Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults

AbstractSynthetic glucocorticoids (sGC) are administered to women at risk of preterm delivery, approximately 10% of all pregnancies. In animal models, offspring exposed to elevated glucocorticoids, either by administration of sGC or endogenous glucocorticoids as a result of maternal stress, show increased risk of developing behavioral, endocrine, and metabolic dysregulation. DNA methylation may play a critical role in long-lasting programming of gene regulation underlying these phenotypes. However, peripheral tissues such as blood are often the only accessible source of DNA for epigenetic analyses in humans. Here, we examined the hypothesis that prenatal sGC administration alters DNA methylation signatures in guinea pig offspring hippocampus and whole blood. We compared these signatures across the two tissue types to assess epigenetic biomarkers of common molecular pathways affected by sGC exposure. Guinea pigs were treated with sGC or saline in late gestation. Genome-wide modifications of DNA methylation were analyzed at single nucleotide resolution using reduced representation bisulfite sequencing in juvenile female offspring. Results indicate that there are tissue-specific as well as common methylation signatures of prenatal sGC exposure. Over 90% of the common methylation signatures associated with sGC exposure showed the same directionality of change in methylation. Among differentially methylated genes, 134 were modified in both hippocampus and blood, of which 61 showed methylation changes at identical CpG sites. Gene pathway analyses indicated that prenatal sGC exposure alters the methylation status of gene clusters involved in brain development. These data indicate concordance across tissues of epigenetic programming in response to alterations in glucocorticoid signaling.

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Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases

Clinical Epigenetics ◽

10.1186/s13148-021-01041-5 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Chen Yao ◽

Roby Joehanes ◽

Rory Wilson ◽

Toshiko Tanaka ◽

Luigi Ferrucci ◽

...

Keyword(s):

Gene Expression ◽

Lung Cancer ◽

Dna Methylation ◽

Cigarette Smoking ◽

Association Study ◽

Whole Blood ◽

Lung Diseases ◽

Epigenetic Modification ◽

Blood Gene Expression ◽

Increased Risk

Abstract Background DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. Results We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. Conclusions Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.

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Urate-induced epigenetic modifications in myeloid cells

Arthritis Research & Therapy ◽

10.1186/s13075-021-02580-1 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

M. Badii ◽

O. I. Gaal ◽

M. C. Cleophas ◽

V. Klück ◽

R. Davar ◽

...

Keyword(s):

Dna Methylation ◽

Whole Blood ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Myeloid Cells ◽

Cytokine Signaling ◽

Human Monocytes ◽

Methylation Array ◽

Histone 3 ◽

Msu Crystals

Abstract Objectives Hyperuricemia is a metabolic condition central to gout pathogenesis. Urate exposure primes human monocytes towards a higher capacity to produce and release IL-1β. In this study, we assessed the epigenetic processes associated to urate-mediated hyper-responsiveness. Methods Freshly isolated human peripheral blood mononuclear cells or enriched monocytes were pre-treated with solubilized urate and stimulated with LPS with or without monosodium urate (MSU) crystals. Cytokine production was determined by ELISA. Histone epigenetic marks were assessed by sequencing immunoprecipitated chromatin. Mice were injected intraarticularly with MSU crystals and palmitate after inhibition of uricase and urate administration in the presence or absence of methylthioadenosine. DNA methylation was assessed by methylation array in whole blood of 76 participants with normouricemia or hyperuricemia. Results High concentrations of urate enhanced the inflammatory response in vitro in human cells and in vivo in mice, and broad-spectrum methylation inhibitors reversed this effect. Assessment of histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac) revealed differences in urate-primed monocytes compared to controls. Differentially methylated regions (e.g. HLA-G, IFITM3, PRKAB2) were found in people with hyperuricemia compared to normouricemia in genes relevant for inflammatory cytokine signaling. Conclusion Urate alters the epigenetic landscape in selected human monocytes or whole blood of people with hyperuricemia compared to normouricemia. Both histone modifications and DNA methylation show differences depending on urate exposure. Subject to replication and validation, epigenetic changes in myeloid cells may be a therapeutic target in gout.

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DNA Methylation in Whole Blood: Uses and Challenges

Current Environmental Health Reports ◽

10.1007/s40572-015-0050-3 ◽

2015 ◽

Vol 2 (2) ◽

pp. 145-154 ◽

Cited By ~ 58

Author(s):

E. Andres Houseman ◽

Stephanie Kim ◽

Karl T. Kelsey ◽

John K. Wiencke

Keyword(s):

Dna Methylation ◽

Whole Blood

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Effects on DNA methylation of arsenic exposure in utero

Arsenic in the Environment - Proceedings - Arsenic Research and Global Sustainability ◽

10.1201/b20466-207 ◽

2016 ◽

pp. 446-447

Author(s):

K Engström ◽

M Kippler ◽

R Raqib ◽

S Ahmed ◽

M Vahter ◽

...

