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

• Published in: Atherosclerosis 2005-12, Vol.183 (2), p.283-292
• Main Authors: Ireland, H., Konstantoulas, C.J., Cooper, J.A., Hawe, E., Humphries, S.E., Mather, H., Goodall, A.H., Hogwood, J., Juhan-Vague, I., Yudkin, J.S., di Minno, G., Margaglione, M., Hamsten, A., Miller, G.J., Bauer, K.A., Kim, Y.T., Stearns-Kurosawa, D.J., Kurosawa, S.
• Format: Article
• Language: English
• Subjects: Animals; Antigens - blood; Antigens - genetics; Antigens, CD; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood Coagulation Factors - genetics; Blood coagulation. Blood cells; Cardiology. Vascular system; Coronary Disease - blood; Coronary Disease - etiology; Coronary Disease - genetics; Coronary heart disease; Cricetinae; Cross-Sectional Studies; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; DNA - genetics; Endothelial Protein C Receptor; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Female; Flow Cytometry; Follow-Up Studies; Fundamental and applied biological sciences. Psychology; Gene Expression; Genotype; Glycoproteins - blood; Glycoproteins - genetics; Heart; Heart disease; Humans; Immunoassay; In Vitro Techniques; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Molecular and cellular biology; Peptide Fragments - blood; Peptide Fragments - genetics; Platelet; Prognosis; Prospective Studies; Prothrombin - genetics; Receptors, Cell Surface - blood; Receptors, Cell Surface - genetics; Risk Factors; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Thrombin; Transfection
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2005.02.028

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 CHD-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, CI 1.38–5.85) and Indian Asians in this study (OR 1.6, CI 1.00–2.57) and the frequency of 219Gly was two-fold higher in Indian Asians. Soluble EPCR levels were strongly associated with genotype, with homozygotes for 219Gly 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 219Gly 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 219Gly. The increased CHD-risk and thrombin generation appears to be acting through increased shedding of the Gly allele from the cell surface.