Integrating SNPs-based genetic risk factor with blood epigenomic response of differentially arsenic-exposed rural subjects reveals disease-associated signaling pathways. (1st January 2022)

• Record Type: Journal Article
• Authors: Rehman, Muhammad Yasir Abdur; Briedé, Jacco Jan; van Herwijnen, Marcel; Krauskopf, Julian; Jennen, Danyel G.J.; Malik, Riffat Naseem; Kleinjans, Jos C.S.
• Is Part Of: Environmental pollution. Volume 292:Part A(2022)
• Publication Date: 2022-01-01
• Subjects: Arsenic -- Epigenome -- SNPs -- Risk factor -- Pathways -- Drinking water -- Pakistan; As Arsenic -- WHO World Health Organization -- CHIP Chromatin Immunoprecipitation -- CTD Comparative Toxicogenomics Database -- DCM Dilated Cardiomyopathy -- DDR DNA Damage Response -- DNMTs DNA Methyl Transferases -- EWAS Epigenome-Wide Association Studies -- HCM Hypertrophic Cardiomyopathy -- IARC International Agency for Research on Cancer -- LMM Linear Mixed Models -- SEG Significantly Expressed Gene -- MeDIP Methylated DNA Immunoprecipitation -- PBMC Peripheral Blood Mononuclear Cells -- SMR Significantly Methylated Region -- SMG Significantly Methylated Gene -- SNP Single Nucleotide Polymorphism; Pollution -- Periodicals; Pollution -- Environmental aspects -- Periodicals; Environmental Pollution -- Periodicals; Pollution -- Périodiques; Pollution -- Aspect de l'environnement -- Périodiques; Pollution -- Effets physiologiques -- Périodiques; Pollution; Pollution -- Environmental aspects; Periodicals; Electronic journals; 363.73
• DOI: 10.1016/j.envpol.2021.118279
• Languages: English
• ISSNs: 0269-7491

Abstract

Abstract: 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. Highlights: Analysis of global blood methylome changes associated with As exposure via drinking water. Integrating As-related SNPs with epigenome data yielded refined methylome profiles. Novel As-related signaling and disease pathways found associated with As exposure. Evidence of As-induced interplay between DNA methylation and gene expression.