Effects of Immunomodulatory Fatty Acids on Lung Function Are Mediated Through Smoking-related Differences in DNA Methylation

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Abstract Rationale: Dietary polyunsaturated fatty acids (PUFAs) found in plant and seed oils and fatty fish have immunomodulatory properties that may influence lung function. Smoking impacts DNA methylation, inflammation, and lung function and may mediate the effects of PUFAs on the lungs. We analyzed omega-3 and omega-6 PUFA biomarker associations with lung function, and investigated whether these associations are mediated through DNA methylation of the AHRR gene, an epigenetic marker of smoking dose and duration. Methods: We evaluated spirometry, AHRR DNA methylation and PUFA biomarker data from 3854 participants in the Genetic Epidemiology of COPD (COPDGene) Study. Infinium MethylationEPIC BeadChip DNAm data was assayed through the NIH NHLBI TOPMed program using peripheral blood leukocyte DNA. Plasma PUFAs were quantified by gas chromatography-mass spectrometry (GC-MS). PUFA associations with FEV1 were estimated using robust linear regression accounting for key lung function covariates. Mediation analyses estimating the average causal effect of PUFAs mediated through AHRR (cg05575921) methylation were performed with the R package ‘mediation’. Results: Higher blood levels of omega-3 PUFAs alpha-linolenic acid (ALA) and eicosapentaenoic acid (EPA) were positively associated with FEV1 while omega-6 PUFA arachidonic acid (AA) was negatively associated with FEV1. Specifically, one standard deviation (SD) higher ALA and EPA were associated with 33.0 (95% confidence interval [CI] 11.2 – 54.8) and 42.4 (95% CI 22.9 – 61.8) ml higher FEV1, while one SD higher AA was associated with 84.3 (95% CI 61.6-107.0) ml lower FEV1. Associations of docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and linoleic acid (LA) with FEV1 were not statistically significant. Mediation analyses revealed significant (p<2E-16) causal mediation through AHRR methylation for EPA and ALA, with the proportion mediated estimated at 0.27 and 0.19 respectively, while there was no statistical evidence (p=0.18) of mediation for AA. In these models, increases in AHRR methylation attributed to one SD higher blood levels of ALA and EPA were associated with 11.6 (95% CI 7.5 – 16.4) and 9.0 (95% CI 5.14 – 13.9) ml higher FEV1. Analyses stratified by smoking status suggest these effects may be realized primarily in former smokers. Conclusions: Omega-3 PUFAs may impact lung function through influences on smoking-associated DNA methylation levels, while the impacts of omega-6 PUFAs may be independent of the epigenetic effects of smoking. These findings shed light on molecular mechanisms underlying intersections of PUFA nutritional status, smoking, and lung function, and highlight a future role for precision nutrition for lung health.

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