Protein Z gene polymorphisms are associated with protein Z plasma levels

Santacroce, Rosa; Cappucci, Filomena; P, Perna; Sessa, Francesco; Margaglione, Maurizio

doi:10.1111/j.1538-7836.2004.00808.x

Cited by 38 publications

(60 citation statements)

References 14 publications

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“…However, we did not determine linkage disequilibrium between the 2 polymorphisms and did not study the numerous other protein Z polymorphisms that have also been described. [13][14][15] In conclusion, our results are consistent with the hypothesis that elevated protein Z concentrations are prothrombotic. Further advances in understanding of the underlying mechanisms of the association between protein Z and thrombosis 23 may provide new insights into the cause, pathogenesis, or prognosis of acute ischemic stroke and could potentially yield new therapeutic strategies in the future.…”

Section: Discussionsupporting

confidence: 91%

“…Our findings are also consistent with the study by Santacroce et al who found a significant association between G79A genotype and protein Z concentrations among healthy Italian subjects. 15 The data reported in this study cannot explain the apparently conflicting results of previous studies examining the association between protein Z concentrations in the blood and cardiovascular disease, including stroke. The same antigenic assay for protein Z was used in all the studies.…”

Section: Discussioncontrasting

confidence: 78%

“…17 Because the A allele also is associated with reduced blood concentrations of protein Z, 15,17 these findings are consistent with the hypothesis that increased blood concentrations of protein Z concentrations are prothrombotic. However, this remains to be independently confirmed and has not been studied in unselected stroke patients.…”

supporting

confidence: 73%

“…[13][14][15] Because protein Z genotypes are determined by random assortment of maternal and paternal alleles at the time of gamete formation, according to Mendel's second law ("Mendelian randomiza-tion"), the association between protein Z genotype and ischemic stroke should not be subject to reverse causality bias and should also be largely free from confounding by other determinants of protein Z concentrations in the blood or risk factors for stroke. 16 Therefore, examining the consistency of the association between (1) protein Z polymorphisms and blood concentrations of protein Z, and (2) protein Z polymorphisms and ischemic stroke, may help to clarify whether the association between protein Z and stroke is causal or confounded.…”

mentioning

confidence: 99%

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Protein Z Gene Polymorphisms, Protein Z Concentrations, and Ischemic Stroke

Staton

Sayer

Hankey

et al. 2005

Stroke

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Background and Purpose-We aimed to determine whether A-13G or G79A polymorphisms of the protein Z gene that have been reported to be an important determinant of blood concentrations of protein Z are associated with risk of ischemic stroke in a broad range of stroke patients and controls. Methods-We conducted a case control study of 151 hospital cases of first-ever ischemic stroke and 164 randomly selected community controls. Protein Z genotype was determined for the A-13G promoter polymorphism and the G79A intron F polymorphism, and plasma protein Z concentrations were measured during the first 7 days and at 3 to 6 months after the acute stroke event. Results-Geometric mean concentrations of protein Z measured within 7 days of acute stroke were significantly higher in cases compared with controls (1.51 g/mL versus 1.13 g/mL; PϽ0⅐0001). Protein Z concentrations were highest among subjects with the A-13G AA genotype, intermediate among those with the AG genotype, and lowest among those with the GG genotype (1.39 g/mL versus 1.05 g/mL versus 0.76 g/mL; PϽ0.0001); and highest among those with the G79A GG genotype, intermediate among those with the GA genotype, and lowest among those with the AA genotype (1.47 g/mL versus 1.13 g/mL versus 0.66 g/mL; PϽ0.0001). The prevalence of A-13G and G79A genotypes was not significantly different between cases of ischemic stroke and controls. However, compared with the G79A GG genotype (reference), the odds of ischemic stroke was progressively lower for the heterozygote GA (odds ratio [OR], 0.83; 95% CI, 0.52 to 1.33) and the homozygote AA genotype (OR, 0.63; 95% CI, 0.20 to 1.98). A pooled analysis showed that compared with the G79A GG genotype (reference), the odds of ischemic stroke was progressively lower for the heterozygote GA (OR, 0.78; 95% CI, 0.57 to 1.07) and the homozygote AA genotype (OR, 0.31; 95% CI, 0.14 to 0.69). Conclusion-The consistency of the association between protein Z genotypes, blood concentrations of protein Z, and ischemic stroke, determined using 2 different methods that have different sources of bias strengthens the evidence that increased blood concentrations of protein Z concentrations are associated causally with an increased risk of ischemic stroke.

