Evidence map›Paper›PMID 39383998›Full record

ArticleJournal of thrombosis and haemostasis : JTH2025

Loss of function in protein Z (PROZ) is associated with increased risk of ischemic stroke in the UK Biobank.

Amelia K Haj, Justine Ryu, Sean J Jurgens, Sharjeel Chaudhry, Satoshi Koyama, Xin Wang, Seung Hoan Choi, Cody Hou, Simone Sanna-Cherchi, Christopher D Anderson and 2 more

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Article in Journal of thrombosis and haemostasis : JTH, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Amelia K HajDepartment of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Justine RyuCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Section of Hematology, Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Sean J JurgensCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA; Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Sharjeel ChaudhryCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Satoshi KoyamaCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Xin WangCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Seung Hoan ChoiCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Cody HouCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Simone Sanna-CherchiDivision of Nephrology, Columbia University Irving Medical Center, New York, New York, USA.
Christopher D AndersonCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Patrick T EllinorCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
Pavan K BendapudiCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA; Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; Division of Hematology and Blood Transfusion Service, Massachusetts General Hospital, Boston, Massachusetts, USA. Electronic address: pbendapudi@mgb.org.

Funding

IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVALR01HL092577 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI BENJAMIN, EMELIA J., ELLINOR, PATRICK THOMAS · 2009 to 2025
$20.6M
Genomics of Cardiac ArrhythmiasR01HL139731 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI ELLINOR, PATRICK THOMAS · 2018 to 2022
$3.3M
Coagulation Factor XII Recruitment and Activation During Thrombus FormationR01HL166246 · NHLBI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI Pavan Bendapudi · 2023 to 2026
$2.8M
Mechanisms of Coagulation Factor XII Recruitment and Activation at the Platelet SurfaceR03HL162761 · NHLBI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI BENDAPUDI, PAVAN · 2022 to 2023
$173k
NHLBI NIH HHS R01 HL092577NHLBI NIH HHS R01 HL139731NHLBI NIH HHS R01 HL166246NHLBI NIH HHS R03 HL162761
6 · The paper itself

Abstract

backgroundThe vitamin K-dependent coagulation factor protein Z (PZ), encoded by the PROZ gene, is canonically considered to have anticoagulant effects through negative regulation of factor Xa. Paradoxically, higher circulating PZ concentrations have repeatedly been associated with an elevated risk of acute ischemic stroke.

objectivesWe performed a large-scale genetic association study to examine the relationship between germline genetic variants in PROZ and the risk of ischemic stroke.

methodsUsing whole-exome sequencing and clinical data for 416 711 participants in the UK Biobank (UKB), we identified individuals with rare (minor allele frequency ≤0.1%) putatively function-altering variants in PROZ. Using Firth's logistic regression and controlling for known stroke risk factors, we evaluated the association between variant carrier status and noncardioembolic ischemic stroke (NCEIS). Additionally, we evaluated differences in the plasma levels of 1472 proteins between PROZ variant carriers and noncarriers in a subset of 48 893 UKB participants.

resultsAfter accounting for missing data, qualifying variants in PROZ were identified in 414 UKB participants (99.0% heterozygous). Variant carriers had a significantly increased risk of NCEIS (odds ratio, 2.34; 95% CI, 1.15-4.13; P = .02) but not of venous thromboembolism, myocardial infarction, or peripheral artery disease. Plasma proteomics analysis revealed that PROZ variant carriers had significantly elevated levels of 2 proteins related to the response to cerebral ischemia, peroxiredoxins 1 and 6 (PRDX1: fold change, 1.83; P = 1.3 × 10

conclusionLifelong exposure to decreased PZ levels confers a significantly increased risk of NCEIS, consistent with the role of PZ as an anticoagulant factor.

Indexed as

Blood Coagulation FactorsIschemic StrokeLoss of Function MutationAgedBiological Specimen BanksBlood ProteinsExome SequencingFemaleGene FrequencyGenetic Association StudiesGenetic Predisposition to DiseaseHeterozygoteHumansMaleMiddle AgedPhenotypeBlood Coagulation FactorsBlood Proteinsplasma protein Zgenomicsischemic strokeproteomicsthrombosis

Identifiers

PMID39383998
PMCPMC11725435

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.