scholarly journals Comparison of DNA Methylation Profiles of Hemostatic Genes between Liver Tissue and Peripheral Blood within Individuals

2020 ◽  
Author(s):  
Annelie Angerfors ◽  
Martina Olsson Lindvall ◽  
Björn Andersson ◽  
Staffan Nilsson ◽  
Marcela Davila Lopez ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Peripheral Blood ◽  
Liver Tissue ◽  
Association Studies ◽  
Epidemiological Studies ◽  
Methylation Pattern ◽  
Cpg Dinucleotides ◽  
Phenotypic Differences ◽  
Targeted Bisulfite Sequencing ◽  
Hemostatic Genes

AbstractDNA methylation has become increasingly recognized in the etiology of complex diseases, including thrombotic disorders. Blood is often collected in epidemiological studies for genotyping and has recently also been used to examine DNA methylation in epigenome-wide association studies. DNA methylation patterns are often tissue-specific, thus, peripheral blood may not accurately reflect the methylation pattern in the tissue of relevance. Here, we collected paired liver and blood samples concurrently from 27 individuals undergoing liver surgery. We performed targeted bisulfite sequencing for a set of 35 hemostatic genes primarily expressed in liver to analyze DNA methylation levels of >10,000 cytosine-phosphate-guanine (CpG) dinucleotides. We evaluated whether DNA methylation in blood could serve as a proxy for DNA methylation in liver at individual CpGs. Approximately 30% of CpGs were nonvariable and were predominantly hypo- (<25%) or hypermethylated (>70%) in both tissues. While blood can serve as a proxy for liver at these CpGs, the low variability renders these unlikely to explain phenotypic differences. We therefore focused on CpG sites with variable methylation levels in liver. The level of blood–liver tissue correlation varied widely across these variable CpGs; moderate correlations (0.5 ≤ r < 0.75) were detected for 6% and strong correlations (r ≥ 0.75) for a further 4%. Our findings indicate that it is essential to study the concordance of DNA methylation between blood and liver at individual CpGs. This paired blood–liver dataset is intended as a resource to aid interpretation of blood-based DNA methylation results.

scholarly journals Genetics and Epigenetics in Asthma

2021 ◽  
Vol 22 (5) ◽  
pp. 2412
Author(s):  
Polyxeni Ntontsi ◽  
Andreas Photiades ◽  
Eleftherios Zervas ◽  
Georgina Xanthou ◽  
Konstantinos Samitas
Keyword(s):  
Dna Methylation ◽  
Association Studies ◽  
Airway Remodeling ◽  
Methylation Pattern ◽  
Atopic Asthma ◽  
Genome Wide Association Studies ◽  
Childhood Onset ◽  
Gene Markers ◽  
Asthmatic Patients ◽  
Asthma Susceptibility

Asthma is one of the most common respiratory disease that affects both children and adults worldwide, with diverse phenotypes and underlying pathogenetic mechanisms poorly understood. As technology in genome sequencing progressed, scientific efforts were made to explain and predict asthma’s complexity and heterogeneity, and genome-wide association studies (GWAS) quickly became the preferred study method. Several gene markers and loci associated with asthma susceptibility, atopic and childhood-onset asthma were identified during the last few decades. Markers near the ORMDL3/GSDMB genes were associated with childhood-onset asthma, interleukin (IL)33 and IL1RL1 SNPs were associated with atopic asthma, and the Thymic Stromal Lymphopoietin (TSLP) gene was identified as protective against the risk to TH2-asthma. The latest efforts and advances in identifying and decoding asthma susceptibility are focused on epigenetics, heritable characteristics that affect gene expression without altering DNA sequence, with DNA methylation being the most described mechanism. Other less studied epigenetic mechanisms include histone modifications and alterations of miR expression. Recent findings suggest that the DNA methylation pattern is tissue and cell-specific. Several studies attempt to describe DNA methylation of different types of cells and tissues of asthmatic patients that regulate airway remodeling, phagocytosis, and other lung functions in asthma. In this review, we attempt to briefly present the latest advancements in the field of genetics and mainly epigenetics concerning asthma susceptibility.

scholarly journals A Comprehensive Sequencing-Based Analysis of Allelic Methylation Patterns in Hemostatic Genes in Human Liver

