Integrating SNPs-based genetic risk factor with blood epigenomic response of differentially arsenic-exposed rural subjects reveals disease-associated signaling pathways.
Autor: | Rehman MYA; Environmental Health Laboratory, Department of Environmental Sciences, Quaid-i-Azam University, Islamabad, Pakistan., Briedé JJ; Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, the Netherlands. Electronic address: J.Briede@maastrichtuniversity.nl., van Herwijnen M; Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, the Netherlands., Krauskopf J; Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, the Netherlands., Jennen DGJ; Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, the Netherlands., Malik RN; Environmental Health Laboratory, Department of Environmental Sciences, Quaid-i-Azam University, Islamabad, Pakistan., Kleinjans JCS; Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, the Netherlands. |
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Jazyk: | angličtina |
Zdroj: | Environmental pollution (Barking, Essex : 1987) [Environ Pollut] 2022 Jan 01; Vol. 292 (Pt A), pp. 118279. Date of Electronic Publication: 2021 Oct 04. |
DOI: | 10.1016/j.envpol.2021.118279 |
Abstrakt: | Arsenic (As) contamination in groundwater is responsible for numerous adverse health outcomes among millions of people. Epigenetic alterations are among the most widely studied mechanisms of As toxicity. To understand how As exposure alters gene expression through epigenetic modifications, a systematic genome-wide study was designed to address the impact of multiple important single nucleotide polymorphisms (SNPs) related to As exposure on the methylome of drinking water As-exposed rural subjects from Pakistan. Urinary As levels were used to stratify subjects into low, medium and high exposure groups. Genome-wide DNA methylation was investigated using MeDIP in combination with NimbleGen 2.1 M Deluxe Promotor arrays. Transcriptome levels were measured using Agilent 8 × 60 K expression arrays. Genotyping of selected SNPs (As3MT, DNMT1a, ERCC2, EGFR and MTHFR) was measured and an integrated genetic risk factor for each respondent was calculated by assigning a specific value to the measured genotypes based on known risk allele numbers. To select a representative model related to As exposure we compared 9 linear mixed models comprising of model 1 (including the genetic risk factor), model 2 (without the genetic risk factor) and models with individual SNPs incorporated into the methylome data. Pathway analysis was performed using ConsensusPathDB. Model 1 comprising the integrated genetic risk factor disclosed biochemical pathways including muscle contraction, cardio-vascular diseases, ATR signaling, GPCR signaling, methionine metabolism and chromatin modification in association with hypo- and hyper-methylated gene targets. A unique pathway (direct P53 effector) was found associated with the individual DNMT1a polymorphism due to hyper-methylation of CSE1L and TRRAP. Most importantly, we provide here the first evidence of As-associated DNA methylation in relation with gene expression of ATR, ATF7IP, TPM3, UBE2J2. We report the first evidence that integrating SNPs data with methylome data generates a more representative epigenome profile and discloses a better insight in disease risks of As-exposed individuals. (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.) |
Databáze: | MEDLINE |
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