Association between long-term air pollution exposure and DNA methylation: the REGICOR study

Abstract

38Background: Limited evidence suggests that epigenetic mechanisms may partially mediate 39 the adverse effects of air pollution on health. Our aims were to identify new genomic loci 40 showing differential DNA methylation associated with long-term exposure to air pollution 41 and to replicate loci previously identified in other studies. 42Methods: A two-stage epigenome-wide association study was designed: 630 individuals from 43 the REGICOR study were included in the discovery and 454 participants of the EPIC-Italy 44 study in the validation stage. DNA methylation was assessed using the Infinium 45 HumanMethylation450 BeadChip. NOX, NO2, PM10, PM2.5, PMcoarse, traffic intensity and 46 traffic load exposure were measured according to the ESCAPE protocol. A systematic review 47 was undertaken to identify those cytosine-phosphate-guanine (CpGs) associated with air 48 pollution in previous studies and we screened for them in the discovery study. 49Results: In the discovery stage of the epigenome-wide association study, 81 unique CpGs 50 were associated with air pollution (p-value <10 -5 ) but none of them were validated in the 51 replication sample. Furthemore, we identified 12 CpGs in the systematic review showing 52 differential methylation with a p-value fulfilling the Bonferroni criteria and 1642 CpGs 53 fulfilling the false discovery rate criteria, all of which were related to PM 2.5 or NO 2 . None of 54 them was replicated in the discovery study, in which the top hits were located in an intergenic 55 region on chromosome 1 (cg10893043, p-value=6.79·10 -5 ) and in the PXK and ARSA genes 56 (cg16560256, p-value=2.23·10 -04 ; cg11953250, p-value=3.64·10 -04 ). 57 Conclusions: Neither new genomic loci associated with long-term air pollution were 58 identified, nor previously identified loci were replicated. Continued efforts to test this 59 potential association are warranted.60 61 BACKGROUND 63Exposure to air pollution remains a global threat with more than 90% of the world's 64 population now exceeding the exposure limits proposed for particulate matter by the World 65 Health Organization (WHO) (1). At the same time, a growing body of evidence consistently 66 supports the adverse health effects of air pollution, which the same WHO report estimates to 67 be related with 3 million premature deaths worldwide each year. However, the mechanisms 68 by which air pollution induces these deleterious effects are not completely understood. 69Epigenetics encompasses mechanisms that regulate gene expression without changing the 70 DNA sequence, and may contribute to the relation between air pollution and health. The most 71 studied epigenetic mechanism is DNA methylation, which is heritable but can also be 72 modified by life-style and environmental factors. Recently, several studies have analyzed the 73 association between air pollution and DNA methylation using a genome-wide approach, and 74 have reported numerous loci showing differential methylation related to this exposure (2-10). 75The aims of this study were bot...

Environmental determinants of cardiovascular disease: lessons learned from air pollution

“…However, the effect of exposure to air pollution on genome-wide methylation status and chromatin structure are not well understood. Small cohort studies have shown various epigenomic changes within networks enriched for pathways related to inflammation, thrombosis, insulin resistance and lipid metabolism, all of which can increase the risk of CVD 122,123 .…”

Gaseous air pollutants and DNA methylation in a methylome-wide association study of an ethnically and environmentally diverse population of U.S. adults

“…Our results highlighted shorter-term (7-and 28-day average) NO 2 and ozone concentrations as potentially important for DNAm. Because availability of data for some of these exposures was limited in the planned replication analyses in KORA and NAS, we also attempted to look up results of analyses in several recently published methylome-wide association studies involving gaseous air pollutants (de F. C. Lichtenfels et al, 2018;Sayols-Baixeras et al, 2019;Lee et al, 2019). However, none of the published studies included O 3 or shorter-term NO 2 exposures that would have enabled a relatively well-harmonized comparison of the top hits identified by the present study.…”

“…The literature examining associations between air pollution and methylome-wide DNAm has largely focused on long-term exposure to particulate matter (PM) and NO 2 air pollution (Panni et al, 2016;de F. C. Lichtenfels et al, 2018;Sayols-Baixeras et al, 2019;Plusquin et al, 2017;Lee et al, 2019;Gondalia et al, 2019); however, other pollutants and varying durations of exposure may affect methylation patterns relevant for health outcomes like CVD (Franklin et al, 2015). Existing DNAm-air pollution research is also geographically and sociodemographically limited, with much of it completed in Boston, Massachusetts and in Europe (Bind et al, 2014;Bind et al, 2012;Panni et al, 2016;de F. C. Lichtenfels et al, 2018;Sayols-Baixeras et al, 2019;Plusquin et al, 2017) among individuals of European descent. To address these gaps in research, we leveraged data from two multi-ethnic and geographically diverse populations, the Women's Health Initiative (WHI) and the Atherosclerosis Risk in Communities Study (ARIC), to examine methylome-wide associations with short-and long-term CO, NO 2 , NO x , O 3 , and SO 2 exposure.…”

DNA methylation: a potential mediator between air pollution and metabolic syndrome

“…Thus, the epigenome is increasingly being proposed as a vital link between environmental exposures and gene expression modifications. A growing body of evidence now shows that air pollution influences DNA methylation [56][57][58][59][60][61][62][63][64].…”