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Section: Discussionsupporting

confidence: 91%

Section: Discussioncontrasting

confidence: 78%

supporting

confidence: 73%

mentioning

confidence: 99%

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Protein Z Gene Polymorphisms, Protein Z Concentrations, and Ischemic Stroke

Staton

Sayer

Hankey

et al. 2005

Stroke

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“…For humans with FV Leiden, low protein Z is associated with an earlier age of first thrombosis and more frequent thrombotic events (11). Protein Z genetic polymorphisms that are associated with reduced protein Z plasma levels were recently reported (12,13). Low protein Z was reported to be associated with ischemic stroke (14 -16), although there are conflicting reports of high protein Z in association with stroke (17) or with large artery stroke (18) and one report of no relationship between protein Z levels and stroke (19).…”

mentioning

confidence: 99%

Down-regulation of Factor IXa in the Factor Xase Complex by Protein Z-dependent Protease Inhibitor

Heeb

Cabral

Ruan

2005

Journal of Biological Chemistry

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Protein Z-dependent protease inhibitor (ZPI) 2 was recently identified as a serpin that potently inhibits activated blood coagulation factor X (FXa) (EC 3.4.21.6) in a manner dependent on protein Z, Ca 2ϩ , and phospholipids (1-3) and the action of which is largely ablated in the presence of FVa (3). ZPI is estimated to be present at 3.8 g/ml (53 nM) in plasma, forms non-covalent complexes with protein Z in plasma, and has an apparent mobility of 72 kDa on SDS-PAGE (3, 4). ZPI is 25-35% homologous to human serpins (2) and 70% homologous to rat liver regeneration protein rasp-1 (5). It has an unusual P1 residue of Tyr-387, and the mutant Y387A did not inhibit FXa (2). Besides inhibiting FXa, ZPI inhibits FXIa (EC 3.4.21.27) in a reaction stimulated 2-fold by heparin and not requiring protein Z (3). Recently, mutations in ZPI that generate stop codons at residues Arg-67 or Trp-303 were found to be significantly associated with venous thrombosis (6), although a different study found no association between ZPI or protein Z levels and venous thrombosis (7).Protein Z is a 62-kDa vitamin K-dependent plasma protein that circulates almost entirely as a complex with protein Z-dependent protease inhibitor and has a wide range in plasma of 2.6 Ϯ 1 g/ml (4, 8). The cofactor role of protein Z in FXa inhibition by ZPI is the first clearly identified function for human protein Z, although bovine and not human protein Z enhances the binding of thrombin to membrane surfaces (9).Protein Z gene knock-out mice have no gross abnormalities, but thrombotic manifestations are exacerbated in an FV Leiden pedigree (10). For humans with FV Leiden, low protein Z is associated with an earlier age of first thrombosis and more frequent thrombotic events (11). Protein Z genetic polymorphisms that are associated with reduced protein Z plasma levels were recently reported (12, 13). Low protein Z was reported to be associated with ischemic stroke (14 -16), although there are conflicting reports of high protein Z in association with stroke (17) or with large artery stroke (18) and one report of no relationship between protein Z levels and stroke (19). Low protein Z is associated with anti-protein Z antibodies and unexplained early fetal loss, which could involve thrombosis (20). Low protein Z levels are associated with antiphospholipid antibodies in women (21) and with a 7-fold increased risk of arterial thrombosis in patients with antiphospholipid syndrome (22).Although ZPI was reported in preliminary studies not to inhibit FIXa (3) (EC 3.4.21.22), we investigated whether ZPI might inhibit FIXa in the FXase complex, as well as FXa in the prothrombinase complex. If so, we wondered whether FVIIIa might protect FIXa from ZPI inhibition, as FVa protects FXa from ZPI inhibition, and whether protein Z might be required for inhibition of FIXa. The homologous prothrombinase and FXase complexes work in tandem to generate thrombin (EC 3.4.21.5), and a physiologic inhibitor of both complexes could be particularly significant. EXPERIMENTAL PROCEDURESPlasma-de...

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Protein Z polymorphisms associated with vaso-occlusive crisis in young sickle cell disease patients

Mahdi

Abu-Hijleh

et al. 2012

Ann Hematol

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We investigated the association of protein Z (PZ) promoter (rs3024718, rs3024719, and rs3024731) and intron (rs3024735; G79A) SNPs with sickle cell disease (SCD) vaso-occlusive crisis (VOC). Study subjects included 239 SCD patients with VOC and 138 pain-free SCD control patients. PZ genotyping was done by allelic discrimination (real-time PCR) assays. The minor allele frequency of rs3024718 (P=0.03), rs3024719 (P=0.02), rs3024731 (P<0.001), and rs3024735 (P<0.001) were higher in VOC patients than control SCD patients. Significant differences in the distribution of rs3024731 (P=0.028) and rs3024735 (P=0.045) genotypes were seen between VOC and steady-state SCD patients. This association remained significant after adjusting for gender, HbS, and HbF. Four-locus (rs3024718/rs3024719/rs3024731/rs3024735) PZ haplotypes analysis demonstrated increased frequency of GAAA (P=0.024), AGAA (P=0.011), and GGTG (P=0.002), and reduced frequency of AGTG haplotype (P=0.001) in VOC than in steady-state control patients, thereby conferring disease susceptibility and protective nature to these haplotypes, respectively. Of these, only AGTG (P(c)=0.001) and GGTG (P(c)=0.018) remained significant after applying the Bonferroni correction. In conclusion, specific PZ variants and haplotypes are significantly associated with SCD VOC.

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Protein Z gene polymorphisms are associated with protein Z plasma levels

Cited by 38 publications

References 14 publications

Protein Z Gene Polymorphisms, Protein Z Concentrations, and Ischemic Stroke

Protein Z Gene Polymorphisms, Protein Z Concentrations, and Ischemic Stroke

Down-regulation of Factor IXa in the Factor Xase Complex by Protein Z-dependent Protease Inhibitor

Protein Z polymorphisms associated with vaso-occlusive crisis in young sickle cell disease patients

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