High levels of protein C are determined by PROCR haplotype 3

Pintão, Maria Carolina; Roshani, S.; Visser, Mijke; Tieken, Chris; Tanck, Michael W.T.; Wichers, Iris; Meijers, Joost C. M.; Fr, Rosendaal; Reitsma, Pieter H.

doi:10.1111/j.1538-7836.2011.04256.x

Cited by 17 publications

(14 citation statements)

References 29 publications

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“…We were able to detect associations between two tightly linked SNPs from the PROCR genomic region (coding for EPCR) and PC plasma levels, also found in previous studies [15], [16], [18], [19]. In this respect, these particular results of ours stand as an independent replication from a family-based perspective.…”

Section: Discussionsupporting

confidence: 88%

“…In addition, a genome-wide linkage analysis reported that a quantitative trait locus in chromosomal region 20q11 (including genes FOXA2 , THBD and PROCR ) influences PC levels in one extended family from the GENES study [17], [18]. A subsequent study revealed that PROCR haplotype 3 and a SNP from FOXA2 (rs1055080) were associated with PC levels in this family, but only PROCR haplotype 3 was associated also with plasma levels in healthy individuals [19].…”

Section: Introductionmentioning

confidence: 94%

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

et al. 2011

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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.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 94%

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

et al. 2011

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“…One of these haplotypes, A3, encodes a protein, which is more sensitive than the other two to the action of shedding enzymes, which can result in a marked increase in the level of sEPCR. The presence of the A3 haplotype therefore coincides with the presence of a high sEPCR level, the latter being a candidate risk factor for venous thrombosis (10–12). Interest in EPCR/aPC in relation to tumor biology is gaining momentum with the appearance of an increasing number of publications (13–16).…”

Section: Introductionmentioning

confidence: 87%

Endothelial protein C receptor expressed by ovarian cancer cells as a possible biomarker of cancer onset

Ducros¹,

Mirshahi

Azzazene

et al. 2012

International Journal of Oncology

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Coagulation disorders often accompany cancer onset and evolution, which, if not properly managed, could have grave consequences. Endothelial protein C is an important regulator of homeostasis and acts through its high affinity binding to its transmembrane receptor (EPCR). Soluble (sEPCR) which results from the proteolytic cleavage of the membrane bound form can trap activated endothelial protein C and deprive it of its anti-coagulant function. In this study, the expression of EPCR and its soluble form (sEPCR) released into plasma as a result of proteolytic cleavage were investigated in ovarian, breast, lung and colorectal cancer biopsies, as well as in ascitic cell clusters and peritoneal fluid from ovarian cancer samples. In parallel, breast, ovarian, lung and colorectal cancer cell lines were investigated for the expression of EPCR. The integrity of the EPCR gene sequence as well gene haplotypes were ascertained in the established cancer cell lines in order to understand their eventual regulatory functions. The results from the present study indicate that in cancer patients, the levels of sEPCR are significantly higher than the normal range compared to healthy volunteers. The increase in the levels of sEPCR parallels the increase in CA125, showing a close correlation. Therefore, the detection of sEPCR in cancer and during the post-treatment period could be taken into account as an additional marker that could re-inforce the one obtained using CA125 alone as a marker of cancer cell mass.

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“…Soluble EPCR is shed from endothelial cells by metalloproteinase TACE/ADAM17 and circulates in plasma 19 . The levels of soluble EPCR differ between individuals and high plasma levels of EPCR (up to 500 ng/ml) are associated with specific PROCR haplotypes 20 , which in turn are associated with a higher risk of contracting venous thrombosis 21 . Of interest, addition of recombinant soluble EPCR at levels between 15–300 ng/ml showed a progressively higher inhibition of the binding between DC8 expressing parasites and endothelial cells (Fig.…”

mentioning

confidence: 99%

Severe malaria is associated with parasite binding to endothelial protein C receptor

Turner

Lavstsen

Berger

et al. 2013

Nature

496

664

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Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year 1 . Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining 2 . Severe malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DC) 8 and 13 3 , but the endothelial receptor for parasites expressing these proteins was unknown 4,5 . Here, we identify endothelial protein C receptor (EPCR), which mediates cytoprotective effects of activated protein C 6 , as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the N-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies and that CIDRα1 interferes with protein C binding to EPCR. This PfEMP1 adhesive property links P. falciparum Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms † Correspondence to: thomasl@sund.ku.dk and lturner@sund.ku.dk. * These authors contributed equally to the work.Supplementary Information is linked to the online version of the paper at www.nature.com/nature.Author Contributions: LT, TL, JDS and AJB produced recombinant proteins; JF performed the protein array experiments; SSB, CWW, JEVP, MAN, MA, JSJ and JDS performed the work with malaria parasites; PM, JL and TGT organized clinical work and processed clinical samples; MKK performed the surface plasmon resonance studies; LT performed the ELISA studies. The study was conceived and planned by LT, TL and TGT. The manuscript was written by TL, TGT, LT, JDS, and MH. All authors read and commented on the manuscript. LT and TL contributed equally to the work.Author Informaton: Reprints and permissions information is available at www.nature.com/reprints.The authors have no competing financial interests. To identify the DC8-PfEMP1 receptor, we produced a full-length DC8-containing PfEMP1 using the var gene IT4var20 from the FCR3/IT4 parasite. This 288 kDa His-tagged recombinant protein (rIT4VAR20) was screened against an array of 2505 full-length human plasma membrane proteins expressed on HEK293 cells (Table S1) S3) and all found to bind brain-derived endothelial cells via EPCR (Table S3). Previous work has shown that DC8-and DC13-variants selected on brain endothelial cells also bind to non-brain microvascular endothelial cells from heart and lung 4,5 . Binding of the FCR3 IT4VAR19b parasite line (described in 4 ) to brain, heart, lung and bone marrow endothelial cells was evaluated and found to be mediated by EPCR (Table S3). Altogether, these results demonstrate cytoadhesion of DC8 PfEMP1 expressing parasites via EPCR on endothelial cells of diverse tissu...

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High levels of protein C are determined by PROCR haplotype 3

Cited by 17 publications

References 29 publications

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

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

Endothelial protein C receptor expressed by ovarian cancer cells as a possible biomarker of cancer onset

Severe malaria is associated with parasite binding to endothelial protein C receptor

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