Abstract P105: Gaseous Air Pollutants and DNA Methlyation in a Methylome-wide Association Study of an Ethnically and Environmentally Diverse Population of U.S. Adults
Authors: Katelyn Holliday, Rahul Gondalia, Antoine Baldassari, Raul Méndez-Giráldez, Anne Justice, James Stewart, Duanping Liao, Jeffrey Yanosky, Kristina Jordahl, Parveen Bhatti, Themistocles Assimes, Jim Pankow, Ellen Demerath, Weihua Guan, Myriam Fornage, Jan Bressler, Kari North, Karen Conneely, Yun Li, Andrea Baccarelli, Lifang Hou, Eric Whitsel
Journal: Circulation (2018)

Background: Epigenetic mechanisms underlying associations between coronary artery disease (CAD) and ambient exposures to carbon monoxide (CO), nitrogen oxides (NO 2 /NOx), ozone (O 3 ), and sulfur dioxide (SO 2 ) are incompletely understood. We therefore examined associations between these gaseous air pollutants and DNA methylation (DNAm)—a process that controls gene expression. Methods: We conducted a race/ethnicity- and study-stratified, methylome-wide association study of 12 Women’s Health Initiative and Atherosclerosis Risk in Communities subpopulations (N=8567, mean age 61.3 years, 83% female, 46% African American, 8% Hispanic/Latino American). In each subpopulation, we estimated daily mean ambient pollutant concentrations at geocoded participant addresses using national-scale, lognormal ordinary kriging. We averaged the concentrations over the 2, 28, and 365 days before phlebotomy, the source of leukocyte DNA used in estimating DNAm at 485,000 Cytosine-phosphate-Guanine (CpG) sites on the Illumina Infinium HumanMethylation450 BeadChip. We estimated pollutant-DNAm associations using multi-level, linear mixed-effects models adjusted for socio-demographic, behavioral, and meteorological factors; estimated leukocyte proportions; and technical covariates. Then we combined estimates from the 12 subpopulations in inverse variance-weighted meta-analyses and characterized CpG sites associated with significant associations and little evidence of heterogeneity among subpopulations ( p &lt;1.0x10 -7 ; p Cochran’s Q &gt;0.05). Results: Although we found no significant or suggestive CO-, O 3 -, or SO 2 -DNAm associations, we found a significant 28-day mean NO 2 -DNAm association at cg01885635 near ZNF621 on chr. 3 ( p =5.01x10 -8 ) and suggestive 365-day mean NO 2 -DNAm associations at cg12684684 near ARPC2 on chr. 2 ( p =9.3x10 -7 ), cg19693031 near TXNIP on chr. 1 ( p =7.3x10 -7 ), and cg01885635 near ZNF621 on chr. 3 ( p =6.7x10 -7 ). We also found 2- and 365-day mean NOx-DNAm associations at cg27032760 near KCTD16 on chr. 5 ( p =4.1x10 -7 ) and cg15008743 near ZNF83 on chr. 19 ( p =2.8x10 -7 ), respectively. ZNF621 and ZNF83 encode zinc finger proteins that possess transcription factor activity. ARPC2 encodes an actin-related protein complex subunit that has been associated with mean platelet volume, a known risk factor for myocardial infarction (MI) and post-MI mortality. TXNIP encodes a thioredoxin-binding protein that protects cells from oxidative stress, is highly glucose responsive, and has been associated with triglycerides, blood pressure, diabetes, and CAD. KCTD16 encodes a potassium channel tetramerization domain-containing protein. Conclusions: Pending replication, the preliminary findings suggest that biologically plausible epigenetic mechanisms may underlie associations between nitrogen oxide exposures and CAD in multi-racial/ethnic populations.