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; Patrick T Ellinor; Pavan K Bendapudi

doi:10.1016/j.jtha.2024.09.016

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

J Thromb Haemost. 2024 Oct 9:S1538-7836(24)00564-6. doi: 10.1016/j.jtha.2024.09.016. Online ahead of print.

Authors

Affiliations

¹ Department 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.
² Cardiovascular 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.
³ Cardiovascular 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.
⁴ Cardiovascular 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.
⁵ Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁶ Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
⁷ Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA.
⁸ Cardiovascular 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.
⁹ Cardiovascular 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.
¹⁰ Cardiovascular 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: [email protected].

PMID: 39383998
DOI: 10.1016/j.jtha.2024.09.016

Abstract

Background: The 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.

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

Methods: Using 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.

Results: After 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^-5; PRDX6: fold change, 1.78; P = 9.6 × 10^-10).

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

Keywords: genomics; ischemic stroke; proteomics; thrombosis.