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. 2016 Jul;124(7):983-90.
doi: 10.1289/ehp.1509966. Epub 2016 Jan 5.

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

Tommaso Panni  1 , Amar J Mehta, Joel D Schwartz, Andrea A Baccarelli, Allan C Just, Kathrin Wolf, Simone Wahl, Josef Cyrys, Sonja Kunze, Konstantin Strauch, Melanie Waldenberger, Annette Peters
Affiliations

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

Tommaso Panni et al. Environ Health Perspect. 2016 Jul.

Abstract

Background: Epidemiological studies have reported associations between particulate matter (PM) concentrations and cancer and 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: We studied the association between DNA methylation and short- and mid-term air pollution exposure using genome-wide data and identified potential biological pathways for additional investigation.

Methods: We collected whole blood samples from three independent studies-KORA F3 (2004-2005) and F4 (2006-2008) in Germany, and the Normative Aging Study (1999-2007) in the United States-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 (1 for 2-day average, 1 for 7-day, and 10 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 I2 for homogeneity assessment across the studies, 4 of these sites (annotated in NSMAF, C1orf212, MSGN1, NXN) showed p > 0.05 and I2 < 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 1,819 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 PM exposure to adverse health effect through variations in DNA methylation.

Citation: Panni T, Mehta AJ, Schwartz JD, Baccarelli AA, Just AC, Wolf K, Wahl S, Cyrys J, Kunze S, Strauch K, Waldenberger M, Peters A. 2016. 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. Environ Health Perspect 124:983-990; http://dx.doi.org/10.1289/ehp.1509966.

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Conflict of interest statement

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this paper are those of the authors and do not necessarily represent the views of the U.S. Department of Veterans Affairs.

The authors declare they have no actual or potential competing financial interests.

Figures

Figure 1
Figure 1
Manhattan plots showing fixed-effect p-values from the meta-analysis of KORA F3, KORA F4, and NAS longitudinal cohort studies across the human genome after fully adjusted model. Each dot corresponds to a CpG methylation site. Panel A: 2-day PM2.5 exposure; Panel B: 7-day PM2.5 exposure; Panel C: 28-day PM2.5 exposure (μg/m3).
Figure 2
Figure 2
Forest plots (left side) and regional plots regarding cg19963313 that achieved genome-wide significance level and cg02608596 that was close to genome-wide significance at 7-day average and showed homogeneity. Forest plots show KORA F3, KORA F4, and NAS longitudinal cohort estimates and pooled meta-analysis results. Regional plots show the p-values from Figure 1, Panel B of each annotated CpG sites (diamonds) in a 200k bp length genome segment around the top CpG. The color and the size of the diamonds represent the intensity of the correlation with the top CpG target (in the center). The blue broken line connects the average methylation value of adjacent CpG sites; the right axis displays the 0–1 methylation scale. Correlations and averages values are calculated as mean of the three studies. Green arrows represent gene extension.
Figure 3
Figure 3
Forest plots (left side) and regional plots regarding the CpGs that achieved Bonferroni genome-wide significance level and homogeneity at 28-day exposure. Forest plots show KORA F3, KORA F4 and NAS longitudinal cohort estimates and pooled meta-analysis results. Regional plots show the p-values from Figure 1, Panel C of each annotated CpG sites (diamonds) in a 200k bp length genome segment around the top CpG. The color and the size of the diamonds represent the intensity of the correlation with the top CpG target (in the center). The blue broken line connects the average methylation value of adjacent CpG sites; the right axis displays the 0–1 methylation scale. Correlations and averages values are calculated as mean of the three studies. Green arrows represent gene extension. Orange outlined diamonds highlight FDR significant CpG sites.
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