DNA methylation mediates the association between occupational exposures and lung function

Introduction: Occupational exposures, such as biological dust, mineral dust and gases/fumes, are associated with lower lung function levels and attribute to 15-20% of all Chronic Obstructive Pulmonary Disease (COPD) cases. Epigenetic mechanisms such as DNA methylation have been suggested to play a role in these associations. Aim: To assess if the association between occupational exposures and lung function (FEV1/FVC) is mediated by DNA methylation. Methods: We included 1,561 subjects of the LifeLines cohort with either no, low, or high occupational exposure to biological dust, mineral dust and gases/fumes based on the current or last held job. Associations between the three exposures and 420,938 blood DNA methylation sites (CpGs, Illumina 450K array) were assessed using robust linear regression adjusted for appropriate confounders. Differentially methylated regions (DMRs) were identified using comb-p in python. Mediation of the top site per region was assessed using bootstrapping in R. Results: Using p<10−5 4, 5 and 6 single CpGs were associated with biological dust, mineral dust and gases/fumes, respectively, but none were genome-wide significant. In total 7, 8, and 30 genome-wide significant DMRs were identified, respectively. The CpG cg06462684 in the promoter of YWHAH, who binds to the glucocorticoid receptor, significantly mediated the association between FEV1/FVC and mineral dust. In addition, cg14870271 in the promoter of LGALS3BP, known to play a role in immune responses, mediated the association between FEV1/FVC and gases/fumes. Conclusion: We show that the association between lung function levels and occupational exposure to mineral dust or gases/fumes is mediated by DNA methylation.