title: 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.
authors.affiliation: Centro Regional de Hemodonación, Universidad de Murcia, Murcia, Spain. javier.corral@carm.es
authors.forename: Javier
authors.initials: J
authors.lastname: Corral
authors.forename: Rocio
authors.initials: R
authors.lastname: González-Conejero
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Soria
authors.forename: Jose Ramón
authors.initials: JR
authors.lastname: González-Porras
authors.forename: Elena
authors.initials: E
authors.lastname: Pérez-Ceballos
authors.forename: Ramón
authors.initials: R
authors.lastname: Lecumberri
authors.forename: Vanessa
authors.initials: V
authors.lastname: Roldán
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Souto
authors.forename: Antonia
authors.initials: A
authors.lastname: Miñano
authors.forename: David
authors.initials: D
authors.lastname: Hernández-Espinosa
authors.forename: Ignacio
authors.initials: I
authors.lastname: Alberca
authors.forename: Jordi
authors.initials: J
authors.lastname: Fontcuberta
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D015843:Serpins / Q000235:genetics*; D013030:Spain / Q000453:epidemiology; D013923:Thromboembolism / Q000453:epidemiology / Q000235:genetics; D020246:Venous Thrombosis / Q000453:epidemiology / Q000235:genetics*
chemical_list: C416370:SERPINA10 protein, human; D015843:Serpins