(P29-023-24) Intersections of Omega-3 Fatty Acids, DNA Methylation and Lung Function: A Nutritional Epigenetic Study in the Genetic Epidemiology of COPD Study

Objectives: Omega-3 fatty acids impact DNA methylation (DNAm) and may influence lung function. We evaluated associations of the omega-3 fatty acid docosahexaenoic acid (DHA) with lung function and its decline in the context of Chronic Obstructive Pulmonary Disease (COPD) and investigated potential interactions with DNAm.

Methods: We evaluated DHA biomarker, DNAm and longitudinal spirometry data from 2680 participants in the Genetic Epidemiology of COPD (COPDGene) Study. Associations of DHA with repeated measures of the forced expiratory volume in the first second (FEV₁) and its rate of decline were evaluated longitudinally with linear mixed effects models. Epigenome-wide (EWAS) DNAm x DHA interactions for FEV₁ were evaluated cross-sectionally with robust linear regression models. All models accounted for age, sex, height, race and ethnicity, and smoking.  EWAS models also accounted for cell type proportions and the smoking-associated CpG site near AHRR (cg05575921). Gene set enrichment and functional downstream analyses of genome-wide significant (p < 6.4 × 10^-8) DNAm x DHA interactions were conducted using missMethyl and eFORGE2.

Results: Higher blood DHA was associated with higher FEV₁ and a slower rate of FEV₁ decline among 2347 participants with lung function decline.  Specifically, one percent higher DHA (% of total fatty acids) was associated with 38.2 (95% confidence interval [CI] 0.96 – 75.5) mL higher FEV₁ and a 4.2 (95% CI 1.6 – 6.9) mL/year attenuation in the rate of FEV₁ decline.  EWAS interaction models revealed 10 CpG probes with genome-wide significant DNAm x DHA interactions for FEV₁, including CpGs annotated to RAB28, PRKDC, UBAP2L and SORCS2. Pathway analysis of CpGs with significant DHA interactions revealed enrichment for inflammation and antigen presentation. Functional annotation revealed associations with DNase I hypersensitive sites, chromatin H3 regulatory elements and enhancers across more than 15 tissue types including lung tissue (FDR q < 0.01).

Conclusions: Omega-3 fatty acids may have beneficial effects on lung function that are associated with DNAm modifications.  Precision nutrition studies focused on epigenetic variability may reveal new pathogenesis pathways for lung function decline and COPD progression.

Funding Sources: Reported research was supported by the NIH and NHLBI. DNA methylation measurement was funded by TOPMed.