在英国生物库中,蛋白质 Z (PROZ) 功能缺失与缺血性中风风险增加有关。

IF 5.5 2区 医学 Q1 HEMATOLOGY Journal of Thrombosis and Haemostasis Pub Date : 2024-10-09 DOI:10.1016/j.jtha.2024.09.016
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
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引用次数: 0

摘要

背景:由PROZ基因编码的维生素K依赖性凝血因子蛋白Z(PZ)被认为通过对因子Xa的负性调节而具有抗凝作用。与此相矛盾的是,循环中 PZ 浓度的升高多次与急性缺血性中风风险的升高有关:我们进行了一项大规模遗传关联研究,以探讨 PROZ 的种系遗传变异与缺血性中风风险之间的关系:利用英国生物库(UKB)中 416,711 名参与者的全外显子组测序和临床数据,我们发现了 PROZ 中存在罕见(MAF ≤ 0.1%)可能改变功能变异的个体。利用 Firth 的逻辑回归并控制已知的卒中风险因素,我们评估了变异体携带者状态与非心栓性缺血性卒中(NCEIS)之间的关联。此外,我们还评估了 48,893 名 UKB 参与者子集中 1,472 种蛋白质在 PROZ 变异携带者和非携带者之间的血浆水平差异:结果:在考虑了缺失数据后,414 名英国广播公司参与者(99.0% 为杂合)中的 PROZ 变异被鉴定为合格。变异携带者罹患NCEIS的风险明显增加(OR=2.34,95% CI:1.15-4.13,P=0.02),但罹患静脉血栓栓塞、心肌梗死或外周动脉疾病的风险没有增加。血浆蛋白质组学分析显示,PROZ变异携带者体内两种与脑缺血反应有关的蛋白质--过氧化物酶1和6(PRDX1,折变=1.83,P=1.3 x 10-5;PRDX6,折变=1.78,P=9.6 x 10-10)的水平显著升高:终生暴露于 PZ 水平下降的环境中会显著增加罹患 NCEIS 的风险,这与 PZ 作为抗凝因子的作用是一致的。
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Loss of function in protein Z (PROZ) is associated with increased risk of ischemic stroke in the UK Biobank.

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.

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来源期刊
Journal of Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis 医学-外周血管病
CiteScore
24.30
自引率
3.80%
发文量
321
审稿时长
1 months
期刊介绍: The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community. Types of Publications: The journal publishes a variety of content, including: Original research reports State-of-the-art reviews Brief reports Case reports Invited commentaries on publications in the Journal Forum articles Correspondence Announcements Scope of Contributions: Editors invite contributions from both fundamental and clinical domains. These include: Basic manuscripts on blood coagulation and fibrinolysis Studies on proteins and reactions related to thrombosis and haemostasis Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.
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