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Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure.

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Title: Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure.
Authors: Bozack, Anne K.1 anne.bozack@mssm.edu, Domingo-Relloso, Arce1,2, Haack, Karin3, Gamble, Mary V.1, Tellez-Plaza, Maria2,4, Umans, Jason G.5,6, Best, Lyle G.7, Yracheta, Joseph7, Gribble, Matthew O.8, Cardenas, Andres9, Francesconi, Kevin A.10, Goessler, Walter10, Wan-Yee Tang4, Fallin, M. Daniele11,12, Cole, Shelley A.3, Navas-Acien, Ana1
Source: Environmental Health Perspectives. Jun2020, Vol. 128 Issue 6, p067015-1-067015-12. 12p. 1 Diagram, 4 Charts, 2 Graphs.
Subject Terms: *Arsenic, *Environmental exposure, Creatinine, DNA, Genetic techniques, Genomes, Native Americans, Regression analysis, Research funding, Statistics, Urinalysis, Data analysis, DNA methylation, Descriptive statistics, Epigenomics, Cluster sampling, Evaluation, Adults
Geographic Terms: North Dakota, South Dakota, Americas
Abstract: BACKGROUND: Chronic exposure to arsenic (As), a human toxicant and carcinogen, remains a global public health problem. Health risks persist after As exposure has ended, suggesting epigenetic dysregulation as a mechanistic link between exposure and health outcomes. OBJECTIVES: We investigated the association between total urinary As and locus-specific DNA methylation in the Strong Heart Study, a cohort of American Indian adults with low-to-moderate As exposure [total urinary As, mean (±SD) μg/g creatinine: 11.7 (10.6)]. METHODS: DNA methylation was measured in 2,325 participants using the Illumina MethylationEPIC array. We implemented linear models to test differentially methylated positions (DMPs) and the DMRcate method to identify regions (DMRs) and conducted gene ontology enrichment analysis. Models were adjusted for estimated cell type proportions, age, sex, body mass index, smoking, education, estimated glomerular filtration rate, and study center. Arsenic was measured in urine as the sum of inorganic and methylated species. RESULTS: In adjusted models, methylation at 20 CpGs was associated with urinary As after false discovery rate (FDR) correction (FDR< 0.05). After Bonferroni correction, 5 CpGs remained associated with total urinary As (ρBonferroni <0.05), located in SLC7A11, ANKS3, LINGO3, CSNK1D, ADAMTSL4. We identified one DMR on chromosome 11 (chr11:2,322,050-2,323,247), annotated to C11orf2; TSPAN32 genes. DISCUSSION: This is one of the first epigenome-wide association studies to investigate As exposure and locus-specific DNA methylation using the Illumina MethylationEPIC array and the largest epigenome-wide study of As exposure. The top DMP was located in SLC7A11A, a gene involved in cystine/glutamate transport and the biosynthesis of glutathione, an antioxidant that may protect against As-induced oxidative stress. Additional DMPs were located in genes associated with tumor development and glucose metabolism. Further research is needed, including research in more diverse populations, to investigate whether As-related DNA methylation signatures are associated with gene expression or may serve as biomarkers of disease development. [ABSTRACT FROM AUTHOR]
Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure.
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  Data: &lt;searchLink fieldCode=&quot;JN&quot; term=&quot;%22Environmental+Health+Perspectives%22&quot;&gt;Environmental Health Perspectives&lt;/searchLink&gt;. Jun2020, Vol. 128 Issue 6, p067015-1-067015-12. 12p. 1 Diagram, 4 Charts, 2 Graphs.
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  Data: BACKGROUND: Chronic exposure to arsenic (As), a human toxicant and carcinogen, remains a global public health problem. Health risks persist after As exposure has ended, suggesting epigenetic dysregulation as a mechanistic link between exposure and health outcomes. OBJECTIVES: We investigated the association between total urinary As and locus-specific DNA methylation in the Strong Heart Study, a cohort of American Indian adults with low-to-moderate As exposure [total urinary As, mean (&#194;&#177;SD) μg/g creatinine: 11.7 (10.6)]. METHODS: DNA methylation was measured in 2,325 participants using the Illumina MethylationEPIC array. We implemented linear models to test differentially methylated positions (DMPs) and the DMRcate method to identify regions (DMRs) and conducted gene ontology enrichment analysis. Models were adjusted for estimated cell type proportions, age, sex, body mass index, smoking, education, estimated glomerular filtration rate, and study center. Arsenic was measured in urine as the sum of inorganic and methylated species. RESULTS: In adjusted models, methylation at 20 CpGs was associated with urinary As after false discovery rate (FDR) correction (FDR&lt; 0.05). After Bonferroni correction, 5 CpGs remained associated with total urinary As (ρBonferroni &lt;0.05), located in SLC7A11, ANKS3, LINGO3, CSNK1D, ADAMTSL4. We identified one DMR on chromosome 11 (chr11:2,322,050-2,323,247), annotated to C11orf2; TSPAN32 genes. DISCUSSION: This is one of the first epigenome-wide association studies to investigate As exposure and locus-specific DNA methylation using the Illumina MethylationEPIC array and the largest epigenome-wide study of As exposure. The top DMP was located in SLC7A11A, a gene involved in cystine/glutamate transport and the biosynthesis of glutathione, an antioxidant that may protect against As-induced oxidative stress. Additional DMPs were located in genes associated with tumor development and glucose metabolism. Further research is needed, including research in more diverse populations, to investigate whether As-related DNA methylation signatures are associated with gene expression or may serve as biomarkers of disease development. [ABSTRACT FROM AUTHOR]
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  Data: &lt;i&gt;Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder&#39;s express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.&lt;/i&gt; (Copyright applies to all Abstracts.)
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        Value: 10.1289/EHP6263
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        Text: English
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        PageCount: 12
        StartPage: 067015-1
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      – SubjectFull: Arsenic
        Type: general
      – SubjectFull: Environmental exposure
        Type: general
      – SubjectFull: Creatinine
        Type: general
      – SubjectFull: DNA
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      – SubjectFull: Genetic techniques
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      – SubjectFull: DNA methylation
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      – SubjectFull: North Dakota
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      – SubjectFull: South Dakota
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      – TitleFull: Locus-Specific Differential DNA Methylation and Urinary Arsenic: An Epigenome-Wide Association Study in Blood among Adults with Low-to-Moderate Arsenic Exposure.
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