Gaseous Air Pollutants and DNA Methylation in a Methylome-wide Association Study of an Ethnically and Environmentally Diverse Population of U.S. Adults

• Type of Material: Article
• Authors: Katelyn M. Holliday, Duke University; Rahul Gondalia, University of North Carolina, Chapel Hill; Antoine Baldassari, University of North Carolina, Chapel Hill; Anne E. Justice, Geisinger Health System; James D. Stewart, University of North Carolina, Chapel Hill; Duanping Liao, Pennsylvania State University; Jeff D. Yanosky, Pennsylvania State University; Kristina M. Jordahl, University of Washington; Parveen Bhatti, Cancer Control Research; Themistocles L. Assimes, Stanford University; James S. Pankow, University of Minnesota; Weihua Guan, University of Minnesota; Myriam Fornage, University of Texas at Houston; Jan Bressler, University of Texas at Houston; Kari E. North, University of North Carolina, Chapel Hill; Yun Li, University of North Carolina, Chapel Hill; Lifang Hou, Northwestern University; Pantel S. Vokonas, Boston University; Karen N Conneely, Emory University; Cavin Ward-Caviness, National Health and Environmental Effects Research Laboratory; Rory Wilson, German Research Center for Environmental Health; Kathrin Wolf, German Research Center for Environmental Health; Melanie Waldenberger, German Research Center for Environmental Health; Josef Cyrys, German Research Center for Environmental Health; Annette Peters, Ludwig Maximilians University; H. Marike Boezen, University of Groningen; Judith M. Vonk, University of Groningen; Sergi Sayols-Baixeras, Universitat Popeu Fabra; Mikyeong Lee, National Institute of Environmental Health; Andrea A. Baccarelli, Columbia University; Eric A. Whitsel, University of North Carolina, Chapel Hill
• Language: English
• Date: 2022-04-30
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1016%2Fj.envres.2022.113360
• Title of Journal or Parent Work: Environmental Research
• Volume: 212
• Issue: Pt C
• Start Page: 113360
• Grant/Funding Information: The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. ARIC DNAm funding was also provided by the American Recovery and Reinvestment Act of 2009 5RC2HL102419 and by R01-NS087541. Data from the ARIC study are available on request at https://www2.cscc.unc.edu/aric/distribution-agreements. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. WHI-AS311 was supported by American Cancer Society award 125299-RSG-13-100-01-CCE, WHI-BAA23 by NHLBI 60442456 BAA23, and WHI-EMPC by R01-ES020836. The authors thank the WHI investigators and staff for their dedication and the study participants for making the program possible. A listing of WHI investigators can be found at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf. Data from the WHI are available on request at https://www.whi.org/researchers/SitePages/Write%20a%20Paper.aspx. The KORA study was initiated and financed by the Helmholtz Zentrum München-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The KORA-Study Group consists of A. Peters (speaker), L. Schwettmann, R. Leidl, M. Heier, B. Linkohr, H. Grallert, C. Gieger, J. Linseisen, and their co-workers, who are responsible for the design and conduct of the KORA studies. NAS co-authors were supported by the National Institute of Environmental Health Sciences (grants ES000002, R01ES015172, 5R01ES027747-02, P30ES009089, R01ES021733, R01ES025225). The VA Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center in Boston, MA. The Lifelines Epigenetics cohort was funded by consortium grant number 4.1.13.007 of the Lung foundation Netherlands. The Lifelines initiative has been made possible by funds from FES (Fonds Economische Structuurversterking), SNN (Samenwerkingsverband Noord Nederland) and REP (Ruimtelijk Economisch Programma). This project was also supported by NIEHS National Research Service Award T32-ES007018 and Building Interdisciplinary Research Careers in Women’s Health K12HD043446 (KMH), NHLBI National Research Service Award T32-HL007055 (RG), NCI grant R25-CA094880 (KJ), NIEHS grant R01-ES017794 (EAW), NHGRI grant R01HG010297 (KEN), and the Basic Science Research Program, National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (2013R1A1A1057961) (ML). The authors declare they have no actual or potential competing financial interests.
• Keywords: DNA methylation; epigenome-wide association study; epigenetics; air pollution; gaseous pollutants
• Research Categories: Biology, Molecular; Environmental Sciences

Abstract

Epigenetic mechanisms may underlie air pollution-health outcome associations. We estimated gaseous air pollutant-DNA methylation (DNAm) associations using twelve subpopulations within Women’s Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) cohorts (n=8397; mean age 61.3 years; 83% female; 46% African-American, 46% European-American, 8% Hispanic/Latino). We used geocoded participant address-specific mean ambient carbon monoxide (CO), nitrogen oxides (NO2; NOx), ozone (O3), and sulfur dioxide (SO2) concentrations estimated over the 2-, 7-, 28-, and 365-day periods before collection of blood samples used to generate Illumina 450k array leukocyte DNAm measurements. We estimated methylome-wide, subpopulation- and race/ethnicity-stratified pollutant-DNAm associations in multi-level, linear mixed-effects models adjusted for sociodemographic, behavioral, meteorological, and technical covariates. We combined stratum-specific estimates in inverse variance-weighted meta-analyses and characterized significant associations (false discovery rate; FDR<0.05) at Cytosine-phosphate-Guanine (CpG) sites without among-strata heterogeneity (PCochran’s Q>0.05). We attempted replication in the Cooperative Health Research in Region of Augsburg (KORA) study and Normative Aging Study (NAS). We observed a −0.3 (95% CI: −0.4, −0.2) unit decrease in percent DNAm per interquartile range (IQR, 7.3 ppb) increase in 28-day mean NO2 concentration at cg01885635 (chromosome 3; regulatory region 290 bp upstream from ZNF621; FDR=0.03). At intragenic sites cg21849932 (chromosome 20; LIME1; intron 3) and cg05353869 (chromosome 11; KLHL35; exon 2), we observed a −0.3 (95% CI: −0.4, −0.2) unit decrease (FDR=0.04) and a 1.2 (95% CI: 0.7, 1.7) unit increase (FDR=0.04), respectively, in percent DNAm per IQR (17.6 ppb) increase in 7-day mean ozone concentration. Results were not fully replicated in KORA and NAS. We identified three CpG sites potentially susceptible to gaseous air pollution-induced DNAm changes near genes relevant for cardiovascular and lung disease. Further harmonized investigations with a range of gaseous pollutants and averaging durations are needed to determine the effect of gaseous air pollutants on DNA methylation and ultimately gene expression.