Epigenome-wide analysis of long-term air pollution exposure and DNA methylation in monocytes: results from the Multi-Ethnic Study of Atherosclerosis

ABSTRACT

Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals and cis-gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM_2.5) and oxides of nitrogen (NO_X) were estimated at participants’ homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals and cis-gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or near SDHAP3, ZFP57, HOXA5, and PRM1, respectively) were associated with PM_2.5. The DMRs on chromosomes 5 and 6 also associated with NO_X. The DMR on chromosome 5 had the smallest p-value for both PM_2.5 (p = 1.4×10⁻⁶) and NO_X (p = 7.7×10⁻⁶). Three differentially methylated CpGs were identified for PM_2.5, and cg05926640 (near TOMM20) had the smallest p-value (p = 5.6×10⁻⁸). NO_X significantly associated with cg11756214 within ZNF347 (p = 5.6×10⁻⁸). Several differentially methylated signals were also associated with cis-gene expression. The DMR located on chromosome 7 was associated with the expression of HOXA5, HOXA9, and HOXA10. The DMRs located on chromosomes 5 and 16 were associated with expression of MRPL36 and DEXI, respectively. The CpG cg05926640 was associated with expression of ARID4B, IRF2BP2, and TOMM20. We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.

KEYWORDS:

• Air pollution
• fine particulate matter
• oxides of nitrogen
• DNA methylation
• gene expression

Acknowledgments

MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. This research was supported by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, 2R01 HL071759, and T32 HL007902 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). This publication was developed under STAR research assistance agreements, No. RD831697 (MESA Air), RD-83830001 (MESA Air Next Stage), and RD-83479601 awarded by the U.S. Environmental Protection Agency. It has not been formally reviewed by the EPA. The views expressed in this document are solely those of the authors and the EPA does not endorse any products or commercial services mentioned in this publication. This work was also supported by National Institute of Environmental Health Sciences (NIEHS) grants 1 F31 ES025475-01, P30 ES007033-01, P30 ES007033, and P50 ES015915-01. The MESA Epigenomics & Transcriptomics Study was funded by NIA grant 1R01HL101250-01 to Wake Forest University Health Sciences. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NHLBI, USEPA, or NIEHS.

Disclosure statement

Gloria Chi completed this work while she was a student at the University of Washington. She is currently employed by Genentech, Inc.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the National Center for Advancing Translational Sciences [UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420]; National Heart, Lung, and Blood Institute [HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, 2R01 HL071759, and T32 HL007902]; National Institute of Environmental Health Sciences [1 F31 ES025475-01, P30 ES007033-01, P30 ES007033, and P50 ES015915-01]; National Institute on Aging [1R01HL101250-01]; U.S. Environmental Protection Agency [RD831697 (MESA Air), RD-83830001, and RD-83479601].