Rationale: Knowledge on
biomarkers of
interstitial lung disease is incomplete. Interstitial lung abnormalities (ILAs) are radiologic changes that may present in its early stages. Objectives: To uncover
blood proteins associated with ILAs using large-scale proteomics methods. Methods: Data from two prospective cohort studies, the AGES-Reykjavik (Age, Gene/Environment Susceptibility-Reykjavik) study (N = 5,259) for
biomarker discovery and the COPDGene (Genetic Epidemiology of
COPD) study (N = 4,899) for replication, were used.
Blood proteins were measured using
DNA aptamers, targeting more than 4,700
protein analytes. The association of
proteins with ILAs and ILA progression was assessed with regression modeling, as were associations with genetic risk factors. Adaptive Least Absolute Shrinkage and Selection Operator models were applied to bootstrap data samples to discover sets of
proteins predictive of ILAs and their progression. Measurements and Main Results: Of 287 associations, SFTPB (
surfactant protein B) (odds ratio [OR], 3.71 [95% confidence interval (CI), 3.20-4.30]; P = 4.28 × 10-67), SCGB3A1 (
Secretoglobin family 3A member 1) (OR, 2.43 [95% CI, 2.13-2.77]; P = 8.01 × 10-40), and WFDC2 (
WAP four-disulfide core domain protein 2) (OR, 2.42 [95% CI, 2.11-2.78]; P = 4.01 × 10-36) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, concentrations of SFTPB were associated with the rs35705950 MUC5B (
mucin 5B) promoter polymorphism, and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILAs in AGES-Reykjavik, ILAs in COPDGene, and ILA progression in AGES-Reykjavik had validated areas under the receiver operating characteristic curve of 0.880, 0.826, and 0.824, respectively. Conclusions: Novel, replicated associations of ILA, its progression, and genetic risk factors with numerous
blood proteins are demonstrated as well as machine-learning-based models with favorable predictive potential. Several
proteins are revealed as potential markers of early fibrotic
lung disease.