Lindberg Eva, Zhou Xingwu, Behndig Annelie F, Caidahl Kenneth, Egesten Arne, Engström Gunnar, Engvall Jan E, Eriksson Maria J, Fall Tove, Gummesson Anders, Hamrefors Viktor, Janson Christer, Johnsson Åse, Lindberg Anne, Mannila Maria, Nyström Fredrik H, Olin Anna-Carin, Sköld C Magnus, Söderberg Stefan, Tanash Hanan, Torén Kjell, Östgren Carl Johan, Malinovschi Andrei, Blomberg Anders
Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.
Department of Statistics, Uppsala University, Uppsala, Sweden.
ERJ Open Res. 2025 Jun 30;11(3). doi: 10.1183/23120541.01045-2024. eCollection 2025 May.
Preserved ratio impaired spirometry (PRISm) is a spirometry pattern of interest regarding incident airflow obstruction and higher mortality risk. We applied a proteomic approach to gain more insight into the biological mechanisms associated with PRISm.
From the population-based Swedish Cardiopulmonary Bioimage Study (SCAPIS), participants in the Main (n=4835) and Pilot (n=1054) studies, were included as discovery and replication cohorts. The lower limit of normal (LLN) of post-bronchodilator forced expiratory volume in 1 s (FEV), forced vital capacity (FVC) and FEV/FVC was defined as the fifth percentile in healthy, never-smoking SCAPIS participants. Participants were subdivided into five groups: reference: FEV/FVC≥LLN and FEV≥LLN and FVC≥LLN (n=4084)); mild chronic airflow limitation (CAL): FEV/FVC<LLN and FEV≥LLN (n=278); moderate-severe CAL: FEV/FVC<LLN and FEV<LLN (n=170); restrictive spirometric pattern (RSP): FEV/FVC ≥LLN and FVC<LLN (n=238); and PRISm: FEV/FVC≥LLN and FEV<LLN (n=238). Proximity extension assays were used to measure 168 proteins. The associations of each standardised protein were assessed with each study group by multiple linear regression models, adjusting for age, sex, body mass index (BMI), smoking, physical activity and study centres, and corrected for multiple testing to control for a false discovery rate of 5%.
Eight proteins were associated with PRISm and replicated: tumour necrosis factor receptor superfamily member 10A, interleukin-6, paraoxonase 3 (negative association), renin, urokinase plasminogen activator surface receptor (U-PAR), E-selectin, matrix metalloproteinase 7 and chitinase-3-like protein 1. Interleukin-6 and U-PAR were also associated with moderate-severe CAL and E-selectin with RSP. In addition, five other proteins were associated with moderate-severe CAL and three with RSP.
Protein profile in PRISm differs from other spirometric patterns suggesting specific disease mechanisms.
肺功能测定中保存比率受损（PRISm）是一种与气流阻塞及较高死亡风险相关的肺功能测定模式。我们采用蛋白质组学方法以更深入了解与PRISm相关的生物学机制。
基于人群的瑞典心肺生物影像研究（SCAPIS）中，主要研究（n = 4835）和试点研究（n = 1054）的参与者被纳入作为发现和验证队列。支气管扩张剂后1秒用力呼气量（FEV）、用力肺活量（FVC）和FEV/FVC的正常下限（LLN）被定义为健康、从不吸烟的SCAPIS参与者中的第五百分位数。参与者被分为五组：参照组：FEV/FVC≥LLN且FEV≥LLN且FVC≥LLN（n = 4084）；轻度慢性气流受限（CAL）：FEV/FVC<LLN且FEV≥LLN（n = 278）；中重度CAL：FEV/FVC<LLN且FEV<LLN（n = 170）；限制性肺功能模式（RSP）：FEV/FVC≥LLN且FVC<LLN（n = 238）；以及PRISm：FEV/FVC≥LLN且FEV<LLN（n = 238）。采用邻位延伸分析来检测168种蛋白质。通过多元线性回归模型评估每种标准化蛋白质与各研究组的关联，并对年龄、性别、体重指数（BMI）、吸烟、体力活动和研究中心进行校正，同时针对多重检验进行校正以控制5%的假发现率。
8种蛋白质与PRISm相关且得到验证：肿瘤坏死因子受体超家族成员10A、白细胞介素-6、对氧磷酶3（负相关）、肾素、尿激酶型纤溶酶原激活物表面受体（U-PAR）、E-选择素、基质金属蛋白酶7和几丁质酶-3-样蛋白1。白细胞介素-6和U-PAR也与中重度CAL相关，E-选择素与RSP相关。此外，还有5种其他蛋白质与中重度CAL相关，3种与RSP相关。
PRISm中的蛋白质谱不同于其他肺功能测定模式，提示存在特定的疾病机制。
