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Numerous genetic risk loci have been linked to a variety of prevalent human diseases. However, the molecular basis of pleiotropy is frequently unknown. The PROCR locus is linked to a lower risk of coronary artery disease (CAD) but a higher risk of venous thromboembolism (VTE). We provide an integrative method to uncover the molecular mechanism behind the PROCR locus. PROCR-p. Ser219Gly is identified as the likely causing mutation at the locus, while protein C is identified as a causal component. We show that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, reducing leukocyte–endothelial cell adhesion and vascular inflammation, using genetic analyses, human recall-by-genotype, and in vitro experimentation. PROCR-219Gly is also linked to an enhanced pro-thrombotic state via coagulation factor VII, an EPCR ligand. Our findings, which link PROCR-219Gly to both CAD and VTE via anti-inflammatory and pro-thrombotic processes, provide a framework for unravelling the mechanisms behind similar cross-phenotype correlations.
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