EPCR Ser219Gly: Elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro
EPCR Ser219Gly: Elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro
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DOI：
10.1016/j.atherosclerosis.2005.02.028
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发表时间：
2005-12-01
期刊：
影响因子：
5.3
通讯作者：
Kurosawa, S
中科院分区：
文献类型：
--
作者：
Ireland, H;Konstantoulas, CJ;Kurosawa, S
我们逐步分析了三项冠心病（CHD）的EPCR（Ser 219 Gly）变异研究。最初，在一项前瞻性研究中，NPHSII，虽然在杂合子中未发现总体CHD风险，但219 Gly纯合子显示出3倍的风险升高（HR 3.3，CI 1.22-8.96）。在NPHSII的糖尿病患者中，有一种建议，即219 Gly+与CHID风险升高相关（HR 1.89，CI 0.39-9.06），尽管数量很少。为了进一步评估变异体在糖尿病中的作用，使用MI的病例对照研究HIFMECH，其中先前的分析通过因子分析定义了代谢综合征组。在基因型和“代谢综合征”因素之间确定了一个显着的CHD风险相互作用（相互作用p = 0.009）。为了进一步评估该变体在2型糖尿病中的CHD风险，并评估该变体对凝血酶生成和血浆可溶性EPCR水平的影响，使用了一项2型糖尿病的横断面研究。在这项研究中，确定了欧洲白人（OR 2.84，CI 1.38-5.85）和印度亚洲人（OR 1.6，CI 1.00-2.57）的显著CHD风险，印度亚洲人中219 Gly的频率高出两倍。可溶性EPCR水平与基因型密切相关，219 Gly纯合子的水平高4倍（p < 0.0001）。EPCR转染细胞的体外研究表明，从表达219 Gly EPCR表型的细胞中sEPCR的基础释放增加。此外，在NPHSII和糖尿病研究的基线样本中，观察到219 Gly的凝血酶原F1+2水平显著增加。CHD风险和凝血酶生成的增加似乎是通过增加Gly等位基因从细胞表面脱落而起作用的。(c)2005爱思唯尔爱尔兰有限公司保留所有权利。
We have progressively analysed three studies of coronary heart disease (CHD) for a variant in EPCR (Ser219Gly). Initially, in a prospective study, NPHSII, while no overall CHD-risk was identified in heterozygotes, homozygotes for 219Gly exhibited a three-fold elevated risk (HR 3.3, CI 1.22-8.96). In diabetics within NPHSII, there was a suggestion that 219Gly+ was associated with elevated CHID-risk (HR 1.89, CI 0.39-9.06) although numbers were small. To further assess the effect of the variant in diabetes, a case-control study of MI, HIFMECH, was used, in which previous analysis had defined a group with metabolic syndrome, by factor analysis. A significant CHD-risk interaction was identified between genotype and the 'metabolic syndrome' factor (interaction p = 0.009). To further assess CHD-risk for this variant in type-2 diabetes and to assess the effect of the variant upon thrombin generation and plasma levels of soluble EPCR, a cross-sectional study of type-2 diabetes was used. A significant CHD-risk was identified for European Whites (OR 2.84, Cl 1.38-5.85) and Indian Asians in this study (OR 1.6, Cl 1.00-2.57) and the frequency of 219GIy was two-fold higher in Indian Asians. Soluble EPCR levels were strongly associated with genotype, with homozygotes for 219GIy having four-fold higher levels (p < 0.0001). In vitro studies of EPCR-transfected cells suggested increased basal release of sEPCR from cells expressing the 219GIy EPCR phenotype. Furthermore, in base-line samples from NPHSII and in the diabetic study, a significant increase in prothrombin F1+2 level was observed for 219GIy. The increased CHD-risk and thrombin generation appears to be acting through increased shedding of the Gly allele from the cell surface. (c) 2005 Elsevier Ireland Ltd. All rights reserved.