Elhusseini Zaid W, Rafique Omar, Ryu Min Hyung, Castaldi Peter, Sin Don D, Ruczinski Ingo, Hersh Craig P
Harvard Medical School.
St. Paul's Hospital, University of British Columbia.
Res Sq. 2025 Aug 19:rs.3.rs-7292685. doi: 10.21203/rs.3.rs-7292685/v1.
Chronic obstructive pulmonary disease (COPD) is characterized by progressive lung function decline, commonly measured by forced expiratory volume in one second (FEV). Uncovering the genetic basis of FEV decline is essential for understanding COPD pathophysiology and for developing therapies. We hypothesized that gene expression patterns in inflammatory pathways are associated with FEV decline.
We analyzed whole blood RNA-sequencing data from the 5 (n = 4,147) and 10 year visits (n = 435) in the COPDGene Study. Gene expression was assessed in three analyses: cross-sectional associations with FEV at two separate time points, association between year 5 gene expression and FEV changes from year 5-10, and longitudinal changes in both gene expression and FEV. A gene signature derived from the 5-year visit was linked to FEV decline across three intervals (baseline to 5 years, 5 to 10 years, and baseline to 10 years) and tested for validation in the ECLIPSE study.
Distinct gene sets emerged in the three analyses (Cross-sectional: 961 genes; FEV Change: 179; Longitudinal: 532). Only two genes ( and ) overlapped across all analyses, while unique genes (e.g., , and ) were context-specific. Pathway analysis of genes from the longitudinal analysis highlighted oxidative stress and immune processes. A 20-gene signature was derived, including 17 genes positively and three negatively associated with FEV. These signatures were significantly associated with FEV-related traits in COPDGene and ECLIPSE.
These findings reveal molecular markers of FEV decline, offering insights into COPD pathophysiology and potential therapeutic targets.
慢性阻塞性肺疾病（COPD）的特征是肺功能进行性下降，通常用一秒用力呼气容积（FEV）来衡量。揭示FEV下降的遗传基础对于理解COPD的病理生理学和开发治疗方法至关重要。我们假设炎症途径中的基因表达模式与FEV下降有关。
我们分析了COPDGene研究中5年（n = 4,147）和10年随访（n = 435）时的全血RNA测序数据。在三项分析中评估基因表达：在两个不同时间点与FEV的横断面关联、5年时的基因表达与5至10年FEV变化之间的关联，以及基因表达和FEV的纵向变化。从5年随访中得出的基因特征与三个时间段（基线至5年、5至十年以及基线至10年）的FEV下降相关，并在ECLIPSE研究中进行了验证测试。
在三项分析中出现了不同的基因集（横断面：961个基因；FEV变化：179个；纵向：532个）。在所有分析中只有两个基因（和）重叠，而独特的基因（例如，和）是特定于上下文的。纵向分析中基因的通路分析突出了氧化应激和免疫过程。得出了一个由20个基因组成的特征，其中17个基因与FEV呈正相关，三个基因与FEV呈负相关。这些特征与COPDGene和ECLIPSE中与FEV相关的特征显著相关。
这些发现揭示了FEV下降的分子标志物，为COPD的病理生理学和潜在治疗靶点提供了见解。
