慢性阻塞性肺疾病（COPD）和COPD急性加重的多性状多基因评分涉及可成药蛋白。

Multi-Trait Polygenic Scores for COPD and COPD Exacerbations Implicate Druggable Proteins.

作者信息

Zhang Chengyue, Konigsberg Iain R, He Yixuan, Zhang Jingzhou, Chikowore Tinashe, Feldman William B, Hu Xiaowei, Ding Yi, Pasaniuc Bogdan, Chang Diana, Chen Qingwen, Lasky-Su Jessica A, Hecker Julian, Tobin Martin D, Chen Jing, Kalra Sean, Pratte Katherine A, Im Hae Kyung, Wan Emily S, Manichaikul Ani, Silverman Edwin K, Bowler Russell P, Lange Leslie A, Ortega Victor E, Martin Alicia R, Cho Michael H, Moll Matthew R

机构信息

Channing Division of Network Medicine, Mass General Brigham, Boston, MA.

Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO.

出版信息

medRxiv. 2025 Aug 26:2025.08.22.25334001. doi: 10.1101/2025.08.22.25334001.

OBJECTIVES

To construct multi-trait polygenic scores (PRS) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validate their performance in diverse cohorts, and identify PRS-related proteins for potential therapeutic targeting.

DESIGN

Prospective cohort studies.

SETTING

Genetic Epidemiology of COPD (COPDGene; 2007-present), Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE; 2005-2008), Mass General Brigham Biobank (MGBB; 2010-present), All of Us (2016-present), and UK Biobank (UKB; 2006-present).

PARTICIPANTS

6,647 non-Hispanic White (NHW) and 2,466 African American (AA) participants from COPDGene; 1,858 participants from ECLIPSE; 118,566 from All of Us; 15,142 from MGBB with genetic data. 5,173 COPDGene and 5,012 UKB participants with proteomic data.

MAIN OUTCOME MEASURES

COPD status (GOLD 2-4 vs. GOLD 0) and COPD exacerbation frequency.

RESULTS

PRSmix+, a multi-trait PRS framework, selected 7 traits for a composite PRS (PRS). In multivariable models, PRS was associated with COPD status (meta-analysis random effects (RE) OR 1.58 [95% CI: 1.28-1.94]) and exacerbation frequency (meta-analysis RE beta 0.21 [95% CI: 0.11-0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRS outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRS that were also validated with measured protein levels in COPDGene and UK biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include AGER (RAGE), IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations.

CONCLUSIONS

Multi-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management.

TRIAL REGISTRATION

COPDGene: NCT00608764; ECLIPSE: NCT00292552.

目的

构建预测慢性阻塞性肺疾病（COPD）及其急性加重的多性状多基因评分（PRS），在不同队列中验证其性能，并识别与PRS相关的蛋白质以进行潜在的治疗靶向。

设计

前瞻性队列研究。

设置

COPD基因流行病学研究（COPDGene；2007年至今）、纵向评估COPD以识别预测性替代终点研究（ECLIPSE；2005 - 2008年）、麻省总医院布莱根生物样本库（MGBB；2010年至今）、全民健康研究项目（All of Us；2016年至今）以及英国生物样本库（UKB；2006年至今）。

参与者

来自COPDGene的6647名非西班牙裔白人（NHW）和2466名非裔美国人（AA）参与者；来自ECLIPSE的1858名参与者；来自全民健康研究项目的118566名参与者；来自MGBB的15142名有基因数据的参与者。来自COPDGene和英国生物样本库的5173名和5012名有蛋白质组学数据的参与者。

主要观察指标

COPD状态（GOLD 2 - 4级与GOLD 0级）和COPD急性加重频率。

结果

PRSmix +，一种多性状PRS框架，为综合PRS（PRS）选择了7个性状。在多变量模型中，PRS与COPD状态（荟萃分析随机效应（RE）比值比1.58 [95%可信区间：1.28 - 1.94]）和急性加重频率（荟萃分析REβ值0.21 [95%可信区间：0.11 - 0.31]）相关，在吸烟人群富集的队列中观察到更高的效应量。在所有测试队列中，PRS的表现均优于传统的单性状PRS。使用蛋白质预测模型，我们识别出73种与PRS相关的蛋白质，这些蛋白质在COPDGene和英国生物样本库中也通过测量的蛋白质水平得到了验证。其中25种蛋白质与已批准或正在研究的药物有关。值得注意的靶点包括AGER（RAGE）、IL1RL1和SCARF2，它们均与COPD发病机制和急性加重有关。

结论

多性状PRS改善了对COPD及其急性加重风险的预测。与蛋白质组学数据相结合可识别出可成药的蛋白质靶点，为COPD管理中的精准医学提供了一条有前景的途径。

试验注册

COPDGene：NCT00608764；ECLIPSE：NCT00292552。