Keyword(s):

Dna Methylation ◽

Arsenic Exposure ◽

In Utero

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Butyrate and related epigenetic changes link Parkinson's disease to inflammatory bowel disease and depressive symptoms

10.1101/2021.09.17.21263343 ◽

2021 ◽

Author(s):

Aoji Xie ◽

Elizabeth Ensink ◽

Peipei Li ◽

Juozas Gordevicius ◽

Lee L. Marshall ◽

...

Keyword(s):

Parkinson’S Disease ◽

Dna Methylation ◽

Parkinson's Disease ◽

Depressive Symptoms ◽

Gut Microbiome ◽

Whole Blood ◽

Blood Samples ◽

Targeted Bisulfite Sequencing ◽

Genome Wide ◽

Whole Blood Samples

Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Here, we investigate whether the changes in the gut microbiome and associated metabolites are linked to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified the genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced Roseburia, Romboutsia, and Prevotella counts are linked to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA (mDNA) regions in PD overlap with those altered in gastrointestinal, autoimmune, and psychiatric diseases.

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Cord blood buffy coat DNA methylation is comparable to whole cord blood methylation

10.1101/181057 ◽

2017 ◽

Author(s):

John Dou ◽

Rebecca J. Schmidt ◽

Kelly S. Benke ◽

Craig Newschaffer ◽

Irva Hertz-Picciotto ◽

...

Keyword(s):

Dna Methylation ◽

Blood Cell ◽

Cord Blood ◽

Whole Blood ◽

Cell Types ◽

Buffy Coat ◽

Sample Type ◽

Blood Samples ◽

Cell Composition ◽

Cell Counts

AbstractBackgroundCord blood DNA methylation is associated with numerous health outcomes and environmental exposures. Whole cord blood DNA reflects all nucleated blood cell types, while centrifuging whole blood separates red blood cells by generating a white blood cell buffy coat. Both sample types are used in DNA methylation studies. Cell types have unique methylation patterns and processing can impact cell distributions, which may influence comparability.ObjectivesTo evaluate differences in cell composition and DNA methylation between buffy coat and whole cord blood samples.MethodsCord blood DNA methylation was measured with the Infinium EPIC BeadChip (Illumina) in 8 individuals, each contributing buffy coat and whole blood samples. We analyzed principal components (PC) of methylation, performed hierarchical clustering, and computed correlations of mean-centered methylation between pairs. We conducted moderated t-tests on single sites and estimated cell composition.ResultsDNA methylation PCs were associated with individual (PPC1=1.4x10-9; PPC2=2.9x10-5; PPC3=3.8x10-5; PPC4=4.2x10-6; PPC5=9.9x10-13), and not with sample type (PPC1-5>0.7). Samples hierarchically clustered by individual. Pearson correlations of mean-centered methylation between paired individual samples ranged from r=0.66 to r=0.87. No individual site significantly differed between buffy coat and whole cord blood when adjusting for multiple comparisons (5 sites had unadjusted P<10-5). Estimated cell type proportions did not differ by sample type (P=0.86), and estimated cell counts were highly correlated between paired samples (r=0.99).ConclusionsDifferences in methylation and cell composition between buffy coat and whole cord blood are much lower than inter-individual variation, demonstrating that both sample preparation types can be analytically combined and compared.

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DNA methylation in cord blood as mediator of the association between prenatal arsenic exposure and gestational age

Epigenetics ◽

10.1080/15592294.2018.1516453 ◽

2018 ◽

Vol 13 (9) ◽

pp. 923-940 ◽

Cited By ~ 3

Author(s):

Anne K. Bozack ◽

Andres Cardenas ◽

Quazi Quamruzzaman ◽

Mahmuder Rahman ◽

Golam Mostofa ◽

...

Keyword(s):

Dna Methylation ◽

Cord Blood ◽

Gestational Age ◽

Arsenic Exposure

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Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease

Nature Communications ◽

10.1038/s41467-019-12228-z ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 14

Author(s):

Tianxiao Huan ◽

Roby Joehanes ◽

Ci Song ◽

Fen Peng ◽

Yichen Guo ◽

...

Keyword(s):

Cardiovascular Disease ◽

Dna Methylation ◽

Whole Blood ◽

Association Studies ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Transcriptional Regulatory ◽

Disease Associations ◽

Independent Replication ◽

Functional Mechanisms

Abstract Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.

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