![]() Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. 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 US National Heart, Lung and Blood Institute (NHLBI) provided support for LITE via R01HL059367. is funded by a NIHR Senior Investigator Award. is supported by a UKRI Innovation Fellowship at Health Data Research UK (MR/S004068/1). This work was further supported by 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), British Heart Foundation and Wellcome. The Cardiovascular Epidemiology Unit is supported by core funding from the: UK Medical Research Council, British Heart Foundation and NIHR. This work was supported by the British Heart Foundation Cambridge Centre of Excellence. became full-time employees of Novo Nordisk and AstraZeneca, respectively. Competing Interest StatementÄuring the drafting of the manuscript, J.M.M.H. Overall, our study illustrates a multi-modal approach that can help reveal molecular underpinnings of cross-disease associations. These results support a role for protein C as a causal factor in arterial and venous diseases, suggesting that PROCR-219Gly protects against CAD through anti-inflammatory mechanisms while it promotes VTE risk through pro-thrombotic mechanisms. Finally, in cell adhesion assays, we found that increasing concentrations of activated protein C, but not soluble EPCR, reduced leukocyte–endothelial cell adhesion, a marker for vascular inflammation. In a recall-by-genotype study of 52 healthy volunteers stratified by p.S219G, we detected 2.5-fold higher soluble EPCR levels and 1.2-fold higher protein C levels in plasma per effect allele, suggesting the allele induces EPCR shedding from the membrane of endothelial cells. Using statistical colocalization and Mendelian randomization analyses, we uncovered shared genetic etiology across activated protein C, factor VII, CAD and VTE, identifying p.S219G as the likely causal variant at the locus. In a phenome scan of 12 cardiometabolic diseases and 24 molecular factors, we found that PROCR-219Gly associated with higher plasma levels of zymogenic and activated protein C as well as coagulation factor VII. To address this challenge, we describe an integrative approach, focusing on the p.Ser219Gly (rs867186 A>G) variant in the PROCR gene (encoding the endothelial protein C receptor, EPCR), which has been associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. There are, however, few examples where the molecular basis of such pleiotropy has been elucidated. Genome-wide association studies have identified many individual genetic loci associated with multiple complex traits and common diseases. ![]()
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