Abstract
The Protein C anticoagulant pathway regulates blood coagulation by preventing the inadequate formation of thrombi. It has two main plasma components: protein C and protein S. Individuals with protein C or protein S deficiency present a dramatically increased incidence of thromboembolic disorders. Here, we present the results of a genome-wide association study (GWAS) for protein C and protein S plasma levels in a set of extended pedigrees from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. A total number of 397 individuals from 21 families were typed for 307,984 SNPs using the Infinium® 317 k Beadchip (Illumina). Protein C and protein S (free, functional and total) plasma levels were determined with biochemical assays for all participants. Association with phenotypes was investigated through variance component analysis. After correcting for multiple testing, two SNPs for protein C plasma levels (rs867186 and rs8119351) and another two for free protein S plasma levels (rs1413885 and rs1570868) remained significant on a genome-wide level, located in and around the PROCR and the DNAJC6 genomic regions respectively. No SNPs were significantly associated with functional or total protein S plasma levels, although rs1413885 from DNAJC6 showed suggestive association with the functional protein S phenotype, possibly indicating that this locus plays an important role in protein S metabolism. Our results provide evidence that PROCR and DNAJC6 might play a role in protein C and free protein S plasma levels in the population studied, warranting further investigation on the role of these loci in the etiology of venous thromboembolism and other thrombotic diseases.
Highlights
The protein C anticoagulant pathway is an important physiological mechanism that regulates blood coagulation
The aim of this study was to shed more light on the genetic mechanisms underlying the protein C anticoagulant pathway through a genome-wide association study (GWAS) of the plasma levels of Protein C (PC), fPS, Functional PS (funcPS) and total PS; these levels are strongly involved in the development of thromboembolic disorders
endothelial PC receptor (EPCR) is an endothelial cell-specific transmembrane protein that is involved in the protein C anticoagulant pathway by enhancing the activation rate of PC [29,30]
Summary
The protein C anticoagulant pathway is an important physiological mechanism that regulates blood coagulation. It prevents the inadequate formation of thrombi and has two main plasma components: protein C and protein S. Protein C (PC) is a vitamin K-dependent serine protease, which acts as an anticoagulant by inactivating activated Factors V (FVa) and VIII (FVIIIa). PC is activated by the thrombin/thrombomodulin complex on the surface of endothelial cells, where it binds with endothelial PC receptor (EPCR) [1,2]. EPCR circulates in a soluble form (sEPCR) with similar affinity to both PC and activated PC (APC). SEPCR acts as an inhibitor of APC [3]
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