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 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.
Corral
Javier
J
Centro Regional de Hemodonación, Universidad de Murcia, Murcia, Spain. javier.corral@carm.es
González-Conejero
Rocio
R
Soria
Jose Manuel
JM
González-Porras
Jose Ramón
JR
Pérez-Ceballos
Elena
E
Lecumberri
Ramón
R
Roldán
Vanessa
V
Souto
Juan Carlos
JC
Miñano
Antonia
A
Hernández-Espinosa
David
D
Alberca
Ignacio
I
Fontcuberta
Jordi
J
Vicente
Vicente
V
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*
C416370:SERPINA10 protein, human; D015843:Serpins