Therapeutic targets for venous thromboemblism: proteome-wide mendelian randomization and colocalization analyses.

IF 2.6 4区医学 Q2 HEMATOLOGY

Thrombosis Journal Pub Date : 2025-05-26 DOI:10.1186/s12959-025-00733-9

Xiaolong Li, Cheng-Hao Yang, Min Zhou, Min-Yi Yin

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Abstract

Background: Venous thromboembolism (VTE) is a significant global health issue, yet effective therapeutic targets for its prevention and treatment remain elusive. This study aimed to identify plasma proteins causally associated with VTE risk using proteome-wide Mendelian randomization (MR) and colocalization analyses.

Methods: We utilized genome-wide association study (GWAS) data from the UK Biobank and FinnGen cohorts, encompassing 38,573 VTE cases and 946,373 controls. Plasma protein levels were quantified using Olink technology in the UK Biobank Pharma Proteomics Project (UKB-PPP) and SomaScan in the deCODE Health study. MR analysis was performed to assess causal relationships, followed by colocalization analysis to evaluate shared genetic variants. Functional enrichment analyses and molecular docking were conducted to explore biological mechanisms and predict potential therapeutic compounds.

Results: Eight proteins showed significant associations with VTE risk after Bonferroni correction (p < 3.19 × 10^-5). Odds ratios ranged from 0.98 (95% CI: 0.98-0.99) for PLEK to 1.03 (95% CI: 1.02-1.04) for LRP12. Strong colocalization evidence (PH4 ≥ 0.8) was found for LRP12, F11, PLCG2, and ABO. Molecular docking identified promising drug candidates including valine, folic acid, ibrutinib, and simvastatin, with valine showing the strongest binding energy (-32.057 kcal/mol).

Conclusions: This study highlights novel therapeutic targets for VTE and provides insights into potential drug candidates. These findings offer a foundation for future research and drug development aimed at reducing VTE risk.

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静脉血栓栓塞的治疗靶点：蛋白质组全孟德尔随机化和共定位分析。

背景：静脉血栓栓塞（VTE）是一个重要的全球性健康问题，但其预防和治疗的有效治疗靶点仍然难以捉摸。本研究旨在通过蛋白质组范围孟德尔随机化（MR）和共定位分析确定与静脉血栓栓塞风险相关的血浆蛋白。方法：我们利用来自UK Biobank和FinnGen队列的全基因组关联研究（GWAS）数据，包括38,573例静脉血栓栓塞病例和946,373例对照。血浆蛋白水平在英国生物银行药物蛋白质组学项目（UKB-PPP）和解码健康研究中的SomaScan中使用Olink技术进行量化。进行MR分析以评估因果关系，然后进行共定位分析以评估共享遗传变异。通过功能富集分析和分子对接，探索其生物学机制，预测潜在的治疗化合物。结果：8种蛋白与Bonferroni矫正后静脉血栓栓塞风险显著相关（p -5）。PLEK的优势比为0.98 (95% CI: 0.98-0.99)， LRP12的优势比为1.03 （95% CI: 1.02-1.04）。LRP12、F11、PLCG2和ABO有很强的共定位证据（PH4≥0.8）。分子对接确定了有前景的候选药物，包括缬氨酸、叶酸、依鲁替尼和辛伐他汀，缬氨酸的结合能最强（-32.057 kcal/mol）。结论：这项研究突出了静脉血栓栓塞的新治疗靶点，并为潜在的候选药物提供了见解。这些发现为未来旨在降低静脉血栓栓塞风险的研究和药物开发奠定了基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Thrombosis Journal Medicine-Hematology

CiteScore

3.80

自引率

3.20%

发文量

审稿时长

16 weeks

期刊介绍： Thrombosis Journal is an open-access journal that publishes original articles on aspects of clinical and basic research, new methodology, case reports and reviews in the areas of thrombosis. Topics of particular interest include the diagnosis of arterial and venous thrombosis, new antithrombotic treatments, new developments in the understanding, diagnosis and treatments of atherosclerotic vessel disease, relations between haemostasis and vascular disease, hypertension, diabetes, immunology and obesity.