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Background: Limited evidence suggests that epigenetic mechanisms may partially mediate the adverse effects of air pollution on health. Our aims were to identify new genomic loci showing differential DNA methylation associated with long-term exposure to air pollution and to replicate loci previously identified in other studies. Methods: A two-stage epigenome-wide association study was designed: 630 individuals from the REGICOR study were included in the discovery and 454 participants of the EPIC-Italy study in the validation stage. DNA methylation was assessed using the Infinium HumanMethylation450 BeadChip. NOX, NO2, PM10, PM2.5, PMcoarse, traffic intensity and traffic load exposure were measured according to the ESCAPE protocol. A systematic review was undertaken to identify those cytosine-phosphate-guanine (CpGs) associated with air pollution in previous studies and we screened for them in the discovery study. Results: In the discovery stage of the epigenome-wide association study, 81 unique CpGs were associated with air pollution (p-value <10-5) but none of them were validated in the replication sample. Furthemore, we identified 12 CpGs in the systematic review showing differential methylation with a p-value fulfilling the Bonferroni criteria and 1642 CpGs fulfilling the false discovery rate criteria, all of which were related to PM2.5 or NO2. None of them was replicated in the discovery study, in which the top hits were located in an intergenic region on chromosome 1 (cg10893043, p-value=6.79*10-5) and in the PXK and ARSA genes (cg16560256, p-value=2.23*10-04; cg11953250, p-value=3.64*10-04). Conclusions: Neither new genomic loci associated with long-term air pollution were identified, nor previously identified loci were replicated. Continued efforts to test this potential association are warranted.

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Working paper