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.
Highlights
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
Human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte–endothelial cell adhesion and vascular inflammation
Using reverse transcription quantitative PCR (RT-Quantitative PCR (qPCR)), we showed that increasing concentrations of activated PC (APC) attenuate the tumor necrosis factor (TNF)-α-induced increase in ICAM1 mRNA levels in both human umbilical vein endothelial cells (HUVECs) (P = 0.0003) and human coronary artery endothelial cells (HCAECs) (P = 0.0009) but not Forward Mendelian randomization (MR): Protein C Protein C Protein C Protein C Protein C Protein C Protein C Protein C Protein C
Summary
Many individual genetic risk loci have been associated with multiple common human diseases. 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. The vast majority of these pleiotropic variants were found to impact the risk of multiple diseases in a directionally consistent manner, but 1.9% of loci (excluding the major histocompatibility complex) showed evidence of both higher and lower risk effects attributable to the same allele[1] One such example is rs9349379 A > G, a wellcharacterized regulatory variant at the PHACTR1-EDN1 locus, which is associated with a higher risk of coronary artery disease but a lower risk of four other vascular diseases including migraine headache and hypertension[2]. A soluble form of EPCR (sEPCR) is present in plasma, which is generated by ectodomain shedding of EPCR from the endothelium
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