Late Breaking Abstract - Repeated cross-sectional epigenome-wide association study (EWAS) on lung function: the ALEC Project

<b>Background:</b> Genetic and environmental determinants and aging contribute to lung function. Some mechanisms of poor lung health might be mediated through differential DNA methylation (DNAm). <b>Aim:</b> To identify lung function methylation signals related to aging and smoking in the population-based cohorts, ECRHS, NFBC, SAPALDIA, of the Ageing Lungs In European Cohorts (ALEC) project. <b>Methods:</b> Blood DNAm was measured twice, 10 years apart, in 2061 subjects. Repeated cross-sectional linear regression was run for each time point separately, as well as combined in a mixed-effect model with random effect for the subject. Adjusted analyses were run in all subjects and in never smokers. Smoking controlled models were additionally adjusted for smoking status and packyears. Inverse variance weighted meta-analyses was applied with genome-wide significant methylation at P&lt;5.0E-7. <b>Results:</b> EWAS on FEV1, FEV1/FVC or FVC unadjusted for smoking showed 136 significant differentially DNAm sites. The most significant being cg05575921, a known smoking-associated CpG in the AHRR gene (P=3.96E-21; FEV1/FVC). The top hit in smoking adjusted EWAS on FEV1, FEV1/FVC or FVC was cg03149958 (P=9.31E-9; FEV1) in gene RFX4, a transcription factor known to interact with ESR1. In the 22 significant hits in never smokers, the top hit was cg14366110 (P=1.72E-10; FEV1/FVC) near gene FIBCD1, known to bind chitin, a risk exposure for lung disease. Overall, stronger associations were observed at follow-up suggesting accumulated insults with aging. <b>Conclusion:</b> Poor lung function is associated with smoking-related methylation signals. Non-smoking related signals provide important mechanistic insights. (Funding; EU No 633212)