CT density gradient texture is associated with blood gene expression and immune cell subtypes in smokers susceptible to COPD

Background Chronic obstructive pulmonary disease (COPD) often progresses silently, with biological and structural changes preceding measurable airflow obstruction. CT density gradient (CTDG) texture, a radiographic feature located primarily around the bronchovascular bundles, has been associated with systemic inflammation, exacerbations and mortality. However, the biological underpinnings of CTDG in smokers without spirometric COPD remain unclear. Methods We conducted cross-sectional analyses of over 2500 smokers from the COPDGene Study who were non-obstructed or had COPD. CTDG texture was quantified from inspiratory scans using the adaptive multiple feature method. Whole-blood RNA sequencing and immune cell RNA-seq deconvolution were performed to identify transcriptomic and immune correlates of CTDG. Differential gene expression and cell type-specific transcriptomic analyses were conducted using covariate-adjusted linear models. Results In non-obstructed smokers, CTDG was significantly associated with 157 differentially expressed genes (DEGs) (false discovery rate<5%) in the Global Initiative for Chronic Obstructive Lung Disease stage-stratified model and 65 DEGs in the interaction model. Enriched pathways in the non-obstructed population included lymphocyte differentiation, cytokine signalling and metabolic regulation. CTDG demonstrated a positive association with neutrophil proportion (β=0.126, p=0.02) and inverse associations with resting memory CD4+ T cells (β=−0.036, p=0.02) and monocytes (β=−0.050, p=0.05); however, these associations were nominal. In non-obstructed participants, neutrophil-specific gene expression linked to CTDG showed upregulation of inflammatory pathway genes, including TLR2, ADAM17 and metabolic genes, such as GRB10 and PFKFB2, suggesting early immune-metabolic dysregulation. Conclusion CTDG captures structural and systemic immunometabolic changes in non-obstructed smokers, supporting its potential as a non-invasive biomarker for early COPD risk and timely intervention.