Elsevier

Thrombosis Research

Volume 123, Issue 2, December 2008, Pages 213-218
Thrombosis Research

Regular Article
Low protein Z levels but not the protein Z gene G79A polymorphism are a risk factor for ischemic stroke

https://doi.org/10.1016/j.thromres.2008.02.006Get rights and content

Abstract

Background

Protein Z (PZ) is a vitamin K-dependent plasma protein that plays a role in both pro-and anticoagulant pathways, but its exact physiological function remains unclear. The aim of this study was to determine the association between the G79A PZ gene polymorphism in intron F, PZ levels and the occurrence of ischemic stroke.

Methods

We performed a case–control study in 118 Caucasian patients with first ever ischemic stroke or TIA confirmed by CT, and 113 age-and sex-matched population controls. Venous blood samples for PZ levels were collected 7 to 14 days and 3 months after stroke onset. Estimates of relative risk (odds ratios) were adjusted for vascular risk factors.

Results

The adjusted relative risk of ischemic stroke associated with PZ levels in the lowest quartile versus the highest quartile was 3.0 (95% CI: 1.1–8.7) at 7–14 days, and 5.1 (95% CI: 1.2–21.9) at 3 months after the stroke. PZ levels in the convalescent sample were significantly lower than in the acute sample. In the convalescent sample, odds ratios increased with lower quartiles of protein Z level (test for trend p = 0.02). Thirty-nine patients (33%) and 32 (28%) controls were heterozygous for the G79A PZ gene polymorphism and 4 (3%) patients and 4 (4%) controls had the AA-genotype. The PZ levels were significantly lower in subjects with the AA-genotype and intermediate in heterozygote subjects. The odds ratio of ischemic stroke associated with A-allele carriers versus GG-homozygotes was 1.2 (95% CI: 0.7–2.1).

Conclusion

No association between the G79A PZ gene polymorphism and the occurrence of stroke was observed. However, low PZ levels are independently associated with an increased risk of ischemic stroke.

Introduction

Protein Z (PZ) is a vitamin K dependent single-chain glycoprotein of 62 kDa that is synthesized in the liver. Its amino-terminal sequence is highly homologous to the vitamin K-dependent coagulation factors II, VII, IX, X and protein C [1], [2]. Although PZ was already purified from bovine plasma in 1977 [3] and later found in human plasma [1], its exact physiological function remains unclear.

Initial data suggested that PZ deficiency was associated with a bleeding tendency [4], but subsequent clinical studies and a PZ deficient mice model failed to confirm these observations [5], [6], [7]. More recently, PZ was found to act as a cofactor in the inhibition of factor Xa by a plasma protein called Z-dependent protease inhibitor (ZPI) [2]. Vasse et al. [8] were the first to report a significant association between PZ deficiency and ischemic stroke. Further support for a role of low PZ levels in arterial thrombosis comes from two additional studies in patients with ischemic stroke and acute coronary syndromes [9], [10], [11]. Several other clinical case–control studies, mainly among younger patients, have yielded contradictory results both for ischemic stroke [12], [13], [14], [15] and coronary heart disease [16].

The gene encoding for PZ has been characterized and several common single nucleotide polymorphisms in the gene have been identified [17], [18]. Recently, the minor A allele of the intron F polymorphism G79A (rs3024735) in the PZ gene was described to be protective against ischemic stroke in the young [19]. In that study, PZ level was determined in controls only, and not in patients. In a more recent study the G103A gene polymorphism seemed to be associated with PZ plasma levels, however, the relationship was not as strong as for the G79A polymorphism [20].

To further clarify the role of PZ level in ischemic stroke and to determine to what extent this role is genetically determined, we studied the association of the PZ G79A promoter gene polymorphism and PZ levels with first-ever ischemic stroke. To determine the effect of the acute phase of ischemic stroke on PZ levels, the measurement of the PZ level was repeated in the convalescent phase.

Section snippets

Study design

We performed a case–control study; cases were consecutively recruited patients aged over 18, with first-ever acute ischemic stroke, who were admitted to the department of neurology of a university hospital. This is an urban area hospital without specific selection criteria for the admission of stroke patients. However, young stroke patients are referred more frequently to this center than to the non-academic centers in the region. Fifty percent of the urban population consists of Caribbean or

Results

The study population consisted of 124 patients and 125 controls. Blood samples were available from 118 patients and 113 controls for determination of the PZ gene polymorphism and in 102 patients and 107 controls for determination of the PZ level. In half of the patients a second blood sample could be collected more than 3 months after the index event. In the remaining patients a second blood sample could not be obtained because patients had been prescribed coumarine derivatives, had died or had

Discussion

In this study, reduced levels of PZ were independently associated with an increased risk of first ischemic stroke. We also found a relationship between protein Z level and presence of the A allele of the G79A PZ gene polymorphism in controls. However, we did not observe an association between the G79A PZ gene polymorphism and risk of ischemic stroke.

A limitation of this study is the inclusion of cases of stroke who survived the first 7–14 days, which may have weakened observed associations. A

Acknowledgements

The technical assistance of Elisabeth Huijskens and Robert Streunding is gratefully acknowledged. This study was supported by a grant from the Revolving Fund of the Erasmus MC, the Hersenstichting Nederland (grant no. 11F03.22) and by the Stichting Neurovasculair Onderzoek Rotterdam.

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