Circulating biomarkers of airflow limitation across the life span

Abstract

Background

Airflow limitation is a hallmark of COPD, which can develop through different lung function trajectories across the life span. There is a need for longitudinal studies aimed at identifying circulating biomarkers of airflow limitation across different stages of life.

Objective

To identify a signature of serum proteins associated with airflow limitation and evaluate their relation to lung function longitudinally in adults and children.

Methods

We used data from three adult (TESAOD, SAPALDIA, LSC) and one birth (TCRS) cohort (total N=1,940). In TESAOD, among 46 circulating proteins, we identified those associated with FEV₁/FVC % predicted levels and generated a score based on the sum of their z-scores. In cross-sectonal analyses, we tested the score for association with concomitant lung function. In longitudinal analyses, we tested the score for association with subsequent lung function growth in childhood and decline in adult life.

Results

After FDR, serum levels of five proteins (Haptoglobin, CEA, ICAM1, CRP, TIMP1) were associated with % predicted levels of FEV₁/FVC and FEV₁ in TESAOD. In cross-sectional multivariate analyses the 5-biomarker score was associated with FEV₁ % predicted in all adult cohorts (meta-analyzed FEV₁ decrease for 1-SD score increase: -2.9%; 95% CI: -3.9%, -1.9%; p=2.4x10^-16). In multivariate longitudinal analyses, the biomarker score at 6 years of age was inversely associated with FEV₁ and FEV₁/FVC levels attained by young adult life (p=0.02 and 0.005, respectively). In adults, persistently high levels of the biomarker score were associated with subsequent accelerated decline of FEV₁ and FEV₁/FVC (p=0.01 and 0.001).

Conclusion

A signature of five circulating biomarkers of airflow limitation was associated with both impaired lung function growth in childhood and accelerated lung function decline in adult life, indicating that these proteins may be involved in multiple lung function trajectories leading to COPD.