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: Holliday Katelyn , Gondalia Rahul , Baldassari Antoine , Méndez-Giráldez Raul , Justice Anne , Stewart James , Liao Duanping , Yanosky Jeffrey , Jordahl Kristina , Bhatti Parveen , Assimes Themistocles , Pankow Jim , Demerath Ellen , Guan Weihua , Fornage Myriam , Bressler Jan , North Kari , Conneely Karen , Li Yun , Baccarelli Andrea , Hou Lifang , Whitsel Eric 
Published: July 2021

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
<1.0x10
-7
;
p
Cochran’s Q
>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.