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BACKGROUND: Long-term air pollution exposure is negatively associated with lung function, yet the mechanisms underlying this association not fully clear. Differential DNA methylation may explain this association.

OBJECTIVES: Our main aim was to study the association between long-term air pollution exposure and DNA methylation.

METHODS: We performed a genome-wide methylation study using robust linear regression models in 1,017 subjects from the LifeLines cohort study to analyze the association between exposure to nitrogen dioxide (NO2) and particulate matter (PM2.5, fine particulate matter with aerodynamic diameter <= 2.5 mu m; PM10, particulate matter with aerodynamic diameter <= 10 mu m) and PM2.5absorbance, indicator of elemental carbon content (estimated with land use-regression models) with DNA methylation in whole blood (Illumina (R) HumanMethylation450K BeadChip). Replication of the top hits was attempted in two independent samples from the population-based Cooperative Health Research in the Region of Augsburg studies (KORA).

RESULTS: Depending on the p-value threshold used, we found significant associations between NO2 exposure and DNA methylation for seven CpG sites (Bonferroni corrected threshold p < 1.19 x 10(-7)) or for 4,980 CpG sites (False Discovery Rate<0.05). The top associated CpG site was annotated to the PSMB9 gene (i.e., cg04908668). None of the seven Bonferroni significant CpG-sites were significantly replicated in the two KORA-cohorts. No associations were found for PM exposure.

CONCLUSIONS: Long-term NO2 exposure was genome-wide significantly associated with DNA methylation in the identification cohort but not in the replication cohort. Future studies arc needed to further elucidate the potential mechanisms underlying NO2-exposure related respiratory disease.