Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults

Lili Zhang; Alan Z. Segal; Dana Leifer; Roy L. Silverstein; Linda M. Gerber; Richard B. Devereux; Jorge R. Kizer

doi:10.1160/TH16-04-0277

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(01): 149-157
DOI: 10.1160/TH16-04-0277

Stroke, Systemic or Venous Thromboembolism

Schattauer GmbH

Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults^{[
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Lili Zhang

¹Department of Medicine, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York, USA

,

Alan Z. Segal

²Department of Neurology, Weill Cornell Medicine, New York, New York, USA

,

Dana Leifer

²Department of Neurology, Weill Cornell Medicine, New York, New York, USA

,

Roy L. Silverstein

³Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

,

Linda M. Gerber

⁴Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, New York, USA

,

Richard B. Devereux

⁵Department of Medicine, Weill Cornell Medicine, New York, New York, USA

,

Jorge R. Kizer

¹Department of Medicine, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York, USA

⁶Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA

› Author Affiliations

Abstract

Summary

Protein Z (PZ) is a vitamin K–dependent plasma protein that exhibits both pro- and anticoagulant properties. Both low and high PZ levels have been linked to ischaemic stroke. Although PZ-lowering gene variants have been found to be less common in ischaemic stroke, the relationship remains unclear. We investigated PZ levels and PROZ variants in a multi-ethnic case-control study of unexplained stroke in participants aged 18 to 64. Plasma PZ was measured in cases (≥2 months post-stroke) and controls. PZ polymorphisms G79A (rs3024735) and A13G (2273971) were genotyped. A combined genetic score (0–4 minor alleles) was created assuming additive effects. A total of 715 individuals (1:1.4 cases:controls) was included. Analyses revealed evidence of a non-linear association. After adjusting for demographic and clinical covariates, PZ levels >2.5 µg/ml (90^th %ile) were significantly associated with cryptogenic stroke (OR 2.41 [95 % CI 1.34, 4.34]) as compared with lower levels. Higher genetic score was related to progressively lower levels of PZ, and the presence of four minor alleles was associated with lower odds of stroke (adjusted OR 0.26 [95 % CI 0.07, 0.96]) versus 0 minor alleles. In this multi-ethnic study of young and middle-aged adults, there was evidence of a nonlinear positive association between PZ level and unexplained stroke, with a directionally consistent association for genetic variants related to PZ levels and cryptogenic stroke. These findings support elevated PZ levels as a risk factor for cryptogenic stroke.

Keywords

Biomarkers - genetic association studies - plasma protein Z - risk factors - stroke

