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Background and Purpose: The vitamin K-dependent protein Z (PZ) has been shown to possess anticoagulant as well as procoagulant properties. Plasma levels of PZ show a broad interindividual variation, but it is unknown to which extent this variation is under genetic control. Recent clinical studies revealed contradictory results on the association of PZ plasma levels and the risk of ischemic stroke., Methods: We performed a case-control study including 200 patients with cerebral ischemia aged < or =50 years and 199 control subjects from the same South German region. We investigated a possible association of 2 common single nucleotide mutations in the PZ gene with the risk of cerebral ischemia. Furthermore, enzyme-linked immunosorbent assay measurements were done in control subjects without vascular disease to detect a potential association of different genotypes with PZ plasma (antigen) levels., Results: In patients, the frequency of the A allele of the intron F polymorphism G79A was significantly lower than in controls (15.7% versus 24.4%; odds ratio, 0.58; 95% CI, 0.39 to 0.86; P=0.007; adjusted for age, sex, and conventional risk factors). The G allele of the promoter polymorphism A-13G tended to be less common in patients (4.2% versus 7.0%; adjusted odds ratio, 0.56; 95% CI, 0.28 to 1.13; P=0.105). In 42 control subjects, the A allele of the intron F polymorphism was associated with lower PZ antigen levels (P=0.0032; Spearman correlation coefficient rs=-0.48)., Conclusions: The A allele of an intron F polymorphism of the PZ gene appears to be a novel protective genetic marker for the risk of cerebral ischemia in young adults. In the context of juvenile stroke, high PZ plasma levels may represent a prothrombotic condition.