Protein biomarkers of interstitial lung abnormalities in relatives of patients with pulmonary fibrosis

Rationale First-degree relatives of patients with pulmonary fibrosis (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. Methods Relatives enrolled in two independent cohorts had protein levels measured using an aptamer-based proteomic platform. ILA was assessed with CT scans per Fleischner Society recommendations. Protein associations with ILA were assessed using regression, and significant proteins were used with clinical variables to detect ILA. Results Of 237 relatives from two independent cohorts, 26% had ILA. Seven proteins were associated with ILA in the discovery cohort after FDR-adjustment, and all remained significant after adjusting for age, gender, and smoking status. Six of seven were significant in the validation cohort including GDF15, SFTPD, and SFTPB. In a multivariable model, six proteins combined with basic demographics in the discovery cohort had AUC=0.92 (0.88 in validation cohort). LASSO modelling identified three proteins and age as predictors with an AUC=0.89. When applied to the combined cohorts, this simple model would reduce the need for CT imaging in one of every three relatives screened. Conclusion Peripheral blood proteins are associated with ILA in relatives of patients with pulmonary fibrosis and can be used to detect ILA. Our findings demonstrate the potential utility of blood biomarkers in this high-risk group and suggests molecular targets for future investigation.