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Blood, 1 July 2006, Vol. 108, No. 1, pp. 177-183.
Prepublished online as a Blood First Edition Paper on March 9, 2006; DOI 10.1182/blood-2005-08-3249.
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Submitted August 11, 2005
Accepted February 23, 2006
A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis
Javier Corral*, Rocio Gonzalez-Conejero, Jose M Soria, Jose R Gonzalez-Porras, Elena Perez-Ceballos, Ramon Lecumberri, Vanessa Roldan, Juan C Souto, Antonia Minano, David Hernandez-Espinosa, Ignacio Alberca, Jordi Fontcuberta, and Vicente Vicente
Centro Regional de Hemodonacion, Universidad de Murcia, Murcia, Spain
Unitat d'Hemostasia i Trombosi, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Hematology Service, Hospital Clinico Universitario, Salamanca, Spain
Hematology Service, Clinica Universitaria de Navarra, Pamplona, Spain
* Corresponding author; email: javier.corral{at}carm.es.
The protein Z-dependent protease inhibitor (ZPI) is a hemostatic serpin with anticoagulant activity. As for antithrombin, deficiency of ZPI could have relevant thrombotic consequences.
We have studied 6 genetic modifications affecting the ZPI gene, identifying five haplotypes. Haplotype H5 is featured by a stop codon at position 67. The relevance of these genetic modifications and haplotypes in venous thrombosis was evaluated in a case-control study including 1018 patients and 1018 age- and sex-matched controls. Surprisingly, the H5 haplotype was found in 0.9% of controls, supporting that the Arg67Stop change is a low frequent nonsense polymorphism. The prevalence of this haplotype increased significantly in patients (3.0%), one in homozygous state. Multivariate analysis confirms that carriers have a 3.3-fold risk to develop venous thrombosis (p= 0.002; 95%CI: 1.5-7.1). Moreover, we observed a significant association of this polymorphism with familial history of thrombosis (p< 0.001).
Our study supports that the ZPI Arg67Stop nonsense polymorphism might be an independent genetic risk factor for venous thrombosis. This polymorphism has slight lower prevalence but similar thrombotic risk than the FV Leiden or prothrombin 20210A. Although further studies are required, all available data support that the ZPI is a candidate to play a significant role in thrombosis, and should be evaluated in thrombophilic studies.
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