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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Authors

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

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

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

Authors

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