内皮蛋白C受体基因单倍型、血浆可溶性内皮蛋白C受体水平与深静脉血栓形成风险

Haplotypes of the EPCR gene, plasma sEPCR levels and the risk of deep venous thrombosis.

作者信息

Uitte de Willige S, Van Marion V, Rosendaal F R, Vos H L, de Visser M C H, Bertina R M

机构信息

Department of Haematology, Haemostasis and Thrombosis Research Center, Leiden University Medical Center, Leiden, The Netherlands.

出版信息

J Thromb Haemost. 2004 Aug;2(8):1305-10. doi: 10.1046/j.1538-7836.2004.00855.x.

DOI:10.1046/j.1538-7836.2004.00855.x

PMID:15304035

Abstract

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.

OBJECTIVES

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).

PATIENTS/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.

摘要

背景

蛋白C（PC）与内皮细胞PC受体（EPCR）结合，通过增加PC对凝血酶 - 血栓调节蛋白复合物的亲和力来刺激PC活化。该受体的可溶性形式（sEPCR）在血浆中循环，并抑制PC活化和APC抗凝活性。

目的

本研究旨在调查EPCR基因变异或血浆sEPCR水平是否为深静脉血栓形成（DVT）的危险因素。

患者/方法：在一项大型病例对照研究——莱顿血栓形成倾向研究（LETS）中，通过ELISA法测量sEPCR水平。对所有受试者进行三个单倍型标签SNP的基因分型，使我们能够检测EPCR基因的所有四种常见单倍型。

结果

对照人群中sEPCR水平的分布呈三峰型，并且由单倍型3（H3）进行遗传控制。该单倍型解释了sEPCR水平变异的86.5%。两个H3等位基因的携带者比一个H3等位基因的携带者具有更高的sEPCR水平（439 ng mL(-1)），而一个H3等位基因的携带者又比非H3携带者（94 ng mL(-1)）具有更高的水平。单倍型4与风险略有增加相关（OR = 1.4，95%CI：1.0 - 2.2）。与第一四分位数（< 81 ng mL(-1)）的受试者相比，sEPCR水平处于最高四分位数（>/= 137 ng mL(-1)）的受试者的风险增加，但由于不存在剂量反应效应，很可能低sEPCR水平会降低DVT的风险。