2019 ◽  
Vol 120 (02) ◽  
pp. 229-242 ◽  
Author(s):  
Martina Olsson Lindvall ◽  
Marcela Davila Lopez ◽  
Sofia Klasson ◽  
Lena Hansson ◽  
Staffan Nilsson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Liver Tissue ◽  
Human Liver ◽  
Genome Wide Association Study ◽  
Warfarin Dose ◽  
Sequencing Data ◽  
Human Liver Tissue ◽  
In Cis ◽  
Hemostatic Genes

AbstractCharacterizing the relationship between genetic, epigenetic (e.g., deoxyribonucleic acid [DNA] methylation), and transcript variation could provide insights into mechanisms regulating hemostasis and potentially identify new drug targets. Several hemostatic factors are synthesized in the liver, yet high-resolution DNA methylation data from human liver tissue is currently lacking for these genes. Single-nucleotide polymorphisms (SNPs) can influence DNA methylation in cis which can affect gene expression. This can be analyzed through allele-specific methylation (ASM) experiments. We performed targeted genomic DNA- and bisulfite-sequencing of 35 hemostatic genes in human liver samples for SNP and DNA methylation analysis, respectively, and integrated the data for ASM determination. ASM-associated SNPs (ASM-SNPs) were tested for association to gene expression in liver using in-house generated ribonucleic acid-sequencing data. We then assessed whether ASM-SNPs associated with gene expression, plasma proteins, or other traits relevant for hemostasis using publicly available data. We identified 112 candidate ASM-SNPs. Of these, 68% were associated with expression of their respective genes in human liver or in other human tissues and 54% were associated with the respective plasma protein levels, activity, or other relevant hemostatic genome-wide association study traits such as venous thromboembolism, coronary artery disease, stroke, and warfarin dose maintenance. Our study provides the first detailed map of the DNA methylation landscape and ASM analysis of hemostatic genes in human liver tissue, and suggests that methylation regulated by genetic variants in cis may provide a mechanistic link between noncoding SNPs and variation observed in circulating hemostatic proteins, prothrombotic diseases, and drug response.

scholarly journals Epigenome-Wide Association Study Using Prediagnostic Bloods Identifies New Genomic Regions Associated With Pancreatic Cancer Risk

2020 ◽  
Vol 4 (5) ◽  
Author(s):  
Dominique S Michaud ◽  
Mengyuan Ruan ◽  
Devin C Koestler ◽  
Dong Pei ◽  
Carmen J Marsit ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Methylation ◽  
Study Design ◽  
Peripheral Blood ◽  
Association Studies ◽  
Gene Set Enrichment Analysis ◽  
Blood Collection ◽  
Blood Draw ◽  
Genomic Regions ◽  
Prospective Study Design

Abstract Background Epigenome-wide association studies using peripheral blood have identified specific sites of DNA methylation associated with risk of various cancers and may hold promise to identify novel biomarkers of risk; however, few studies have been performed for pancreatic cancer and none using a prospective study design. Methods Using a nested case-control study design, incident pancreatic cancer cases and matched controls were identified from participants who provided blood at baseline in 3 prospective cohort studies. DNA methylation levels were measured in DNA extracted from leukocytes using the Illumina MethylationEPIC array. Average follow-up period for this analysis was 13 years. Results Several new genomic regions were identified as being differentially methylated in cases and controls; the 5 strongest associations were observed for CpGs located in genes TMEM204/IFT140, MFSD6L, FAM134B/RETREG1, KCNQ1D, and C6orf227. For some CpGs located in chromosome 16p13.3 (near genes TMEM204 and IFT140), associations were stronger with shorter time to diagnosis (eg, odds ratio [OR] = 5.95, 95% confidence interval [CI] = 1.52 to 23.12, for top vs bottom quartile, for &lt;5 years between blood draw and cancer diagnosis), but associations remained statistically significantly higher even when cases were diagnosed over 10 years after blood collection. Statistically significant differences in DNA methylation levels were also observed in the gastric secretion pathway using Gene Set Enrichment Analysis (GSEA) analysis. Conclusions Changes in DNA methylation in peripheral blood may mark alterations in metabolic or immune pathways that play a role in pancreatic cancer. Identifying new biological pathways in carcinogenesis of pancreatic cancer using epigenome-wide association studies approach could provide new opportunities for improving treatment and prevention.

scholarly journals DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

2020 ◽  
Author(s):  
Jenny van Dongen ◽  
Fiona A. Hagenbeek ◽  
Matthew Suderman ◽  
Peter Roetman ◽  
Karen Sugden ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Aggressive Behavior ◽  
Peripheral Blood ◽  
Association Studies ◽  
Meta Analysis ◽  
Risk Tolerance ◽  
Blood Samples ◽  
Chemical Exposures ◽  
Starting Point

AbstractDNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N=15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha=1.2×10−7; Bonferroni correction). In cord blood samples of 2,425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r=0.74, p=0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripherl blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range=3-82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

scholarly journals DNA methylation covariation in human whole blood and sperm: implications for studies of intergenerational epigenetic effects

2020 ◽  
Author(s):  
Fredrika Åsenius ◽  
Tyler J. Gorrie-Stone ◽  
Ama Brew ◽  
Yasmin Panchbaya ◽  
Elizabeth Williamson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Human Blood ◽  
Peripheral Blood ◽  
Human Sperm ◽  
Epidemiological Studies ◽  
Somatic Tissue ◽  
Tissue Samples ◽  
Genome Wide ◽  
Wide Range ◽  
Dna Methylation Profile

AbstractBackgroundEpidemiological studies suggest that paternal obesity may increase the risk of fathering small for gestational age offspring. Studies in non-human mammals suggest that such associations could be mediated by DNA methylation changes in spermatozoa that influence offspring development in utero. Human obesity is associated with differential DNA methylation in peripheral blood. It is unclear, however, whether this differential DNA methylation is reflected in spermatozoa. We profiled genome-wide DNA methylation using the Illumina MethylationEPIC array in matched human blood and sperm from lean (discovery n=47; replication n=21) and obese (n=22) males to analyse tissue covariation of DNA methylation, and identify whether this covariation is influenced by obesity.ResultsDNA methylation signatures of human blood and spermatozoa are highly discordant, and methylation levels are correlated at only a minority of CpG sites (∼1%). While at the majority of these sites, DNA methylation appears to be influenced by genetic variation, obesity-associated DNA methylation in blood was not generally reflected in spermatozoa, and obesity did not influence covariation patterns. However, one cross-tissue obesity-specific hypermethylated site (cg19357369; chr4:2429884; P=8.95 × 10−8; beta=0.02) was identified, warranting replication and further investigation. When compared to a wide range of human somatic tissue samples (n=5,917), spermatozoa displayed differential DNA methylation in pathways enriched in transcriptional regulation.ConclusionsHuman sperm displays a unique DNA methylation profile that is highly discordant to, and practically uncorrelated with, that of matched peripheral blood. Obesity only nominally influences sperm DNA methylation, making it an unlikely mediator of intergenerational effects of metabolic traits.

scholarly journals Genome-Wide DNA Methylation Pattern in Whole Blood Associated With Primary Intracerebral Hemorrhage

2021 ◽  
Vol 12 ◽  
Author(s):  
Yupeng Zhang ◽  
Hongyu Long ◽  
Sai Wang ◽  
Wenbiao Xiao ◽  
Meishan Xiong ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Intracerebral Hemorrhage ◽  
Whole Blood ◽  
Peripheral Blood ◽  
Methylation Status ◽  
Methylation Pattern ◽  
Healthy Controls ◽  
Differentially Methylated Genes ◽  
Dna Methylation Pattern ◽  
Methylation Patterns

Primary intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality throughout the world. ICH is a multifactorial disease that emerges from interactions among multiple genetic and environmental factors. DNA methylation plays an important role in the etiology of complex traits and diseases. We used the Illumina Infinium Human Methylation 850k BeadChip to detect changes in DNA methylation in peripheral blood samples from patients with ICH and healthy controls to explore DNA methylation patterns in ICH. Here, we compared genomic DNA methylation patterns in whole blood from ICH patients (n = 30) and controls (n = 34). The ICH and control groups showed significantly different DNA methylation patterns at 1530 sites (p-value &lt; 5.92E-08), with 1377 hypermethylated sites and 153 hypomethylated sites in ICH patients compared to the methylation status in healthy controls. A total of 371 hypermethylated sites and 35 hypomethylated sites were in promoters, while 738 hypermethylated sites and 67 hypomethylated sites were in coding regions. Furthermore, the differentially methylated genes between ICH patients and controls were largely related to inflammatory pathways. Abnormalities in the DNA methylation pattern identified in the peripheral blood of ICH patients may play an important role in the development of ICH and warranted further investigation.

