Aggarwal Mohit, Hwang Shih-Jen, Lee Dong Heon, Huan Tianxiao, McNeill Jenna N, Courchesne Paul, Joehanes Roby, Ho Jennifer E, Dupuis Josée, Hedman Åsa K, O'Connor George, Levy Daniel
Framingham Heart Study, Framingham, MA; Population Sciences Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
Pulmonary, Allergy and Critical Care Medicine, Duke University Hospital, Durham, NC.
Chest. 2025 Jun;167(6):1557-1577. doi: 10.1016/j.chest.2024.11.012. Epub 2024 Nov 22.
Impaired pulmonary function carries significant risks for lung, cardiovascular, and metabolic disorders.
Can circulating protein biomarkers of pulmonary function provide insight into the pathophysiologic features of lung function impairment and links to comorbidities?
We analyzed plasma levels of 2,922 proteins in 32,493 UK Biobank participants (53% female; mean [SD] age, 57 [8] years) to investigate their associations with spirometry measures of lung function (FEV, FVC, FEV to FVC ratio), and with obstructive (n = 4,713) and restrictive (n = 3,886) spirometry patterns. Significant protein signatures were annotated functionally and validated externally in 740 Framingham Heart Study (FHS) participants. We inferred causality using Mendelian randomization and examined colocalization of genetic signals of protein biomarkers with corresponding lung traits.
In the UK Biobank, we identified 1,240 proteins associated significantly (P < .000017 observed in the UK Biobank) with FEV, 1,310 proteins associated significantly with FVC, and 513 proteins associated significantly with FEV to FVC ratio. Of these, 44, 99, and 13 proteins, respectively, were nominally significant (P < .01 obeserved in the FHS) in the FHS. Plasma levels of 737 proteins (seven with P < .01 obeserved in the FHS) differed in individuals with an obstructive spirometry pattern (OSP), and 811 proteins (38 with P < .01 obeserved in the FHS) differed in restrictive spirometry pattern compared with normal spirometry in the UK Biobank. Putatively causal relationships to FEV, FVC, FEV to FVC ratio, and OSP were observed for 55, 63, 28, and 14 proteins, respectively. Of note, several circulating decoy receptors, including IL-1 receptor-like 1, tumor necrosis factor receptor superfamily member-6B, and macrophage scavenger receptor-1, emerged as causal and protective biomarkers of lung function. Enrichment analysis suggested a connection between reduced lung function and systemic inflammation driven by adipose tissue dysfunction and gut dysbiosis. Protein biomarkers associated with lung function also were enriched for susceptibility to cardiovascular conditions and cancers.
This study identified proteomic signatures of reduced lung function linked to comorbidities, paving the way for improved diagnostics for and treatment of lung disease.
肺功能受损会给肺部、心血管和代谢紊乱带来重大风险。
肺功能的循环蛋白生物标志物能否深入了解肺功能损害的病理生理特征以及与合并症的联系？
我们分析了32493名英国生物银行参与者（53%为女性；平均[标准差]年龄，57[8]岁）血浆中2922种蛋白质的水平，以研究它们与肺功能的肺活量测定指标（第一秒用力呼气容积[FEV]、用力肺活量[FVC]、FEV与FVC比值）以及阻塞性（n = 4713）和限制性（n = 3886）肺活量测定模式之间的关联。对显著的蛋白质特征进行功能注释，并在740名弗雷明汉心脏研究（FHS）参与者中进行外部验证。我们使用孟德尔随机化推断因果关系，并检查蛋白质生物标志物的遗传信号与相应肺特征的共定位。
在英国生物银行中，我们鉴定出1240种与FEV显著相关（在英国生物银行中观察到P < .000017）的蛋白质、1310种与FVC显著相关的蛋白质以及513种与FEV与FVC比值显著相关的蛋白质。其中，分别有44、99和13种蛋白质在FHS中具有名义显著性（在FHS中观察到P < .01）。在英国生物银行中，与正常肺活量测定相比，737种蛋白质（7种在FHS中观察到P < .01）的血浆水平在具有阻塞性肺活量测定模式（OSP）的个体中有所不同，811种蛋白质（38种在FHS中观察到P < .01）的血浆水平在限制性肺活量测定模式中有所不同。分别观察到55、63、28和14种蛋白质与FEV、FVC、FEV与FVC比值和OSP存在推定的因果关系。值得注意的是，几种循环诱饵受体，包括白细胞介素-1受体样1、肿瘤坏死因子受体超家族成员-6B和巨噬细胞清道夫受体-1，成为肺功能的因果性和保护性生物标志物。富集分析表明，肺功能下降与由脂肪组织功能障碍和肠道菌群失调驱动的全身炎症之间存在联系。与肺功能相关的蛋白质生物标志物在心血管疾病和癌症易感性方面也有富集。
本研究确定了与合并症相关的肺功能降低的蛋白质组特征，为改善肺部疾病的诊断和治疗铺平了道路。
