Late Breaking Abstract - SERPINA1 methylation and lung function: Results from SAPALDIA, the Swiss population-based cohort study

<b>Background:</b> Mutations in the <i>SERPINA1</i> gene can lead to alpha-1 antitrypsin (AAT) deficiency and subsequently emphysema. Differential <i>SERPINA1</i> methylation was associated with COPD, FEV1/FVC and FEV1 in a family-based study of predominantly smoking adults without severe AAT deficiency. This study is the first to assess if <i>SERPINA1</i> methylation is cross-sectionally and longitudinally associated with lung function (FEV1/FVC, FEV1, FVC) in a population-based study of smokers. <b>Methods:</b> Novel SAPALDIA data from 1121 participants collected at baseline and 10 years later were analyzed. Associations of methylation beta values with lung function adjusted for potential confounders (except for smoking, neutrophils and BMI) and corrected for principal components of technical covariates were assessed in ever smokers using repeat cross-sectional and longitudinal models. In the <i>SERPINA1</i> gene region (<i>PPP4R4-SERPINA13P</i>), 108 CpGs were investigated for association. <b>Results:</b> Several differentially methylated CpGs in <i>SERPINA1</i> gene were significantly associated with lung function in cross-sectional and longitudinal models. One of the top two <i>SERPINA1</i> signals from the family-based study was replicated in SAPALDIA; yet as expected in a population-based study, with a lower significance level. Lastly, the most strongly associated CpG with change in FEV1/FVC was the smoking-related cg08257009. This result was replicated in the ECRHS cohort. While nominally significant, none of the results reached a Bonferroni-corrected significance level. <b>Conclusion:</b> SAPALDIA findings suggest that methylation in <i>SERPINA1</i> may not be a relevant predictor of lung function. Replication in the ECRHS and NFBC cohorts is ongoing.