EPCR Ser219Gly: elevated sEPCR, prothrombin F1+2, risk for coronary heart disease, and increased sEPCR shedding in vitro.
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.
Ireland
H
H
Cardiovascular Genetics, Department Medicine, University College London, 5 University St., London, WC1E 6JF, UK. h.ireland@ucl.ac.uk
Konstantoulas
C J
CJ
Cooper
J A
JA
Hawe
E
E
Humphries
S E
SE
Mather
H
H
Goodall
A H
AH
Hogwood
J
J
Juhan-Vague
I
I
Yudkin
J S
JS
di Minno
G
G
Margaglione
M
M
Hamsten
A
A
Miller
G J
GJ
Bauer
K A
KA
Kim
Y T
YT
Stearns-Kurosawa
D J
DJ
Kurosawa
S
S
D000818:Animals; D000941:Antigens / Q000097:blood* / Q000235:genetics; D015703:Antigens, CD; D001779:Blood Coagulation Factors / Q000235:genetics; D003327:Coronary Disease / Q000097:blood* / Q000209:etiology / Q000235:genetics; D006224:Cricetinae; D003430:Cross-Sectional Studies; D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000235:genetics; D000074283:Endothelial Protein C Receptor; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D015870:Gene Expression; D005838:Genotype; D006023:Glycoproteins / Q000097:blood* / Q000235:genetics; D006801:Humans; D007118:Immunoassay; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood* / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D011516:Prothrombin / Q000235:genetics; D011956:Receptors, Cell Surface / Q000097:blood* / Q000235:genetics; D012307:Risk Factors; D014162:Transfection
D000941:Antigens; D015703:Antigens, CD; D001779:Blood Coagulation Factors; D000074283:Endothelial Protein C Receptor; D006023:Glycoproteins; C478370:PROCR protein, human; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C045879:prothrombin fragment 1.2; D011516:Prothrombin; D004247:DNA