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

Abstract

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. (Blood. 2006;108:177-183)

Crystal structure of protein Z–dependent inhibitor complex shows how protein Z functions as a cofactor in the membrane inhibition of factor X

“…12 Mice lacking ZPI or PZ developed enhanced thrombosis after arterial injury, 13,14 and the deficiency of ZPI or PZ in humans has been associated with venous thrombosis and peripheral arterial disease. [15][16][17][18] In plasma, PZ circulates as a complex with ZPI. 19 It has been suggested that PZ binds ZPI through its C-terminal protease domain; 11 however, the detailed interactions between PZ and ZPI are unknown, and no structure of either PZ or ZPI is available.…”

Predicting individual risk of venous thrombosis

“…Some of these rare variants are also affecting hemostatic factors, such as the A384S in the SERPINC1 gene, 7 the R67X in SERPIN10 gene, 8 or Ser219Gly in the PROCR gene. 9 • In addition, all the protective factors should be incorporated to better estimate the actual individual risk of suffering the disease.…”

“…7 Interestingly, angiogenesis and immune suppression often go hand-in-hand, sharing similar molecular and cellular mediators. 8 Also in the context of wound healing, immunesuppressive cells would come in handy as safeguards against inappropriate immune reactivity toward endogenous danger signals. Cells such as myeloid-derived suppressor cells (MDSCs), which include a monocytic (MO)-MDSC and a granulocytic polymorphonuclear (PMN)-MDSC fraction, 9 are best known for their ability to suppress the activation of various lymphoid and myeloid cell types, but are also potently pro-angiogenic.…”

Hybridization Probe Genotyping of the R67X Nonsense Polymorphism in the Protein Z-Dependent Protease Inhibitor Reveals a New R67Q Mutation

“…The application of various ultrafiltration devices to radiolabeled water, T 3 , and T 4 yielded striking inconsistencies ( Fig. 1, A-D).…”

“…However, the exact role of ZPI in the coagulation system is still unknown. In a recent study, 1018 patients with an episode of venous thromboembolism and 1018 controls with no history of thromboembolic disease were screened for different ZPI polymorphisms (3 ). A multivariant analysis, which included the Factor V Leiden mutation and the prothombin 20210 GϾA sequence alteration, showed that the R67X change is an independent risk factor for venous thrombosis.…”