Rose Jonathan A, Steele Mark P, Kosak Lopez Esteban J, Axelsson Gisli Thor, Galecio Chao Andrea G, Waich Alan, Regan Katie, Gulati Swati, Maeda Anthony H, Sultana Sharmin, Cutting Claire, Tukpah Ann-Marcia C, Synn Andrew J, Rice Mary B, Goldberg Hilary J, Lee Joyce S, Lynch David A, Putman Rachel K, Hatabu Hiroto, Raby Benjamin A, Schwartz David A, Rosas Ivan O, Hunninghake Gary M
Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
These authors contributed equally to this work.
Eur Respir J. 2025 Jun 5;65(6). doi: 10.1183/13993003.01349-2024. Print 2025 Jun.
First-degree relatives of patients with pulmonary fibrosis (referred to here as relatives) are at high risk for interstitial lung abnormalities (ILA), highlighting the need for biomarkers for risk prediction. We aimed to identify blood proteins associated with and predictive of ILA among relatives of patients with pulmonary fibrosis.
Relatives enrolled in two independent cohorts had protein levels measured using an aptamer-based proteomic platform. ILA were assessed with computed tomography scans as per Fleischner Society recommendations. Protein associations with ILA were assessed using regression. Significant proteins were used with clinical variables to detect ILA.
Of 237 relatives from two independent cohorts, 26% had ILA. Seven proteins were associated with ILA in the discovery cohort after false discovery rate adjustment, and all remained significant after adjusting for age, gender and smoking status. Six of the seven proteins were significantly associated in the validation cohort, including growth differentiation factor 15, surfactant protein D and surfactant protein B. In a multivariable model, six proteins combined with basic demographics in the discovery cohort had an area under the curve of 0.92 (0.88 in the validation cohort). Least absolute shrinkage and selection operator modelling identified three proteins and age as predictors, with an area under the curve of 0.89 in the validation cohort. When applied to the combined cohorts, this simple model would reduce the need for computed tomography imaging in one of every three relatives screened.
Peripheral blood proteins are associated with ILA in relatives of patients with pulmonary fibrosis and can be used to detect them. Our findings demonstrate the potential use of blood biomarkers in this high-risk group and suggest molecular targets for future investigation.
肺纤维化患者的一级亲属（以下简称亲属）发生间质性肺异常（ILA）的风险很高，这凸显了对风险预测生物标志物的需求。我们旨在识别与肺纤维化患者亲属中ILA相关并可预测ILA的血液蛋白。
纳入两个独立队列的亲属使用基于适体的蛋白质组学平台测量蛋白质水平。根据弗莱施纳学会的建议，通过计算机断层扫描评估ILA。使用回归分析评估蛋白质与ILA的关联。将显著的蛋白质与临床变量结合起来以检测ILA。
在来自两个独立队列的237名亲属中，26%有ILA。在发现队列中，经过错误发现率调整后，有7种蛋白质与ILA相关，在调整年龄、性别和吸烟状态后，所有这些蛋白质仍具有显著性。这7种蛋白质中的6种在验证队列中显著相关，包括生长分化因子15、表面活性蛋白D和表面活性蛋白B。在多变量模型中，发现队列中6种蛋白质与基本人口统计学数据相结合，曲线下面积为0.92（验证队列中为0.88）。最小绝对收缩和选择算子建模确定了3种蛋白质和年龄为预测因子，验证队列中的曲线下面积为0.89。当应用于合并队列时，这个简单的模型将减少三分之一接受筛查亲属的计算机断层扫描成像需求。
外周血蛋白与肺纤维化患者亲属中的ILA相关，可用于检测ILA。我们的研究结果证明了血液生物标志物在这一高风险群体中的潜在用途，并为未来的研究提出了分子靶点。
