Format

Send to

Choose Destination
Philos Trans R Soc Lond B Biol Sci. 2018 Jun 5;373(1748). pii: 20170084. doi: 10.1098/rstb.2017.0084.

In silico epigenetics of metal exposure and subclinical atherosclerosis in middle aged men: pilot results from the Aragon Workers Health Study.

Author information

1
Area of Cardiometabolic Risk, Institute for Biomedical Research Hospital Clinic of Valencia, Menendez Pelayo 4 Accesorio, 46010 Valencia, Spain.
2
Genomics and Genetic Diagnostic Unit, Institute for Biomedical Research Hospital Clinic of Valencia, Menendez Pelayo 4 Accesorio, 46010 Valencia, Spain.
3
Department of Environmental Health and Engineering, Johns Hopkins University, Baltimore, MD 21205, USA.
4
Instituto de Investigación Sanitaria de Aragon, 50009 Zaragoza, Spain.
5
Institute of Chemistry, University of Graz, 8010 Graz, Austria.
6
Department of Epidemiology, Johns Hopkins University, Baltimore, MD 21205, USA.
7
Servicio Aragones de Salud, 50071 Zaragoza, Spain.
8
Instituto Aragonés de Ciencias de Salud, 50009 Zaragoza, Spain.
9
Universidad de Zaragoza, 50009 Zaragoza, Spain.
10
Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY 10032, USA.
11
Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
12
Area of Cardiometabolic Risk, Institute for Biomedical Research Hospital Clinic of Valencia, Menendez Pelayo 4 Accesorio, 46010 Valencia, Spain maria.tellez@incliva.es.

Abstract

We explored the association of metal levels with subclinical atherosclerosis and epigenetic changes in relevant biological pathways. Whole blood DNA Infinium Methylation 450 K data were obtained from 23 of 73 middle age men without clinically evident cardiovascular disease (CVD) who participated in the Aragon Workers Health Study in 2009 (baseline visit) and had available baseline urinary metals and subclinical atherosclerosis measures obtained in 2010-2013 (follow-up visit). The median metal levels were 7.36 µg g-1, 0.33 µg g-1, 0.11 µg g-1 and 0.07 µg g-1, for arsenic (sum of inorganic and methylated species), cadmium, antimony and tungsten, respectively. Urine cadmium and tungsten were associated with femoral and carotid intima-media thickness, respectively (Pearson's r = 0.27; p = 0.03 in both cases). Among nearest genes to identified differentially methylated regions (DMRs), 46% of metal-DMR genes overlapped with atherosclerosis-DMR genes (p < 0.001). Pathway enrichment analysis of atherosclerosis-DMR genes showed a role in inflammatory, metabolic and transport pathways. In in silico protein-to-protein interaction networks among proteins encoded by 162 and 108 genes attributed to atherosclerosis- and metal-DMRs, respectively, with proteins known to have a role in atherosclerosis pathways, we observed hub proteins in the network associated with both atherosclerosis and metal-DMRs (e.g. SMAD3 and NOP56), and also hub proteins associated with metal-DMRs only but with relevant connections with atherosclerosis effectors (e.g. SSTR5, HDAC4, AP2A2, CXCL12 and SSTR4). Our integrative in silico analysis demonstrates the feasibility of identifying epigenomic regions linked to environmental exposures and potentially involved in relevant pathways for human diseases. While our results support the hypothesis that metal exposures can influence health due to epigenetic changes, larger studies are needed to confirm our pilot results.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

KEYWORDS:

DNA methylation; cohort study; environmental metals; subclinical atherosclerosis

PMID:
29685964
PMCID:
PMC5915723
DOI:
10.1098/rstb.2017.0084
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center