Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis.
BACKGROUND
Binding of protein C (PC) to the endothelial cell PC receptor (EPCR) stimulates PC activation by increasing the affinity of PC for the thrombin-thrombomodulin complex. A soluble form of this receptor (sEPCR) circulates in plasma and inhibits both PC activation and APC anticoagulant activity.


OBJECTIVE
The aim of this study was to investigate whether variations in the EPCR gene or plasma sEPCR levels are risk factors for deep venous thrombosis (DVT).


METHODS
In a large case-control study, the Leiden Thrombophilia Study (LETS), sEPCR levels were measured by ELISA. All subjects were genotyped for three haplotype-tagging SNPs, enabling us to detect all four common haplotypes of the EPCR gene.


RESULTS
The distribution of sEPCR levels in the control population was trimodal and was genetically controlled by haplotype 3 (H3). This haplotype explained 86.5% of the variation in sEPCR levels. Carriers of two H3 alleles had higher sEPCR levels (439 ng mL(-1)) than carriers of one H3 allele (258 ng mL(-1)), which had higher levels than non-H3 carriers (94 ng mL(-1)). Haplotype 4 was associated with a slightly increased risk (OR = 1.4, 95%CI:1.0-2.2). The risk of subjects with sEPCR levels in the top quartile (>/= 137 ng mL(-1)) was increased compared to that of subjects in the first quartile (< 81 ng mL(-1)), but since there was no dose-response effect, it is most likely that low sEPCR levels reduce the risk of DVT.


CONCLUSIONS
Our data do not suggest a strong association between EPCR haplotypes and thrombosis risk, but low sEPCR levels appear to reduce the risk of DVT.
Uitte de Willige
S
S
Department of Haematology, Haemostasis and Thrombosis Research Center, Leiden University Medical Center, Leiden, The Netherlands. suitte@lumc.nl
Van Marion
V
V
Rosendaal
F R
FR
Vos
H L
HL
de Visser
M C H
MC
Bertina
R M
RM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D015703:Antigens, CD; D016022:Case-Control Studies; D000074283:Endothelial Protein C Receptor; D016232:Endothelins / Q000097:blood* / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D006023:Glycoproteins; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D016017:Odds Ratio; D011486:Protein C / Q000096:biosynthesis; D011956:Receptors, Cell Surface; D012306:Risk; D012307:Risk Factors; D013927:Thrombosis / Q000175:diagnosis / Q000235:genetics*; D020246:Venous Thrombosis / Q000097:blood* / Q000175:diagnosis*
D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D016232:Endothelins; D006023:Glycoproteins; C478370:PROCR protein, human; D011486:Protein C; D011956:Receptors, Cell Surface