Published online 1 September 2008
Haematologica, Vol 93, Issue 9, 1358-1363 doi:10.3324/haematol.13066
Copyright © 2008 by Ferrata Storti Foundation
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Thrombosis

Endothelial protein C receptor polymorphisms and risk of myocardial infarction

Pilar Medina1, Silvia Navarro1, Javier Corral2, Esther Zorio3, Vanessa Roldán2, Amparo Estellés1, Amparo Santamaría4, Francisco Marín5, Joaquín Rueda3, Rogier M. Bertina6, Francisco España1, for the RECAVA Thrombosis Groups

1 Centro de Investigación, Hospital Universitario La Fe, Valencia, Spain
2 Centro Regional de Hemodonación, Universidad de Murcia, Murcia, Spain
3 Servicio de Cardiología, Hospital Universitario La Fe, Valencia, Spain
4 Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
5 Servicio de Cardiología, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
6 Hemostasis and Thrombosis Research Centre, Department of Hematology, Leiden University Medical Centre, Leiden, The Netherlands

Correspondence: Francisco España, Hospital Universitario La Fe, Centro de Investigación, Av. Campanar 21, 46009 Valencia, Spain. E-mail:espanya_fra{at}gva.es

Background: Haplotypes A1 and A3 in the endothelial protein C receptor gene are tagged by the 4678G/C and 4600A/G polymorphisms, respectively, and have been reported to influence the risk of venous thromboembolism. We assessed whether these haplotypes modify the risk of premature myocardial infarction.

Design and Methods: We genotyped these polymorphisms in 689 patients with premature myocardial infarction and 697 control subjects. Activated protein C and soluble endothelial protein C receptor levels were also measured.

Results: After adjustment for other cardiovascular risk factors, A1 and A3 haplotypes protected against premature myocardial infarction (odds ratio 0.7, 95% CI 0.4–0.8, p=0.044 and 0.5, 0.3–0.6, p<0.001, respectively). Moreover, the protective role of these haplotypes seemed to be additive, as carriers of both the A1 and A3 haplotypes had adjusted odds ratios of 0.3 (0.2–0.5, p<0.001) and 0.4 (0.2–0.8, p=0.006) compared to those carrying only the A1 or A3 haplotype, respectively. The presence of the A1 haplotype was associated with increased levels of activated protein C whereas individuals carrying the A3 haplotype showed the highest soluble endothelial protein C receptor levels.

Conclusions: These results show that A1 haplotype carriers have a reduced risk of premature myocardial infarction via the association of this haplotype with increased activated protein C plasma levels. The study also shows that carriers of the A3 haplotype have a reduced risk of myocardial infarction, only in part due to increased soluble endothelial protein C levels.

Key words: endothelial protein C receptor, haplotypes, premature myocardial infarction, activated protein C, soluble EPCR.