-
Diabetologia Feb 2018Epigenetic mechanisms may play an important role in the aetiology of type 2 diabetes. Recent epigenome-wide association studies (EWASs) identified several DNA... (Review)
Review
DNA methylation markers associated with type 2 diabetes, fasting glucose and HbA levels: a systematic review and replication in a case-control sample of the Lifelines study.
AIMS/HYPOTHESIS
Epigenetic mechanisms may play an important role in the aetiology of type 2 diabetes. Recent epigenome-wide association studies (EWASs) identified several DNA methylation markers associated with type 2 diabetes, fasting glucose and HbA levels. Here we present a systematic review of these studies and attempt to replicate the CpG sites (CpGs) with the most significant associations from these EWASs in a case-control sample of the Lifelines study.
METHODS
We performed a systematic literature search in PubMed and EMBASE for EWASs to test the association between DNA methylation and type 2 diabetes and/or glycaemic traits and reviewed the search results. For replication purposes we selected 100 unique CpGs identified in peripheral blood, pancreas, adipose tissue and liver from 15 EWASs, using study-specific Bonferroni-corrected significance thresholds. Methylation data (Illumina 450K array) in whole blood from 100 type 2 diabetic individuals and 100 control individuals from the Lifelines study were available. Multivariate linear models were used to examine the associations of the specific CpGs with type 2 diabetes and glycaemic traits.
RESULTS
From the 52 CpGs identified in blood and selected for replication, 15 CpGs showed nominally significant associations with type 2 diabetes in the Lifelines sample (p < 0.05). The results for five CpGs (in ABCG1, LOXL2, TXNIP, SLC1A5 and SREBF1) remained significant after a stringent multiple-testing correction (changes in methylation from -3% up to 3.6%, p < 0.0009). All associations were directionally consistent with the original EWAS results. None of the selected CpGs from the tissue-specific EWASs were replicated in our methylation data from whole blood. We were also unable to replicate any of the CpGs associated with HbA levels in the healthy control individuals of our sample, while two CpGs (in ABCG1 and CCDC57) for fasting glucose were replicated at a nominal significance level (p < 0.05).
CONCLUSIONS/INTERPRETATION
A number of differentially methylated CpGs reported to be associated with type 2 diabetes in the EWAS literature were replicated in blood and show promise for clinical use as disease biomarkers. However, more prospective studies are needed to support the robustness of these findings.
Topics: Blood Glucose; CpG Islands; DNA Methylation; Diabetes Mellitus, Type 2; Epigenesis, Genetic; Fasting; Genome-Wide Association Study; Glycated Hemoglobin; Humans
PubMed: 29164275
DOI: 10.1007/s00125-017-4497-7 -
Nutrition, Metabolism, and... Jul 2016New evidence suggests the potential involvement of epigenetic mechanisms in type 2 diabetes (T2D) as a crucial interface between the effects of genetic predisposition... (Review)
Review
BACKGROUND
New evidence suggests the potential involvement of epigenetic mechanisms in type 2 diabetes (T2D) as a crucial interface between the effects of genetic predisposition and environmental influences.
AIM
To systematically review studies investigating the association between epigenetic marks (DNA methylation and histone modifications) with T2D and glycemic traits (glucose and insulin levels, insulin resistance measured by HOMA-IR).
METHOD AND RESULTS
Six bibliographic databases (Embase.com, Medline (Ovid), Web-of-Science, PubMed, Cochrane Central and Google Scholar) were screened until 28th August 2015. We included randomized controlled trials, cohort, case-control and cross-sectional studies in humans that examined the association between epigenetic marks (global, candidate or genome-wide methylation of DNA and histone modifications) with T2D, glucose and insulin levels and insulin metabolism. Of the initially identified 3879 references, 53 articles, based on 47 unique studies met our inclusion criteria. Overall, data were available on 10,823 participants, with a total of 3358 T2D cases. There was no consistent evidence for an association between global DNA-methylation with T2D, glucose, insulin and insulin resistance. The studies reported epigenetic regulation of several candidate genes for diabetes susceptibility in blood cells, muscle, adipose tissue and placenta to be related with T2D without any general overlap between them. Histone modifications in relation to T2D were reported only in 3 observational studies.
CONCLUSIONS AND RELEVANCE
Current evidence supports an association between epigenetic marks and T2D. However, overall evidence is limited, highlighting the need for further larger-scale and prospective investigations to establish whether epigenetic marks may influence the risk of developing T2D.
