Clustering Pulmonary Hypertension Patients Using the Plasma Proteome.

IF 19.3 1区医学 Q1 CRITICAL CARE MEDICINE

American journal of respiratory and critical care medicine Pub Date : 2025-05-09

Athénaïs Boucly, Shanshan Song, Merve Keles, Dennis Wang, Luke S Howard, Marc Humbert, Olivier Sitbon, Allan Lawrie, A A Roger Thompson, Philipp Frank, Mika Kivimaki, Christopher J Rhodes, Martin R Wilkins

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Abstract

Introduction: Patients with pulmonary hypertension are classified according to clinical criteria to inform treatment decisions. Knowledge of the molecular drivers of pulmonary hypertension might better inform treatment choice.

Methods: Between 2013 and 2021, 470 patients with pulmonary hypertension, 136 disease controls and 59 healthy controls were enrolled as a discovery cohort. Plasma levels of 7288 proteins were assayed (SomaScan 7K platform). Proteins that distinguished pulmonary hypertension from both control groups were selected for unsupervised clustering (k-means clustering of UMAP dimensions). Clinical characteristics and outcomes were compared across clusters. Separate cohorts of serially sampled patients from pulmonary hypertension centers in the United Kingdom (n=229) and France (n=79) provided independent validation.

Results: 156 plasma proteins that distinguished pulmonary hypertension from disease and healthy controls formed 4 clusters with diverse 5-year survival rates: 78% (cluster 4), 62% (cluster 2), 44% (cluster 3), and 33% (cluster 1). The distinction and clinical relevance of the clusters were confirmed in validation cohorts by their association with survival. To further characterise the therapeutic relevance of the clusters we investigated 2 experimental drug targets: the Platelet-Derived Growth Factor (PDGF) pathway was up-regulated in cluster 3 compared to other clusters and the Transforming Growth Factor-β (TGF-β) pathway was up-regulated in cluster 1.

Conclusion: Plasma proteomic profiling of patients with pulmonary hypertension distinguishes 4 clusters, independent of the clinical classification. These groups, based on differential plasma protein levels, could act as theragnostic biomarkers for new therapies targeting PDGF and TGF-β pathways. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

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血浆蛋白质组学对肺动脉高压患者的聚类分析

简介：根据临床标准对肺动脉高压患者进行分类，以指导治疗决策。了解肺动脉高压的分子驱动因素可以更好地为治疗选择提供信息。方法：2013年至2021年间，纳入470例肺动脉高压患者、136例疾病对照者和59例健康对照者作为发现队列。检测血浆7288蛋白水平（SomaScan 7K平台）。选择与两个对照组区分肺动脉高压的蛋白进行无监督聚类（UMAP维度的k-均值聚类）。比较各组间的临床特征和结果。来自英国（n=229）和法国（n=79）肺动脉高压中心的连续抽样患者的单独队列提供了独立的验证。结果：156种血浆蛋白可将肺动脉高压与疾病和健康对照区分开，形成4个簇，5年生存率不同：78%（簇4）、62%（簇2）、44%（簇3）和33%（簇1）。这些群集的区别和临床相关性在验证队列中通过它们与生存的关联得到证实。为了进一步表征这些集群的治疗相关性，我们研究了2个实验药物靶点：与其他集群相比，血小板衍生生长因子（PDGF）途径在集群3中上调，转化生长因子-β (TGF-β)途径在集群1中上调。结论：肺动脉高压患者血浆蛋白质组学分析可区分4个簇，与临床分型无关。这些基于血浆蛋白水平差异的组可以作为针对PDGF和TGF-β途径的新疗法的诊断性生物标志物。本文在知识共享署名4.0国际许可协议（https://creativecommons.org/licenses/by/4.0/）的条款下开放获取和分发。

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来源期刊

American journal of respiratory and critical care medicine 医学-呼吸系统

CiteScore

27.30

自引率

4.50%

发文量

1313

审稿时长

3-6 weeks

期刊介绍： The American Journal of Respiratory and Critical Care Medicine focuses on human biology and disease, as well as animal studies that contribute to the understanding of pathophysiology and treatment of diseases that affect the respiratory system and critically ill patients. Papers that are solely or predominantly based in cell and molecular biology are published in the companion journal, the American Journal of Respiratory Cell and Molecular Biology. The Journal also seeks to publish clinical trials and outstanding review articles on areas of interest in several forms. The State-of-the-Art review is a treatise usually covering a broad field that brings bench research to the bedside. Shorter reviews are published as Critical Care Perspectives or Pulmonary Perspectives. These are generally focused on a more limited area and advance a concerted opinion about care for a specific process. Concise Clinical Reviews provide an evidence-based synthesis of the literature pertaining to topics of fundamental importance to the practice of pulmonary, critical care, and sleep medicine. Images providing advances or unusual contributions to the field are published as Images in Pulmonary, Critical Care, Sleep Medicine and the Sciences. A recent trend and future direction of the Journal has been to include debates of a topical nature on issues of importance in pulmonary and critical care medicine and to the membership of the American Thoracic Society. Other recent changes have included encompassing works from the field of critical care medicine and the extension of the editorial governing of journal policy to colleagues outside of the United States of America. The focus and direction of the Journal is to establish an international forum for state-of-the-art respiratory and critical care medicine.