A Genome-Wide Association Study of the Protein C Anticoagulant Pathway

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.

Genome-wide association scans for idiopathic osteonecrosis of the femoral head in a Korean population

“…The four variants, rs10493374, rs12032616, rs17127529 and rs6679032, with modest associations were located in and around the DNAJC6 locus. A previous GWAS of the anticoagulant pathway also detected significant associations between certain SNPs in the DNAJC6 gene and free protein S plasma levels (27). The protein C anticoagulant pathway regulates blood coagulation by preventing the formation of thrombi.…”

“…The protein C anticoagulant pathway regulates blood coagulation by preventing the formation of thrombi. This pathway has two main plasma components, protein C and protein S. Deficiencies in antithrombin, protein C and protein S, or an impaired anticoagulant pathway, increase the incidence of thromboembolic disorders (27). Notably, a number of researchers have suggested that intravascular coagulation and microcirculatory thrombotic occlusion may provide a common pathway to non-traumatic osteonecrosis.…”

“…The exact function of DNAJC6 remains unknown, however, the protein encoded by DNAJC6 resembles a tyrosine-protein phosphatase auxilin, which is an enzyme that promotes the uncoating of clathrin-coated vesicles, thus, it potentially has a role in endocytosis. Endocytosis itself, which is followed by partial proteolysis, is involved in coagulation via molecular modification of factor V and factor VIII (27,28). Thus, a similar mechanism involving DNAJC6 and free protein S plasma levels may be associated with ONFH, although validation of this hypothesis requires further investigation.…”

Age-specific onset and distribution of the natural anticoagulant deficiency in pediatric thromboembolism

“…The first nationwide survey for pediatric thrombophilia in Japan suggested a higher prevalence of PC deficiency than expected (24,25). The discrepancy may be explained by the wider range of PC activity than that of PS or AT activity in infant and children (18,26), partly arising from the inherent variation of PC pathway (27,28). Clinical manifestation and thrombin generation differ among the family members having the same PROC mutation (29).…”

Cohn process influences the functional anticoagulant activity of human protein C

“…Human protein C (PC), a 62-kDa vitamin K-dependent zymogen of serine protease, is a glycoprotein mainly synthesized in the liver (Kisiel, 1979;Athanasiadis et al, 2011). Its structure is similar to other vitamin K-dependent proteins that affect blood clotting, such as factor II, VII, IX, and X.…”