Rationale: Early detection of respiratory diseases is critical to facilitate delivery of disease-modifying interventions. Extracellular vesicle-enriched microRNAs (EV-miRNAs) may represent reliable markers of early lung injury. Objectives: Evaluate associations of plasma EV-miRNAs with lung function. Methods: The prospective NAS (Normative Aging Study) collected plasma EV-miRNA measurements from 1996-2015 and spirometry every 3-5 years through 2019. Associations of EV-miRNAs with baseline lung function were modeled using linear regression. To complement the individual miRNA approach, unsupervised machine learning was used to identify clusters of participants with distinct EV-miRNA profiles. Associations of EV-miRNA profiles with multivariate latent longitudinal lung function trajectories were modeled using log binomial regression. Biological functions of significant EV-miRNAs were explored using pathway analyses. Results were replicated in an independent sample of NAS participants and in the HEALS (Health Effects of Arsenic Longitudinal Study). Measurements and Main Results: In the main cohort of 656 participants, 51 plasma EV-miRNAs were associated with baseline lung function (false discovery rate-adjusted P value < 0.05), 28 of which were replicated in the independent NAS sample and/or in the HEALS cohort. A subset of participants with distinct EV-miRNA expression patterns had increased risk of declining lung function over time, which was replicated in the independent NAS sample. Significant EV-miRNAs were shown in pathway analyses to target biological pathways that regulate respiratory cellular immunity, the lung inflammatory response, and airway structural integrity. Conclusions: Plasma EV-miRNAs may represent a robust biomarker of subclinical lung injury and may facilitate early identification and treatment of patients at risk of developing overt lung disease.

中文翻译：

---

细胞外囊泡封装的 microRNA 作为肺部健康的新型生物标志物。


理由：早期发现呼吸道疾病对于促进疾病缓解干预措施的实施至关重要。富含细胞外囊泡的 microRNA (EV-miRNA) 可能是早期肺损伤的可靠标志物。目的：评估血浆 EV-miRNA 与肺功能的关联。方法：前瞻性 NAS（规范老化研究）从 1996 年至 2015 年收集血浆 EV-miRNA 测量值，并在 2019 年之前每 3-5 年收集一次肺量测定值。使用线性回归对 EV-miRNA 与基线肺功能的关联进行建模。为了补充个体 miRNA 方法，使用无监督机器学习来识别具有不同 EV-miRNA 图谱的参与者集群。使用对数二项式回归对 EV-miRNA 谱与多变量潜在纵向肺功能轨迹的关联进行建模。使用通路分析探索重要 EV-miRNA 的生物学功能。结果在 NAS 参与者的独立样本和 HEALS（砷的健康影响纵向研究）中得到了重复。测量和主要结果：在 656 名参与者的主要队列中，51 种血浆 EV-miRNA 与基线肺功能相关（错误发现率调整后的 P 值 < 0.05），其中 28 种在独立 NAS 样本和/或治愈队列。随着时间的推移，具有不同 EV-miRNA 表达模式的参与者子集肺功能下降的风险增加，这一点在独立 NAS 样本中得到了复制。通路分析显示，重要的 EV-miRNA 能够靶向调节呼吸细胞免疫、肺部炎症反应和气道结构完整性的生物通路。 结论：血浆 EV-miRNA 可能代表亚临床肺损伤的强有力的生物标志物，并可能有助于早期识别和治疗有明显肺疾病风险的患者。