静脉血栓栓塞的遗传概率的发展和验证

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis Pub Date : 2025-05-01 DOI:10.1016/j.rpth.2025.102876

Zhuqing Shi , Ashley J. Mulford , Huy Tran , Michal Filipczak , Song Gao , Stevie Xie , Jason Lobel , Jun Wei , Andrew S. Rifkin , Annabelle Ashworth , Siqun Lilly Zheng , Clay Wiske , David Duggan , Brian T. Helfand , Arman Qamar , Alan R. Sanders , Alfonso J. Tafur , Jianfeng Xu

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引用次数: 0

摘要

Leiden因子（FVL）和凝血酶原基因突变（PGMs）以及最近开发的多基因评分（PGSs）一直与欧洲血统人群的静脉血栓栓塞（VTE）风险相关。目的建立一种结合突变和PGS的风险评估工具。方法采用英国生物银行（UK Biobank）的多变量分析，检验VTE风险与FVL/PGM和PGS的关系。对PGS和FVL/PGM组合的VTE （genprobi -VTE）进行遗传概率分析。分别用观察到的VTE率和连续净重分类指数评价其对FVL/PGM单独的判别和重分类性能。结果在Endeavor Health的基因组健康倡议中得到了验证，这是一个基于祖先多样化医疗保健系统的生物库。结果在英国生物银行的432,831名参与者中，FVL、PGM和PGS与静脉血栓栓塞风险显著且独立相关(P <；措施)。与单独使用FVL/PGM相比，genprobi -VTE检测到的VTE发生率比FVL/PGM携带者高1.5倍。genprobi -VTE还显著地将VTE风险从单独使用FVL/PGM的模型中重新分类，连续净重新分类指数为0.10 (P <；措施)。VTE风险在FVL/PGM杂合子携带者（51%）、纯合子/复合杂合子携带者（46%）和非携带者（14%）中重新分类。这些结果在基因组健康计划的16341名参与者中得到了验证，参与者包括欧洲和非欧洲血统。结论在不同祖先人群中，与单独使用FVL/PGM相比，将PGS与FVL/PGM结合使用的优化工具genprobi -VTE可显著改善VTE风险评估。它为静脉血栓栓塞的遗传风险评估提供了一种新的工具。

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Development and validation of a genetic probability for venous thromboembolism

Background

Factor V Leiden (FVL) and prothrombin gene mutations (PGMs), as well as recently developed polygenic scores (PGSs), have been consistently associated with venous thromboembolism (VTE) risk in European ancestry populations.

Objectives

This study aimed to develop an optimized risk-assessment tool combining mutations and PGS for diverse ancestry populations.

Methods

The association of VTE risk with FVL/PGM and PGS was tested using multivariable analyses in the UK Biobank. A genetic probability for VTE (GenProb-VTE) combining PGS and FVL/PGM was developed. Its discriminative and reclassification performances over FVL/PGM alone were assessed using observed VTE rate and the continuous net reclassification index, respectively. Results were validated in the Genomic Health Initiative of Endeavor Health, an ancestry-diverse health care system–based biobank.

Results

Among 432,831 participants in the UK Biobank, FVL, PGM, and PGS were significantly and independently associated with VTE risk (P < .001). Compared with FVL/PGM alone, GenProb-VTE identified 1.5 times more high-risk subjects whose observed VTE rates exceeded those of FVL/PGM carriers. GenProb-VTE also significantly reclassified VTE risk from the model with FVL/PGM alone, with continuous net reclassification index of 0.10 (P < .001). VTE risk was reclassified in FVL/PGM heterozygous carriers (51%) and homozygous/compound heterozygous carriers (46%) as well as noncarriers (14%). These results were validated among 16,341 participants in the Genomic Health Initiative, in participants of both European and non-European ancestry.

Conclusion

GenProb-VTE, an optimized tool combining PGS with FVL/PGM, significantly improves VTE risk assessment compared with FVL/PGM alone in diverse ancestry populations. It provides a novel tool for genetic risk assessment of VTE.

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