ORCID Profile
0000-0002-4126-4278
Current Organisation
National University of Singapore
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Publisher: Wiley
Date: 19-02-2007
Publisher: Elsevier BV
Date: 03-2013
Publisher: Springer Science and Business Media LLC
Date: 09-03-2022
DOI: 10.1038/S41467-022-28729-3
Abstract: Many in idual 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.
Publisher: Elsevier BV
Date: 10-2018
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0021-9150(03)00286-7
Abstract: Inflammation and innate immunity may play a role in the pathogenesis of atherosclerosis. The Asp299Gly polymorphism in the toll-like receptor 4 (TLR4) gene reduces responsiveness to lipopolysaccharide and has been associated with reduced incidence and slower progression of carotid atherosclerosis. We analyzed this polymorphism in relation to susceptibility to and severity of coronary artery disease. 1400 participants (mean age: 63 years, 31% female) in the South ton Atherosclerosis Study were genotyped for the TLR4 Asp299Gly polymorphism using the tetra-primer PCR method. There was no significant difference between the frequencies of the Asp/Gly or Gly/Gly genotypes combined, compared to the Asp/Asp genotype, in patients with 0, 1, 2 or 3 coronary arteries with >50% stenosis (chi2(3 d.f.)2=0.4, P=0.94). No associations were observed between genotype groups and cardiac risk factors (P>0.05). The findings of this study do not support the hypothesis that the TLR4 Asp299Gly polymorphism influences predisposition to and progression of coronary artery disease.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Shu Ye.