A genome-wide analysis of DNA methylation and fine particulate matter air pollution in three study populations: KORA F3, KORA F4, and the Normative Aging Study.

BACKGROUND: Epidemiological studies have reported associations between particulate matter (PM) concentrations and cancer, respiratory, and cardiovascular diseases. DNA methylation has been identified as a possible link but so far it has only been analyzed in candidate sites. OBJECTIVES: To study the association between DNA methylation and short- and mid-term air pollution exposure using genome-wide data, and identify potential biological pathways for additional investigation. METHODS: We collected whole blood samples from three independent studies, KORA F3 (2004-05) and F4 (2006-08) from Germany and Normative Aging Study (1999-2007) from the US, and measured genome-wide DNA methylation proportions with the Illumina 450k BeadChip. PM concentration was measured daily at fixed monitoring stations and three different trailing averages were considered and regressed against DNA methylation: 2-day, 7-day and 28-day. Meta-analysis was performed to pool the study-specific results. RESULTS: Random-effect meta-analysis revealed 12 CpG (cytosine-guanine dinucleotide) sites as associated with PM concentration (one for 2-day average, one for 7-day and ten for 28-day) at a genome-wide Bonferroni significance level (p<=7.5E-8); 9 out of these 12 sites expressed increased methylation. Through estimation of I-squared statistics for homogeneity assessment across the studies, four of these sites (annotated in NSMAF, C1orf212, MSGN1, NXN) showed p>0.05 and I(2)<0.5: the site from the 7-day average results and 3 for the 28-day average. Applying False Discovery Rate, p-value<0.05 was observed in 8 and 1819 additional CpGs at 7- and 28-day average PM2.5 exposure respectively. CONCLUSION: The PM-related CpG sites found in our study suggest novel plausible systemic pathways linking ambient particulate matter exposure to adverse health effect through variations in DNA methylation