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 Kizer

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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 (90th %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.

Original languageEnglish (US)
Pages (from-to)149-157
Number of pages9
JournalThrombosis and Haemostasis
Volume117
Issue number1
DOIs
StatePublished - 2017

Fingerprint

Cerebral Infarction
Stroke
Alleles
plasma protein Z
Vitamin K
Anticoagulants
Case-Control Studies
Blood Proteins
Demography

Keywords

  • Biomarkers
  • Genetic association studies
  • Plasma protein Z
  • Risk factors
  • Stroke

ASJC Scopus subject areas

  • Hematology

Cite this

Zhang, L., Segal, A. Z., Leifer, D., Silverstein, R. L., Gerber, L. M., Devereux, R. B., & Kizer, J. (2017). Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults. Thrombosis and Haemostasis, 117(1), 149-157. https://doi.org/10.1160/TH16-04-0277

Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults. / Zhang, Lili; Segal, Alan Z.; Leifer, Dana; Silverstein, Roy L.; Gerber, Linda M.; Devereux, Richard B.; Kizer, Jorge.

In: Thrombosis and Haemostasis, Vol. 117, No. 1, 2017, p. 149-157.

Research output: Contribution to journalArticle

Zhang, L, Segal, AZ, Leifer, D, Silverstein, RL, Gerber, LM, Devereux, RB & Kizer, J 2017, 'Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults', Thrombosis and Haemostasis, vol. 117, no. 1, pp. 149-157. https://doi.org/10.1160/TH16-04-0277
Zhang, Lili ; Segal, Alan Z. ; Leifer, Dana ; Silverstein, Roy L. ; Gerber, Linda M. ; Devereux, Richard B. ; Kizer, Jorge. / Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults. In: Thrombosis and Haemostasis. 2017 ; Vol. 117, No. 1. pp. 149-157.
@article{30d56a9e876547d8ad979979325cbcbd,
title = "Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults",
abstract = "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 (90th {\%}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",
author = "Lili Zhang and Segal, {Alan Z.} and Dana Leifer and Silverstein, {Roy L.} and Gerber, {Linda M.} and Devereux, {Richard B.} and Jorge Kizer",
year = "2017",
doi = "10.1160/TH16-04-0277",
language = "English (US)",
volume = "117",
pages = "149--157",
journal = "Thrombosis and Haemostasis",
issn = "0340-6245",
publisher = "Schattauer GmbH",
number = "1",

}

TY - JOUR

T1 - Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults

AU - Zhang, Lili

AU - Segal, Alan Z.

AU - Leifer, Dana

AU - Silverstein, Roy L.

AU - Gerber, Linda M.

AU - Devereux, Richard B.

AU - Kizer, Jorge

PY - 2017

Y1 - 2017

N2 - 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 (90th %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.

AB - 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 (90th %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.

KW - Biomarkers

KW - Genetic association studies

KW - Plasma protein Z

KW - Risk factors

KW - Stroke

UR - http://www.scopus.com/inward/record.url?scp=85007367223&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85007367223&partnerID=8YFLogxK

U2 - 10.1160/TH16-04-0277

DO - 10.1160/TH16-04-0277

M3 - Article

C2 - 27683756

AN - SCOPUS:85007367223

VL - 117

SP - 149

EP - 157

JO - Thrombosis and Haemostasis

JF - Thrombosis and Haemostasis

SN - 0340-6245

IS - 1

ER -