LPCAT2 Methylation, a Novel Biomarker for the Severity of Cedar Pollen Allergic Rhinitis in Japan

2020 ◽  
pp. 194589242098364
Author(s):  
Hiroyuki Watanabe ◽  
Kunio Miyake ◽  
Tomokazu Matsuoka ◽  
Reiji Kojima ◽  
Daiju Sakurai ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Negative Correlation ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Immunoglobulin E ◽  
Association Studies ◽  
Significant Negative Correlation ◽  
Specific Ige ◽  
Interleukin 4 ◽  
Cedar Pollen

Background Recently, the role of the epigenome in allergies has been receiving increasing attention. Although several genes that are methylated in relation to serum immunoglobulin E (IgE) concentration have been reported by epigenome-wide association studies, little is known about the DNA methylation sites associated with the symptoms and severity of cedar pollinosis (CP). Objective Our aim was to analyze the association between DNA methylation and the symptoms and severity of CP in peripheral blood mononuclear cells (PBMCs) and nasal mucosa scraping cells (NMSCs). Methods We recruited 70 participants during the cedar pollen dispersal season. IgE levels were measured by a fluorescence enzyme immunoassay. We analyzed DNA methylation of acyl-CoA thioesterase 7 ( ACOT7), mucin 4 ( MUC4), schlafen 12 ( SLFN12), lysophosphatidylcholine acyltransferase 2 ( LPCAT2), and interleukin-4 ( IL4) in PBMCs and NMSCs using bisulfite next-generation sequencing; the correlation of DNA methylation with non-specific IgE and cedar pollen-specific IgE levels in peripheral blood samples was also investigated. Symptom severity and DNA methylation were investigated in 15 untreated CP patients. Results Non-specific IgE levels showed a significant negative correlation with average IL4 methylation in PBMCs (r = −0.46, P < 0.0001) but not with methylation of ACOT7, MUC4, SLFN12, and LPCAT2. Cedar pollen-specific IgE levels showed a significant negative correlation with average IL4 and MUC4 methylation in PBMCs (r = −0.31, P = 0.01 and r = −0.241, P = 0.046, respectively) but not with methylation of ACOT7, SLFN12, and LPCAT2. The methylation of some genes in NMSCs was not significantly correlated with IgE levels. The mean methylation of LPCAT2 in NMSCs showed a decreasing trend with increasing severity of CP (P = 0.027). Conclusion LPCAT2 methylation in NMSCs may reflect the severity of CP and could be used as a novel biomarker to identify suitable treatment options for CP.

scholarly journals Epigenome-wide association study using prediagnostic bloods identifies a new genomic region (near TMEM204 and IFT140) associated with pancreatic cancer risk

2020 ◽  
Author(s):  
Dominique S. Michaud ◽  
Mengyuan Ruan ◽  
Devin C. Koestler ◽  
Dong Pei ◽  
Carmen J. Marsit ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Methylation ◽  
Study Design ◽  
Peripheral Blood ◽  
Association Studies ◽  
Health Study ◽  
Blood Collection ◽  
Blood Draw ◽  
Prospective Study Design

AbstractBackgroundEpigenome-wide association studies (EWAS) using peripheral blood have identified specific sites of DNA methylation associated with risk of various cancers and may hold promise to identify novel biomarkers of risk; however, few studies have been performed for pancreatic cancer and none using a prospective study design.MethodsUsing a nested case-control study design, incident pancreatic cancer cases and matched controls were identified from participants who provided blood at baseline in three prospective cohort studies (Nurses’ Health Study, Health Professionals Follow-up Study and Physicians’ Health Study). DNA methylation levels were measured in DNA extracted from leukocytes using the Illumina MethylationEPIC array. Average follow-up period for this analysis was 13 years.ResultsA region in chromosome 16 near genesTMEM204 and IFT140 was identified as being differentially methylated in cases and controls. For some CpGs in the region, the associations were stronger with shorter time to diagnosis (e.g., OR= 5.95, 95% CI = 1.52-23.12, for top vs bottom quartile, for <5 years between blood draw and cancer diagnosis) but associations remained significantly higher even when cases were diagnosed over 10 years after blood collection. Statistically significant differences in DNA methylation levels were also observed in the gastric secretion pathway using GSEA analysis.ConclusionsChanges in DNA methylation in peripheral blood may mark alterations in metabolic or immune pathways (potentially including alterations in immune subtypes) that play a role in pancreatic cancer. Identifying new biological pathways in carcinogenesis of pancreatic cancer using EWAS approach could provide new opportunities for improving treatment and prevention.

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