A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis

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 5 haplotypes. Haplotype H5 is featured...

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Authors: Corral, J. (Javier)|||/items/e0855d2a-94d9-419c-9ab0-7537cb172f4e, Gonzalez-Conejero, R. (Rocío)|||/items/8c80f6cc-d4f4-4b46-80bf-62f7a2578764, Soria, J.M. (José Manuel)|||/items/e82db6e8-eb89-48bd-b50d-13c793513e9f, Gonzalez-Porras, J.R. (José Ramón)|||/items/f9f2f5bb-d08c-4f13-94aa-cc3634bd6822, Perez-Ceballos, E. (Elena)|||/items/8596a5e7-b795-4d57-af2f-5c8dd6f9865a, Lecumberri-Villamediana, R. (Ramón)|||/items/d804c113-76a8-47fb-85ad-0f01acbe605a, Roldan, V. (Vanessa)|||/items/eeddc1d7-3b3e-4176-9b03-7e5a344e4980, Souto, J.C. (Juan Carlos)|||/items/f2f70337-9976-43a1-ab02-ea147b0fc101, Miñano, A. (Antonia)|||/items/9fcfbed0-2d75-4f0e-8e44-5bcdeb7b1f26, Hernandez-Espinosa, D. (David)|||/items/f22ddd07-88c3-4416-9b36-61fb04a3b22a, Alberca, I. (Ignacio)|||/items/1aa955d3-7cce-4b5b-af63-a911fb0acca3, Fontcuberta, J. (Jordi)|||/items/e28db848-87a3-41a4-beb3-1ca48b140c45, Vicente, V. (Vicente)|||/items/51e8e909-356e-4de4-8294-d4c0f509c67c
Format: article
Publication Date:2006
Country:España
Institution:Universidad de Navarra
Repository:Dadun. Depósito Académico Digital de la Universidad de Navarra
Language:English
OAI Identifier:oai:dadun.unav.edu:10171/36172
Online Access:https://hdl.handle.net/10171/36172
Access Level:Open access
Keyword:Venous thrombosis/epidemiology
Risk factors
Haplotypes
Serpins
Description
Summary: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 5 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 frequency nonsense polymorphism. The prevalence of this haplotype increased significantly in patients (3.0%), one of whom was in a homozygous state. Multivariate analysis confirms that carriers have a 3.3-fold risk of developing venous thrombosis (P = .002; 95% CI: 1.5-7.1). Moreover, we observed a significant association of this polymorphism with familial history of thrombosis (P < .001). Our study supports that the ZPI Arg67Stop nonsense polymorphism might be an independent genetic risk factor for venous thrombosis. This polymorphism has slightly 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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