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EPCR Ser219Gly: Elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro

Ireland, H; Konstantoulas, CJ; Cooper, JA; Hawe, E; Humphries, SE; Mather, H; ... Kurosawa, S; + view all (2005) EPCR Ser219Gly: Elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro. ATHEROSCLEROSIS , 183 (2) 283 - 292. 10.1016/j.atherosclerosis.2005.02.028.

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Abstract

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.

Type:Article
Title:EPCR Ser219Gly: Elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro
DOI:10.1016/j.atherosclerosis.2005.02.028
Keywords:endothelial protein C receptor, thrombin, heart disease, PROTEIN-C RECEPTOR, THROMBOMODULIN GENE, VENOUS THROMBOSIS, INFLAMMATION, COAGULATION, ACTIVATION, MECHANISMS, PLASMA, VARIANTS, HIFMECH
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science

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