Full Text

References

References
1 Prowse CV, Esnouf MP. The isolation of a new warfarin-sensitive protein from bovine plasma. Biochem Soc Trans 1977; 05: 255-256.
2 Broze Jr GJ, Miletich JP. Human Protein Z. J Clin Invest 1984; 73: 933-938.
3 Hogg PJ, Stenflo J. Interaction of vitamin K-dependent protein Z with thrombin Consequences for the amidolytic activity of thrombin and the interaction of thrombin with phospholipid vesicles. J Biol Chem 1991; 266: 10953-10958.
4 Han X, Fiehler R, Broze Jr GJ. Isolation of a protein Z-dependent plasma protease inhibitor. Proc Natl Acad Sci USA 1998; 95: 9250-9255.
5 Han X, Fiehler R, Broze Jr. GJ. Characterization of the protein Z-dependent protease inhibitor. Blood 2000; 96: 3049-3055.
6 Vasse M, Guegan-Massardier E, Borg JY, Woimant F, Soria C. Frequency of protein Z deficiency in patients with ischaemic stroke. Lancet 2001; 357: 933-934.
7 Yin ZF, Huang ZF, Cui J. et al. Prothrombotic phenotype of protein Z deficiency. Proc Natl Acad Sci USA 2000; 97: 6734-6738.
8 Kobelt K, Biasiutti FD, Mattle HP. et al. Protein Z in ischaemic stroke. Br J Haematol 2001; 114: 169-173.
9 Heeb MJ, Paganini-Hill A, Griffin JH, Fisher M. Low protein Z levels and risk of ischaemic stroke: differences by diabetic status and gender. Blood Cells Mol Dis 2002; 29: 139-144.
10 Heeb MJ, Fisher M, Paganini-Hill A. Association of low protein Z levels with ischaemic stroke in young women. Thromb Haemost 2007; 97: 495-496.
11 Lopaciuk S, Bykowska K, Kwiecinski H. et al. Protein Z in young survivors of ischaemic stroke. Thromb Haemost 2002; 88: 536.
12 McQuillan AM, Eikelboom JW, Hankey GJ. et al. Protein Z in ischaemic stroke and its aetiologic subtypes. Stroke 2003; 34: 2415-2419.
13 Fedi S, Sofi F, Brogi D. et al. Low protein Z plasma levels are independently associated with acute coronary syndromes. Thromb Haemost 2003; 90: 1173-1178.
14 Sofi F, Cesari F, Abbate R. et al. A meta-analysis of potential risks of low levels of protein Z for diseases related to vascular thrombosis. Thromb Haemost 2010; 103: 749-756.
15 Morange PE, Juhan-Vague I. Protein Z plasma levels are not associated with the risk of coronary heart disease: the PRIME Study. J Thromb Haemost 2004; 02: 2050-2051.
16 Refaai MA, Ahn C, Lu L. et al. Protein Z and ZPI levels and cardiovascular events. J Thromb Haemost 2006; 04: 1628-1629.
17 Al-Shanqeeti A, van Hylckama Vlieg A, Berntorp E. et al. Protein Z and protein Z-dependent protease inhibitor Determinants of levels and risk of venous thrombosis. Thromb Haemost 2005; 93: 411-413.
18 Martinelli I, Razzari C, Biguzzi E. et al. Low levels of protein Z and the risk of venous thromboembolism. J Thromb Haemost 2005; 03: 2817-2819.
19 Santacroce R, Sarno M, Cappucci F. et al. Low protein Z levels and risk of occurrence of deep vein thrombosis. J Thromb Haemost 2006; 04: 2417-2422.
20 Santacroce R, Cappucci F, Di Perna P. et al. Protein Z gene polymorphisms are associated with protein Z plasma levels. J Thromb Haemost 2004; 02: 1197-1199.
21 Lichy C, Kropp S, Dong-Si T. et al. A common polymorphism of the protein Z gene is associated with protein Z plasma levels and with risk of cerebral ischaemia in the young. Stroke 2004; 35: 40-45.
22 Staton J, Sayer M, Hankey GJ. et al. Protein Z gene polymorphisms, protein Z concentrations, and ischaemic stroke. Stroke 2005; 36: 1123-1127.
23 Obach V, Munoz X, Sala N. et al. Intronic c.573 + 79G>A polymorphism of protein Z gene in haemorrhagic and ischaemic stroke. Thromb Haemost 2006; 95: 1040-1041.
24 Beheshtian A, Shitole SG, Segal AZ. et al. Lipoprotein(a) level, apolipoprotein(a) size, and risk of unexplained ischaemic stroke in young and middle-aged adults. Atherosclerosis 2016; 253: 47-53.
25 Adams Jr HP, Bendixen BH, Kappelle LJ. et al. Classification of subtype of acute ischaemic stroke Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24: 35-41.
26 Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Headache Classification Committee of the International Headache Society. Cephalalgia 1988; 08 (Suppl. 07) 1-96.
27 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 04: 295-306.
28 WS Cleveland RM. Graphical Perception: Theory, Experimentation, and Application to the Development of Graphical Methods. J Am Stat Assoc 1984; 79: 531-554.
29 Austin PC, Steyerberg EW. Graphical assessment of internal and external calibration of logistic regression models by using loess smoothers. Stat Med 2014; 33: 517-535.
30 Miletich JP, Broze Jr GJ. Human plasma protein Z antigen: range in normal subjects and effect of warfarin therapy. Blood 1987; 69: 1580-1586.
31 Nowak-Gottl U, Frohlich B, Thedieck S. et al. Association of the protein Z ATG haplotype with symptomatic nonvascular stroke or thromboembolism in white children: a family-based cohort study. Blood 2009; 113: 2336-2341.
32 Butschkau A, Wagner NM, Genz B. et al. Protein z exerts pro-angiogenic effects and upregulates CXCR4. PLoS One 2014; 09: e113554.

Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults[ * ]

Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults^{[
^*
]}