Long-term Air Pollution Exposure, Genome-wide DNA Methylation and Lung Function in the LifeLines Cohort Study

Abstract

BACKGROUND: Long-term air pollution exposure is negatively associated with lung function, yet the mechanisms underlying this association are 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 (NO 2 ) and particulate matter (PM 2:5 , fine particulate matter with aerodynamic diameter 2:5 lm; PM 10 , particulate matter with aerodynamic diameter 10 lm) and PM 2:5absorbance , indicator of elemental carbon content (estimated with landuse-regression models) with DNA methylation in whole blood (Illumina 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 NO 2 exposure and DNA methylation for seven CpG sites (Bonferroni corrected threshold p < 1:19 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 KORAcohorts. No associations were found for PM exposure. CONCLUSIONS: Long-term NO 2 exposure was genome-wide significantly associated with DNA methylation in the identification cohort but not in the replication cohort. Future studies are needed to further elucidate the potential mechanisms underlying NO 2 -exposure-related respiratory disease.