C39-10 Longitudinal Transcriptomics Reveals Evolving Gene Expression Patterns Associated With 12-month Disease Progression in Patients With Idiopathic Pulmonary Fibrosis

Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease affecting over 3 million people worldwide, with a median survival of 3-5 years post-diagnosis. Increasing evidence indicates that the molecular mechanisms underlying IPF are dynamic, with early pathogenic events differing from those that sustain chronic fibrosis. Longitudinal peripheral blood transcriptomic analysis may provide a means to disentangle these temporal changes and improve our understanding of how systemic molecular activity relates to disease progression. Methods PROFILE is a prospective observational cohort study of over 600 patients with incident diagnosis of IPF. Disease progression was defined as death or ≥ 10% decline in percent predicted forced vital capacity (ppFVC) at 12 months post-enrollment. Differential expression (DE) analyses comparing progressors and non-progressors were performed using samples at baseline, 3 months, 6 months, and 12 months. A linear regression model was applied, adjusting for age, sex, smoking status, baseline ppFVC, and batch effects. Pathway enrichment analyses were performed using gene set enrichment analysis (GSEA) on DE analysis results at each time point, with Reactome as the reference database. Results The cohort had a baseline median age of 71 years (IQR: 11), was 23% female, and had an average ppFVC of 80% (SD: 19). Nearly half (49%) of the patients were classified as progressors. The number of differentially expressed genes increased at timepoints approaching 12 months, with 47 at baseline, 101 at 3 months, 1082 at 6 months and 1811 at 12 months (adjusted p-value 0.05, absolute Log2FC 0.2). Pathway analysis identified 153 pathways consistently upregulated in progressors compared to non-progressors across all four timepoints, including innate immune signaling. Nine pathways, such as signaling by ERBB4, signaling by the B cell receptor and cohesin loading onto chromatin, were upregulated in progressors only at early timepoints (baseline and 3 months). Conclusions Our findings indicate that there is a persistent molecular signal of systemic immune dysfunction in patients with progressive disease, as well as evolving molecular mechanisms that may inform future biomarker discovery and therapeutic strategies. This abstract is funded by: AstraZeneca; Imperial College London