British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
Nat Commun. 2022 Mar 9;13(1):1222. doi: 10.1038/s41467-022-28729-3.
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.
许多个体遗传风险位点与多种常见人类疾病有关。然而，这种多效性的分子基础通常仍不清楚。我们提出了一种综合方法来揭示与较低的冠状动脉疾病（CAD）风险但较高的静脉血栓栓塞（VTE）风险相关的 PROCR 基因座的分子机制。我们确定 PROCR-p.Ser219Gly 是该基因座的可能因果变异，而蛋白 C 是一个因果因素。通过遗传分析、人类根据基因型回忆和体外实验，我们证明 PROCR-219Gly 通过内皮细胞中内皮细胞蛋白 C 受体（EPCR）的外显子脱落增加（激活的）蛋白 C 的血浆水平，从而减轻白细胞-内皮细胞黏附和血管炎症。我们还通过凝血因子 VII（EPCR 的配体）将 PROCR-219Gly 与血栓前状态相关联。我们的研究将 PROCR-219Gly 通过抗炎机制与 CAD 相关联，通过促血栓形成机制与 VTE 相关联，为揭示类似的跨表型关联的机制提供了一个框架。
