|Beitragstitel||Epigenome-wide association of SERPINA1 methylation with lung function: Results from SAPALDIA, a Swiss population-based cohort study.|
BACKGROUND: Environmental and genetic factors together with epigenetic mechanisms, such as DNA methylation (DNAm), can have an impact on lung disease. Mutations in the SERPINA1 gene leading to alpha-1 antitrypsin (AAT) deficiency are shown to increase the risk for emphysema. Recently, differential SERPINA1 methylation was found to be associated with chronic obstructive pulmonary disease (COPD), airflow limitation (FEV1/FVC) and forced expired volume in one second (FEV1) in a family-based study of predominantly smoking adults without severe AAT deficiency. Our study is the first to assess whether SERPINA1 methylation is cross-sectionally and longitudinally associated with lung function (FEV1/FVC, FEV1, forced vital capacity (FVC)) in a population-based study of smokers.
METHODS: Novel and rich SAPALDIA data, from 1121 participants, collected at baseline and 10 years later using the Illumina 450k beadchip, were analyzed. Associations of DNAm with lung function, in the SERPINA gene cluster (between PPP4R4 and SERPINA13P genes), adjusted for potential confounders (except for smoking, neutrophils and BMI) and corrected for technical bias were assessed in ever smokers. Cross-sectional analyses were first carried out for each time-point and then on a combined sample using data from both time-points. Longitudinal analyses were performed using mixed-effect models with a random effect for the subject. One hundred and eight CpGs were investigated for associations.
RESULTS: Several differentially methylated CpGs in SERPINA1 gene were significantly associated with lung function, but especially for FEV1/FVC, in both cross-sectional and longitudinal analyses. One of the top two SERPINA1 signals from the family-based study was replicated in SAPALDIA; yet as expected in a population-based study, with a lower significance level. The most strongly associated CpG with change in FEV1/FVC was cg08257009 a known smoking-related CpG. This result was replicated in the ECRHS cohort. While nominally significant, none of the results reached a Bonferroni-corrected significance level.
CONCLUSION: SAPALDIA preliminary findings imply that methylation in SERPINA1 may not be a relevant predictor of lung function. Replications in the ECRHS and NFBC cohorts, from the Aging Lungs in the European Cohorts (ALEC) project, are ongoing (Funding; EU No 633212).