Epigenome-wide profiling of DNA methylation in paired samples of adipose tissue and blood

<p>Many epigenetic association studies have attempted to identify DNA methylation markers in blood that are able to mirror those in target tissues. Although some have suggested potential utility of surrogate epigenetic markers in blood, few studies have collected data to directly compare DNA methylation across tissues from the same individuals. Here, epigenomic data were collected from adipose tissue and blood in 143 subjects using Illumina HumanMethylation450 BeadChip array. The top axis of epigenome-wide variation differentiates adipose tissue from blood, which is confirmed internally using cross-validation and externally with independent data from the two tissues. We identified 1,285 discordant genes and 1,961 concordant genes between blood and adipose tissue. RNA expression data of the two classes of genes show consistent patterns with those observed in DNA methylation. The discordant genes are enriched in biological functions related to immune response, leukocyte activation or differentiation, and blood coagulation. We distinguish the CpG-specific correlation from the within-subject correlation and emphasize that the magnitude of within-subject correlation does not guarantee the utility of surrogate epigenetic markers. The study reinforces the critical role of DNA methylation in regulating gene expression and cellular phenotypes across tissues, and highlights the caveats of using methylation markers in blood to mirror the corresponding profile in the target tissue.</p

Nightshift work and genome-wide DNA methylation

<div><p>The negative health effects of shift work, including carcinogenesis, may be mediated by changes in DNA methylation, particularly in the circadian genes. Using the Infinium HumanMethylation450 Bead Array (Illumina, San Diego, CA), we compared genome-wide methylation between 65 actively working dayshift workers and 59 actively working nightshift workers in the healthcare industry. A total of 473 800 loci, including 391 loci across the 12 core circadian genes, were analyzed to identify methylation markers associated with shift work status using linear regression models adjusted for gender, age, body mass index, race, smoking status and leukocyte cell profile as measured by flow cytometry. Analyses at the level of gene, CpG island and gene region were also conducted. To account for multiple comparisons, we controlled the false discovery rate (FDR ≤0.05). Significant differences between nightshift and dayshift workers were found at 16 135 of 473 800 loci, across 3769 of 20 164 genes, across 7173 of 22 721 CpG islands and across 5508 of 51 843 gene regions. For each significant loci, gene, CpG island or gene region, average methylation was consistently found to be decreased among nightshift workers compared to dayshift workers. Twenty-one loci located in the circadian genes were also found to be significantly hypomethylated among nightshift workers. The largest differences were observed for three loci located in the gene body of <i>PER3</i>. A total of nine significant loci were found in the <i>CSNK1E</i> gene, most of which were located in a CpG island and near the transcription start site of the gene. Methylation changes in these circadian genes may lead to altered expression of these genes which has been associated with cancer in previous studies. Gene ontology enrichment analysis revealed that among the significantly hypomethylated genes, processes related to host defense and immunity were represented. Our results indicate that the health effects of shift work may be mediated by hypomethylation of a wide variety of genes, including those related to circadian rhythms. While these findings need to be followed-up among a considerably expanded group of shift workers, the data generated by this study supports the need for future targeted research into the potential impacts of shift work on specific carcinogenic mechanisms.</p></div

Association between <i>TMC8</i> genotype and risk of HNSCC.

<p>^a cases/controls.</p><p>^b All OR’s adjusted for sex, age, packyears smoked and average drinks per week.</p><p>Association between <i>TMC8</i> genotype and risk of HNSCC.</p

Association between <i>TMC8</i> genotype and HPV L1 seropositivity—all subjects.

<p>^a number of individuals L1 positive/L1 negative.</p><p>^b All OR’s adjusted for sex and age.</p><p>Association between <i>TMC8</i> genotype and HPV L1 seropositivity—all subjects.</p

Odds ratios for HNSCC and <i>TMC8</i> genotype among seronegative individuals.

<p>^a cases/controls.</p><p>^b OR’s adjusted for sex, age, packyears smoked and average drinks per week.</p><p>Odds ratios for HNSCC and <i>TMC8</i> genotype among seronegative individuals.</p

Demographic characteristics of cases and controls.

<p>Demographic characteristics of cases and controls.</p

Plot of model assessing effect modification by genotype on the association of blood lead and uric acid in Korean lead workers whose ages are ≥ 40

<p><b>Copyright information:</b></p><p>Taken from "Associations of Uric Acid with Polymorphisms in the δ-Aminolevulinic Acid Dehydratase, Vitamin D Receptor, and Nitric Oxide Synthase Genes in Korean Lead Workers"</p><p>Environmental Health Perspectives 2005;113(11):1509-1515.</p><p>Published online 27 Jun 2005</p><p>PMCID:PMC1310911.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p>6 years (, panel 2). Regression lines, generated using mean values of covariates in the model (age, sex, BMI, and alcohol use), are overlaid on crude data. The solid regression line represents the adjusted relation between blood lead and uric acid in older participants with the genotype (circles); the dashed regression line represents the adjusted relation between blood lead and uric acid in older participants with the genotype (stars)

Added variable plot of the model assessing effect modification by genotype on the association between tibia lead and uric acid in Korean lead workers ≥ 40

<p><b>Copyright information:</b></p><p>Taken from "Associations of Uric Acid with Polymorphisms in the δ-Aminolevulinic Acid Dehydratase, Vitamin D Receptor, and Nitric Oxide Synthase Genes in Korean Lead Workers"</p><p>Environmental Health Perspectives 2005;113(11):1509-1515.</p><p>Published online 27 Jun 2005</p><p>PMCID:PMC1310911.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p>6 years of age (median) (, panel 2). For each plot, the regression line (dashed line) and the lowess line (solid line) of the partial residual data points, adjusted for age, sex, BMI, and alcohol use, are overlaid. For ease of interpretation, axes have been scaled so that the plotted residuals are centered around mean uric acid and tibia lead, rather than around zero

<em>HSD3B</em> and Gene-Gene Interactions in a Pathway-Based Analysis of Genetic Susceptibility to Bladder Cancer

<div><p>Bladder cancer is the 4^th most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case–control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene–gene interactions using Multifactor Dimensionality Reduction (MDR) and Statistical Epistasis Network analysis. The 3′UTR flanking variant form of the hormone regulation gene <em>HSD3B2</em> was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31–2.62). This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06–12.63). The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40–3.25) than females (OR 1.56 95%CI 0.83–2.95), (SNP-gender interaction <em>P</em> = 0.048). We also identified a SNP-SNP interaction between T-cell activation related genes <em>GATA3</em> and <em>CD81</em> (interaction <em>P</em> = 0.0003). The fact that bladder cancer incidence is 3–4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.</p> </div

HSD3B2 proxy SNP is associated with bladder cancer risk in the Texas population.

<p>Adjusted for age, gender, smoking.</p