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

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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.
Environmental Health Perspectives ( IF 10.1 ) Pub Date : 2020-6-30 , DOI: 10.1289/ehp6263
Anne K Bozack ₁ , Arce Domingo-Relloso _{1,

2} , Karin Haack ₃ , Mary V Gamble ₁ , Maria Tellez-Plaza _{2,

4} , Jason G Umans _{5,

6} , Lyle G Best ₇ , Joseph Yracheta ₇ , Matthew O Gribble ₈ , Andres Cardenas ₉ , Kevin A Francesconi ₁₀ , Walter Goessler ₁₀ , Wan-Yee Tang ₄ , M Daniele Fallin _{11,

12} , Shelley A Cole ₃ , Ana Navas-Acien ₁

Affiliation

Department of Environmental Health Science, Columbia University, New York, New York, USA.
Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institutes, Madrid, Spain.
Population Health Program, Texas Biomedical Research Institute, San Antonio, Texas, USA.
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
MedStar Health Research Institute, Washington, District of Columbia, USA.
Center for Clinical and Translational Sciences, Georgetown/Howard Universities, Washington, DC, USA.
Missouri Breaks Industries Research, Eagle Butte, South Dakota, USA.
Department of Environmental Health, Emory University Rollins School of Public Health, Atlanta, Georgia, USA.
Division of Environmental Health Sciences, School of Public Health, University of California, Berkley, California, USA.
Institute of Chemistry, University of Graz, Graz, Austria.
Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Wendy Klag Center for Autism and Developmental Disabilities, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

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, $mean (\pm SD) μ g / g$ 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 ( $FDR less than 0.05$ ). After Bonferroni correction, 5 CpGs remained associated with total urinary As ( $p subscript Bonferroni less than 0.05$ ), 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. https://doi.org/10.1289/EHP6263

中文翻译：

位点特异性差异 DNA 甲基化和尿砷：低至中度砷暴露成人血液中的表观基因组范围关联研究。

抽象的

背景：

长期接触砷（As）这种人类毒物和致癌物，仍然是一个全球公共卫生问题。砷暴露结束后，健康风险仍然存在，这表明表观遗传失调是暴露与健康结果之间的机制联系。

目标：

我们在“强心脏研究”中研究了尿总砷与位点特异性 DNA 甲基化之间的关联，该研究是一组具有低至中度砷暴露的美洲印第安成年人[总尿砷， $意思是（ \pm 标清） μ 克 / 克$ 肌酐：11.7 (10.6)]。

方法：

使用 Illumina MmethylationEPIC 阵列测量了 2,325 名参与者的 DNA 甲基化。我们实施线性模型来测试差异甲基化位置（DMP）和DMRcate方法来识别区域（DMR）并进行基因本体富集分析。根据估计的细胞类型比例、年龄、性别、体重指数、吸烟、教育、估计的肾小球滤过率和研究中心对模型进行了调整。尿液中的砷是无机砷和甲基化砷的总和。

结果：

在调整后的模型中，错误发现率 (FDR) 校正后，20 个 CpG 的甲基化与尿 As 相关（ $罗斯福 < 0.05$ ）。 Bonferroni 校正后，5 个 CpG 仍与尿总砷相关（ $p_{邦费罗尼} < 0.05$ ），位于SLC7A11 、 ANKS3 、 LINGO3 、 CSNK1D 、 ADAMTSL4 。我们在 11 号染色体 (chr11:2,322,050-2,323,247) 上发现了一个 DMR，注释为C11orf2 ； TSPAN32基因。

讨论：

这是使用 Illumina MmethylationEPIC 阵列研究砷暴露和位点特异性 DNA 甲基化的首批全表观基因组关联研究之一，也是最大的砷暴露全表观基因组研究。顶部 DMP 位于SLC7A11A中，该基因参与胱氨酸/谷氨酸转运和谷胱甘肽的生物合成，谷胱甘肽是一种抗氧化剂，可以防止砷诱导的氧化应激。其他 DMP 位于与肿瘤发展和葡萄糖代谢相关的基因中。需要进一步的研究，包括在更多样化的人群中进行研究，以调查 As 相关的 DNA 甲基化特征是否与基因表达相关或可以作为疾病发展的生物标志物。 https://doi.org/10.1289/EHP6263

更新日期：2020-06-30

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