C93-06 Differential Gene Expression Associated With the Multidimensional Diagnostic Schema for Chronic Obstructive Pulmonary Disease

Rationale The new multidimensional diagnostic schema for COPD incorporates symptoms, imaging abnormalities, and spirometry. This framework identifies additional individuals with COPD who do not have spirometric airflow obstruction but also excludes some individuals with airflow obstruction who do not have symptoms or imaging abnormalities. We aimed to evaluate differential gene expression associated with those newly diagnosed and those excluded by the multidimensional diagnostic schema. Methods We analyzed current and former smokers from the COPDGene Phase 2 cohort. Using the multidimensional diagnostic schema, COPD was diagnosed either by (1) major diagnostic category: presence of the major criterion (airflow obstruction, FEV1/FVC <0.70) and at least 1 of 5 minor criteria (emphysema or bronchial wall thickening on computed tomography, dyspnea, poor respiratory quality of life, and chronic bronchitis); or (2) minor diagnostic category: presence of at least 3 of 5 minor criteria. Four categories were created: No COPD (no airflow obstruction and no COPD per new schema), New COPD (No airflow obstruction but met minor diagnostic criteria), Excluded (airflow obstruction but no COPD per new schema), and COPD (airflow obstruction and COPD per new schema). Whole-blood RNA-seq data underwent quality control, low-expression filtering, and trimmed mean of M-values (TMM) normalization. Models were adjusted for age, sex, race, peripheral blood cell composition, and library batch. Differential gene expression was assessed for the New COPD and Excluded groups with No COPD as the reference group, using the voom-limma method. Pathway enrichment analysis was conducted using Fast Gene Set Enrichment Analysis (FGSEA) across combined Gene Ontology and Hallmark gene sets with genes ranked moderated t-statistics from the voom-limma model. Statistical significance was defined at a false discovery rate (FDR) < 0.05. Results Among 3,619 participants with complete data, 245 (11.3%) of 2,171 individuals without airflow obstruction were classified as New COPD, while 153 (10.6%) of 1,447 individuals with airflow obstruction were classified as Excluded. The New COPD group exhibited prominent pro-inflammatory signatures, including elevated neutrophil markers (S100A8, S100A12), Th1 cytokines (IFN-γ), and tissue-remodeling genes (HMMR, ANXA1), with enrichment of inflammatory and mRNA translation pathways (FDR<0.05). The Excluded group demonstrated minimal inflammatory activity and relatively higher expression of anti-inflammatory modulators (LYNX1, PDZD2, PTGES). No significant differential expression was observed between the Excluded and the No COPD groups (Figure1). Conclusion The multidimensional diagnostic schema reveals biologically distinct subtypes, with New COPD marked by more active inflammatory gene expression while those excluded did not differ from those with no COPD.