Polyunsaturated fatty acids modulation of smoking-related epigenetics and pulmonary outcomes

Cigarette smoking results in epigenetic alterations that persist after smoking cessation and is a major risk factor for chronic lung disease. Polyunsaturated fatty acids (PUFAs) may promote epigenetic recovery and support lung health. We aimed to characterize PUFA biomarker associations with lung phenotypes in high-risk populations with a smoking history and determine whether smoking-related DNA methylation (DNAm) mediates these associations.

In this observational study we analyzed blood-based omega-3 and omega-6 PUFA biomarkers, spirometry, chest computed tomography (CT) measures, and smoking-related DNAm in 3857 former and current smokers in the Genetic Epidemiology of COPD (COPDGene) study. PUFA associations with lung phenotypes and DNAm were modeled with robust linear regression and linear mixed models. Mediation analysis estimated PUFA effects mediated through DNAm. Models adjusted for demographics, smoking history, genotype principal components, and, where relevant, cell type proportions and CT scanner. Replication in blood and extension to lung tissue were tested in the Lung Tissue Resource Consortium (LTRC).

Higher omega-3s were associated with higher lung function, less emphysema, and less airway wall thickening, while higher omega-6s and a higher omega 6:3 ratio were associated with worse lung phenotypes. Higher omega-3s and omega-6s were each associated with higher DNAm at cg05575921 in the aryl hydrocarbon receptor repressor gene (AHRR), lower epigenetic smoking scores, and a slower epigenetic pace of aging; the omega 6:3 ratio showed opposite associations. Smoking-related DNAm partially mediated some PUFA- lung phenotype asssociations. Omega-3s showed beneficial direct and mediated effects; some omega-6s showed detrimental direct effects but beneficial mediated effects; and the omega 6:3 ratio showed detrimental direct and mediated effects. For example, direct and AHRR DNAm-mediated effects on FEV1 were 0.0201 and 0.0049 for total omega-3s, -0.0049 and 0.0009 for total omega-6s, and - 0.0074 and - 0.0014 for the omega 6:3 ratio. Replication analysis in LTRC generally showed consistent directions of effects across blood and lung tissue.

PUFAs may mitigate smoking-related epigenetic alterations, with omega-3s particularly associated with better lung outcomes. These findings have implications for PUFA-focused precision nutrition strategies in high-risk populations.