(P21-011-25) Associations of Polyunsaturated Fatty Acids With Smoking-Related Epigenetic Alterations

Objectives: Cigarette smoking results in chronic inflammation and is associated with epigenetic alterations that persist even after smoking cessation. We hypothesized that anti-inflammatory polyunsaturated fatty acids (PUFAs) may protect against the epigenetic effects of cigarette smoking in current and former smokers.

Methods: We evaluated concurrent PUFA biomarker and DNA methylation (DNAm) measurements in 3857 current and former smokers in the Genetic Epidemiology of COPD study.  We considered DNAm at 8 established smoking CpGs, a multi-CpG epigenetic smoking score, and the Horvath epigenetic aging clock (a measure of molecular versus chronological age). Associations of PUFAs with DNAm were modeled with robust linear regression. Modification of PUFA effects by years since quitting in former smokers and total smoking duration in current smokers were evaluated with interaction terms in smoking-stratified models.  All models adjusted for age, sex and genetic principal components.

Results: PUFA associations with DNAm were generally consistent across the PUFAs alpha-linolenic acid (ALA), docosahexaenoic acid (DHA) and linoleic acid (LA), and opposite in direction from previously established epigenetic effects of smoking.  Specifically, higher ALA, DHA and LA were associated with higher DNAm at CpGs in AHRR, F2RL3, chr6p21, chr2q37, GFI1 (which are lower with smoking) and a lower epigenetic smoking score (which is higher with smoking). Higher ALA and LA were also associated with reduced epigenetic age, suggesting a protective effect against molecular aging. Analyses in former smokers suggest the beneficial associations of ALA with AHRR DNAm, the epigenetic smoking score, and epigenetic age may be greatest in those who have recently quit smoking (PUFA x years since quit interaction p-values < 0.05). Analyses in current smokers suggest the association of LA with chr2q37 DNAm may diminish with longer total smoking duration.

Conclusions: PUFAs are associated with DNAm at smoking-related CpGs and may promote resilience against smoking-related epigenetic alterations. Further research investigating the impact of PUFAs in relation to the timing of cigarette smoke exposure and smoking cessation could inform nutrition interventions to mitigate the molecular effects of cigarette smoking.

Funding Sources: This research was supported by the NIH and NHLBI.