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

Goor, M; Dippel, Diederik W.J.; Jie, K. S. G.; Maat, Moniek P.M. de; Koudstaal, Peter J.; Leebeek, Frank W.G.

doi:10.1016/j.thromres.2008.02.006

Cited by 19 publications

(32 citation statements)

References 21 publications

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“…Among the four studied PZ SNPs, only rs3024731 and rs3025735 were positively associated with VOC. A number of polymorphisms in the PZ gene were previously reported [21,36], and differential linkage disequilibrium (LD) between PZ functional variants controlling PZ production [36], and disease association were described [21]. In this study, marked LD was seen between the PZ variants studied, which allowed construction of PZ haplotypes.…”

Section: Discussionmentioning

confidence: 64%

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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Section: Discussionmentioning

confidence: 64%

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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“…The wide variability in plasma PZ levels is attributed to the presence of genetic factors influencing PZ biosynthesis (Rice et al 2001, and common and rare gene variants have been reported in the PROZ Protein Z in reproductive biology locus (Rice et al 2001, van Goor et al 2008, Le Cam-Duchez et al 2009, AlShaikh et al 2013. The differential linkage disequilibrium (LD) pattern between PROZ variants controlling PZ production (Rice et al 2001, van Goor et al 2008, Le Cam-Duchez et al 2009, and thus disease association (Rice et al 2001, Nowak-Gö ttl et al 2009, AlShaikh et al 2013, indicates that PZ deficiency is, at least in part, constitutional (Miletich & Broze 1987).…”

Section: Proz/serpina10 (Zpi ) Polymorphisms In Adverse Pregnancy Outmentioning

confidence: 99%

“…The differential linkage disequilibrium (LD) pattern between PROZ variants controlling PZ production (Rice et al 2001, van Goor et al 2008, Le Cam-Duchez et al 2009, and thus disease association (Rice et al 2001, Nowak-Gö ttl et al 2009, AlShaikh et al 2013, indicates that PZ deficiency is, at least in part, constitutional (Miletich & Broze 1987). While the functional aspects of these variants have not been thoroughly assessed, some have been shown to influence plasma PZ levels, in particular G79A, A13G, and G42A; the lowest plasma PZ levels have been observed with the G/G genotype (A13G) and the A/A (G42A) and A/A (G79A) homozygous variant genotypes (Lichy et al 2004).…”

Section: Proz/serpina10 (Zpi ) Polymorphisms In Adverse Pregnancy Outmentioning

confidence: 99%

“…Furthermore, both rs3024719 (G103A) and rs3024731 (T119A) PROZ promoter variants have been associated with reduced PZ levels and an increased risk of fetal loss (AlShaikh et al 2013). Based on the LD pattern between PROZ variants (van Goor et al 2008, Le Cam-Duchez et al 2009, AlShaikh et al 2013, specific PROZ haplotypes have recently been shown to be associated with poor pregnancy outcomes (AlShaikh et al 2013). Larger studies on different ethnic groups are needed to confirm the nature of the association of PROZ G79A and other variants with adverse pregnancy outcomes.…”

Section: Proz/serpina10 (Zpi ) Polymorphisms In Adverse Pregnancy Outmentioning

confidence: 99%

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Protein Z, an anticoagulant protein with expanding role in reproductive biology

Almawi¹,

AlShaikh²,

Melemedjian³

et al. 2013

Reproduction

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Protein Z (PZ) is a vitamin K-dependent factor characterized by its homology to other vitamin K-dependent factors (factors VII, IX, and X, protein C and protein S), but lacks any enzymatic activity. Instead, PZ acts as a cofactor for the inhibition of factor Xa through the serpin PZ-dependent protease inhibitor (ZPI). PZ deficiency is associated with a procoagulant state, highlighted by excessive FXa secretion and thrombin production, and is linked with several thrombotic disorders, including arterial vascular and venous thromboembolic diseases. A role for the PZ-ZPI complex in the regulation of physiological pregnancy has been demonstrated, highlighted by the progressive elevation in PZ levels in the first trimester of gestation, which then steadily decline toward delivery. An association between altered plasma PZ concentrations and adverse pregnancy outcomes (recurrent miscarriage, stillbirth, preeclampsia, intrauterine growth restriction, and placental abruption) has been reported. The mechanism by which PZ deficiency leads to adverse pregnancy outcomes is not clear, but it is multifactorial. It may be attributed to the anti-PZ IgG and IgM autoantibodies, which apparently act independently of classical antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-b2-glycoprotein I antibodies). PZ deficiency has also been reported to be constitutional, and a number of variants in the PROZ (PZ) gene and SERPINA10 (ZPI) gene are linked with specific adverse pregnancy complications. This review summarizes the relationship between adverse pregnancy outcomes and acquired and constitutional PZ-ZPI deficiency, in order to understand whether or not PZ deficiency could be considered as a risk factor for poor pregnancy outcomes.

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“…Several PZ single-nucleotide polymorphisms (SNPs) were found to be correlated with PZ plasma levels and thus effect PZ coagulation function (Lichy et al 2004;Santacroce et al 2004;van Goor et al 2008;Topalidou et al 2009). This was same with FVII (Grant 1997;Heywood et al 1997;Kang et al 2004;Rubattu et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Association of protein Z and factor VII gene polymorphisms with risk of cerebral hemorrhage: a case–control and a family-based association study in a Chinese Han population

Zeng

Zhang

et al. 2016

J Genet

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Protein Z (PZ) and factor (F) VII are two important factors in the clotting pathway which have similar structure, linked function and nearby gene sites. The aims of this study were to investigate whether the common variants of PZ and FVII genes are associated with the risk of cerebral hemorrhage (CH) and to explore the combined effects of PZ and FVII polymorphisms for CH risk. We performed genotyping analysis for two single-nucleotide polymorphisms (SNPs) of FVII (rs510317 and rs6046) and three SNPs of PZ (rs2273971, rs3024718 and rs3024731) both in a population-based case-control study and in a family-based association study. Case-control analysis found no evidence of significant association. But family-based association study revealed that the G allele of PZ rs2273971, and three haplotypes carrying the 'G' allele of PZ rs2273971: haplotype GA, CG and CGA of PZ and FVII genes, all had a significant effect on CH susceptibility (Z = 1.882, P = 0.049; Z = 1.922, P = 0.044; Z = 1.826, P = 0.047; Z = 1.977, P = 0.048, respectively). While, the A allele of PZ rs2273971, and four haplotypes carrying or crossing the 'A' allele of PZ rs2273971: haplotypes CA, ACAA, ACAT and ACAAT of PZ and FVII genes, may confer protection against CH (Z= -1.882, P = 0.049; Z= -2.000, P = 0.045; Z= -2.319, P = 0.020; Z= -2.002, P = 0.045; Z= -2.015, P = 0.043, respectively). This is a first family-based association study providing genetic evidences that PZ and FVII genes, especially PZ rs2273971 are involved in the development of CH in Han-Chinese families.

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

Cited by 19 publications

References 21 publications

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

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

Protein Z, an anticoagulant protein with expanding role in reproductive biology

Association of protein Z and factor VII gene polymorphisms with risk of cerebral hemorrhage: a case–control and a family-based association study in a Chinese Han population

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