TY - JOUR
T1 - In silico epigenetics of metal exposure and subclinical atherosclerosis in middle aged men
T2 - Pilot results from the aragon workers health study
AU - Riffo-Campos, Angela L.
AU - Fuentes-Trillo, Azahara
AU - Tang, Wan Y.
AU - Soriano, Zoraida
AU - De Marco, Griselda
AU - Rentero-Garrido, Pilar
AU - Adam-Felici, Victoria
AU - Lendinez-Tortajada, Veronica
AU - Francesconi, Kevin
AU - Goessler, Walter
AU - Ladd-Acosta, Christine
AU - Leon-Latre, Montse
AU - Casasnovas, Jose A.
AU - Chaves, F. Javier
AU - Navas-Acien, Ana
AU - Guallar, Eliseo
AU - Tellez-Plaza, Maria
N1 - Publisher Copyright:
© 2018 The Author(s) Published by the Royal Society. All rights reserved.
PY - 2018/6/5
Y1 - 2018/6/5
N2 - 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.
AB - 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.
KW - Cohort study
KW - DNA methylation
KW - Environmental metals
KW - Subclinical atherosclerosis
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U2 - 10.1098/rstb.2017.0084
DO - 10.1098/rstb.2017.0084
M3 - Article
C2 - 29685964
AN - SCOPUS:85045925443
SN - 0962-8436
VL - 373
JO - Philosophical Transactions of the Royal Society B: Biological Sciences
JF - Philosophical Transactions of the Royal Society B: Biological Sciences
IS - 1748
M1 - 20170084
ER -