BackgroundEpigenetics may play an important role in the pathogenesis of lung diseases. However, little is known about the epigenetic factors that influence impaired gas exchange at the lung.AimTo identify the epigenetic signatures of the diffusing capacity of the lung measured by carbon monoxide uptake (the diffusing capacity of the lung for carbon monoxide (D_LCO)).MethodsAn epigenome-wide association study (EWAS) was performed on diffusing capacity, measured by carbon monoxide uptake (D_LCO) and per alveolar volume (V_A) (as D_LCO/V_A), using the single-breath technique in 2674 individuals from two population-based cohort studies. These were the Rotterdam Study (RS, the “discovery panel”) and the Framingham Heart Study (FHS, the “replication panel”). We assessed the clinical relevance of our findings by investigating the identified sites in whole blood and by lung tissue specific gene expression.ResultsWe identified and replicated two CpG sites (cg05575921 and cg05951221) that were significantly associated with D_LCO/V_A and one (cg05575921) suggestively associated with D_LCO. Furthermore, we found a positive association between aryl hydrocarbon receptor repressor (AHRR) gene (cg05575921) hypomethylation and gene expression of exocyst complex component 3 (EXOC3) in whole blood. We confirmed that the expression of EXOC3 in lung tissue is positively associated with D_LCO/V_A and D_LCO.ConclusionsWe report on epigenome-wide associations with diffusing capacity in the general population. Our results suggest EXOC3 to be an excellent candidate, through which smoking-induced hypomethylation of AHRR might affect pulmonary gas exchange.