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. 2025 Jun 30;11(3):01045-2024.
doi: 10.1183/23120541.01045-2024. eCollection 2025 May.

Proteins associated with preserved ratio impaired spirometry

Eva Lindberg  1 , Xingwu Zhou  1   2   3 , Annelie F Behndig  4 , Kenneth Caidahl  5   6 , Arne Egesten  7 , Gunnar Engström  8 , Jan E Engvall  9   10 , Maria J Eriksson  11   12 , Tove Fall  13 , Anders Gummesson  14   15 , Viktor Hamrefors  16   17 , Christer Janson  1 , Åse Johnsson  18   19 , Anne Lindberg  4 , Maria Mannila  20 , Fredrik H Nyström  21 , Anna-Carin Olin  22   23 , C Magnus Sköld  24   25 , Stefan Söderberg  4 , Hanan Tanash  26 , Kjell Torén  22   23 , Carl Johan Östgren  9   21 , Andrei Malinovschi  3 , Anders Blomberg  4
Affiliations

Proteins associated with preserved ratio impaired spirometry

Eva Lindberg et al. ERJ Open Res. .

Abstract

Background: 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.

Methods: 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 (FEV1), forced vital capacity (FVC) and FEV1/FVC was defined as the fifth percentile in healthy, never-smoking SCAPIS participants. Participants were subdivided into five groups: reference: FEV1/FVC≥LLN and FEV1≥LLN and FVC≥LLN (n=4084)); mild chronic airflow limitation (CAL): FEV1/FVC<LLN and FEV1≥LLN (n=278); moderate-severe CAL: FEV1/FVC<LLN and FEV1<LLN (n=170); restrictive spirometric pattern (RSP): FEV1/FVC ≥LLN and FVC<LLN (n=238); and PRISm: FEV1/FVC≥LLN and FEV1<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%.

Results: 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.

Conclusion: Protein profile in PRISm differs from other spirometric patterns suggesting specific disease mechanisms.

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Conflict of interest statement

Conflict of interest: A. Egesten reports consultancy fees from Arcede Pharma, Lund, Sweden. J.E. Engvall reports support for attending meetings from Acta Pediatrica. A. Lindberg reports consultancy fees from Swedish Medical Products Agency, SBU – Swedish Agency for Health Technology Assessment and Assessment of Social Service, Ongoing; payment or honoraria for lectures, presentations, manuscript writing or educational events from Bonnier Healthcare Sweden AB and AstraZeneca; participation on a data safety monitoring board or advisory board with AstraZeneca, Novartis, Boehringer Ingelheim and GSK; and a leadership role with Research Council for the Swedish Heart and Lung foundation 2019–2023. A-C. Olin reports consultancy fees from Chiesi AB; patents planned, issued or pending (WO2009045163, “Collection and measurement of exhaled particles”; WO2013117747, “A device and method for noninvasive analysis of particles during medical ventilation”); a leadership role with PExA AB; and stock (or stock options) with PExA AB. S. Söderberg reports payment or honoraria for lectures, presentations, manuscript writing or educational events, and support for attending meetings from, and participation on a data safety monitoring board or advisory board with Johnson & Johnson. The remaining authors have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Flow chart. SCAPIS: Swedish Cardiopulmonary Bioimage Study; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; QC: quality control.
FIGURE 2
FIGURE 2
Estimated association between plasma proteins (left panels) and a) moderate–severe chronic airflow limitation (CAL), b) restrictive spirometric pattern (RSP) and c) preserved ratio impaired spirometry (PRISm) of the SCAPIS Main cohort, adjusted for age, sex, body mass index (BMI), smoking (category and pack-years), physical activity and centre, and corrected for multiple testing. The red dots are those with adjusted p<0.05 by Benjamini–Hochberg method. Validation results in the Pilot cohort, adjusted for age, sex, BMI, smoking (category and pack-years) and physical activity (right panels). The red dots are those with p<0.05. All proteins were previously adjusted according to storage time and plate ID, and standardised with mean 0 and sd 1.
FIGURE 3
FIGURE 3
Proteins associated with each lung function impairment group. (−) indicates a negative association. CAL: chronic airflow limitation; PRISm: preserved ratio impaired spirometry; RSP: restrictive spirometric pattern. GDF-15: growth/differentiation factor 15; ADM: adrenomedullin; IL-1RA: interleukin-1 receptor antagonist; TFF3: trefoil factor 3; LOX-1: lectin-like oxidised LDL receptor 1; U-PAR: urokinase plasminogen activator surface receptor; IL-6: interleukin-6; CHI3L1: chitinase-3-like protein 1; TNFRSF10A: tumour necrosis factor receptor superfamily member 10A; PON3: paraoxonase 3; REN: renin; MMP7: matrix metalloproteinase 7; SELE: E-selectin; ACE-2: angiotensin-converting enzyme 2; RAGE: receptor for advanced glycosylation end products.
See this image and copyright information in PMC

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