song for her technical support. This work was supported by the British Heart Foundation (BHF) Cambridge Center of Excellence [RE/13/6/30180]. The Cardiovascular Epidemiology Unit is supported by core funding from the: UK Medical Research Council [MR/L003120/1], BHF [RG/13/13/30194; RG/18/13/33946] and NIHR Cambridge Biomedical Research Center [BRC-1215-20014]. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This work was further supported by BHF-DZHK VIAgenomics [SP/19/2/344612], a BHF Program Grant [RG/19/9/34655], the Van Geest Heart and Cardiovascular Diseases Research Fund and Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), BHF and Wellcome. D.S. is supported by a BHF Program Grant [RG/18/13/33946]. L.C was supported by a BHF Program Grant [RG/16/4/32218]. J.M.M.H. was supported by a BHF Program Grant [RG/13/13/30194] and the NIHR Cambridge Biomedical Research Center [BRC-1215-20014]. A.M. is funded by the NIHR Cambridge Biomedical Research Center [BRC-1215-20014] and the EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart [116074]. J.E.P. is supported by a UKRI Innovation Fellowship at Health Data Research UK (MR/S004068/2). M.S-L is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute [CP17/00142] and co-financed by the European Social Fund. P.S. deVries is supported by American Heart Association grant number 18CDA34110116. C.S. is funded by the NIHR [NIHR133788] and the Medical Research Council [MR/P502091/1], and supported by the NIHR Cambridge Biomedical Research Center [BRC-1215-20014]. J.D. holds a BHF Professorship and a NIHR Senior Investigator Award. The US National Heart, Lung and Blood Institute (NHLBI) provided support for LITE via R01HL059367. This work was carried out in part using computing resources at the University of Minnesota Supercomputing Institute. The Atherosclerosis Risk in Communities (ARIC) study has been funded in whole or in part with US federal funds from the National Heart, Lung and Blood Institute (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, HHSN268201700005I, R01HL087641, R01HL086694); National Human Genome Research Institute (U01HG004402); and National Institutes of Health (HHSN268200625226C). The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The CHARGE Hemostasis Working Group acknowledges a NIH R01 HL134894 grant. SomaScan and SOMAmer reagent are registered trademarks of SomaLogic, Inc. This research has been conducted using the UK Biobank resource under Application Number 26865. ® ®
Publisher Copyright:
© 2022, The Author(s).