Topics: Acetylation; Biomarkers; Blood Glucose; Chromatin Assembly and Disassembly; DNA Methylation; Diabetes Mellitus, Type 2; Epigenesis, Genetic; Female; Gene Expression Regulation; Gene-Environment Interaction; Genetic Association Studies; Genetic Predisposition to Disease; Histones; Humans; Insulin; Insulin Resistance; Male; Phenotype; Risk Factors
PubMed: 27146363
DOI: 10.1016/j.numecd.2016.04.002 -
Progress in Lipid Research Oct 2016Epigenetic mechanisms, including DNA methylation and histone modifications, might be involved in the regulation of blood lipid concentration variability and may thereby... (Review)
Review
Epigenetic mechanisms, including DNA methylation and histone modifications, might be involved in the regulation of blood lipid concentration variability and may thereby affect cardiovascular health. We aimed to systematically review studies investigating the association between epigenetic marks and plasma concentrations of triacylglycerol, total cholesterol, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. Six medical databases were searched until September 3rd 2015, reference lists were screened, and experts in the field were contacted. Of the 757 identified references, 31 articles reporting on 23 unique studies met all inclusion criteria. These studies included data on 8027 unique participants. Overall, no consistent associations were observed between global DNA methylation and blood lipids. Candidate gene and epigenome-wide association studies reported epigenetic regulation of several genes to be related with blood lipids, of which results for ABCG1, CPT1A, TNNT1, MIR33B, SREBF1, and TNIP were replicated. To date, no studies have been performed on histone modification in relation to blood lipids. To conclude, promising results have been reported in the field of epigenetics and dyslipidaemia, however, further rigorous studies are needed to expand our understanding on the role of epigenetics in regulating human's blood lipid levels and its effects on health and disease.
Topics: ATP Binding Cassette Transporter 1; Carrier Proteins; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; DNA Methylation; Dyslipidemias; Epigenomics; Humans; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins; Niemann-Pick C1 Protein; Triglycerides
PubMed: 27746199
DOI: 10.1016/j.plipres.2016.10.002 -
International Journal of Molecular... May 2023Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, the underlying pathological mechanisms of which are not yet completely understood. Although... (Review)
Review
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, the underlying pathological mechanisms of which are not yet completely understood. Although several genetic and genomic alterations have been linked to ASD, for the majority of ASD patients, the cause remains unknown, and the condition likely arises due to complex interactions between low-risk genes and environmental factors. There is increasing evidence that epigenetic mechanisms that are highly sensitive to environmental factors and influence gene function without altering the DNA sequence, particularly aberrant DNA methylation, are involved in ASD pathogenesis. This systematic review aimed to update the clinical application of DNA methylation investigations in children with idiopathic ASD, investigating its potential application in clinical settings. To this end, a literature search was performed on different scientific databases using a combination of terms related to the association between peripheral DNA methylation and young children with idiopathic ASD; this search led to the identification of 18 articles. In the selected studies, DNA methylation is investigated in peripheral blood or saliva samples, at both gene-specific and genome-wide levels. The results obtained suggest that peripheral DNA methylation could represent a promising methodology in ASD biomarker research, although further studies are needed to develop DNA-methylation-based clinical applications.
Topics: Humans; Child; Child, Preschool; DNA Methylation; Autism Spectrum Disorder; Epigenesis, Genetic; Biomarkers; Phenotype
PubMed: 37298088
DOI: 10.3390/ijms24119138 -
PloS One 2014Accumulating evidence supports a role of DNA methylation in the pathogenesis of leukemia. The aim of our study was to evaluate the potential genes with aberrant DNA... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Accumulating evidence supports a role of DNA methylation in the pathogenesis of leukemia. The aim of our study was to evaluate the potential genes with aberrant DNA methylation in the prediction of leukemia risk by a comprehensive meta-analysis of the published data.
METHODS
A series of meta-analyses were done among the eligible studies that were harvested after a careful filtration of the searching results from PubMed literature database. Mantel-Haenszel odds ratios and 95% confidence intervals were computed for each methylation event assuming the appropriate model.
RESULTS
A total of 535 publications were initially retrieved from PubMed literature database. After a three-step filtration, we harvested 41 case-control articles that studied the role of gene methylation in the prediction of leukemia risk. Among the involving 30 genes, 20 genes were shown to be aberrantly methylated in the leukemia patients. A further subgroup meta-analysis by subtype of leukemia showed that CDKN2A, CDKN2B, ID4 genes were significantly hypermethylated in acute myeloid leukemia.
CONCLUSIONS
Our meta-analyses identified strong associations between a number of genes with aberrant DNA methylation and leukemia. Further studies should be required to confirm the results in the future.
Topics: DNA Methylation; Genetic Predisposition to Disease; Humans; Leukemia
PubMed: 24810788
DOI: 10.1371/journal.pone.0096822 -
Journal of Traumatic Stress Apr 2020Most people will experience a traumatic event within their lifetime. One commonly recognized response to trauma exposure is posttraumatic stress disorder (PTSD). The...
Most people will experience a traumatic event within their lifetime. One commonly recognized response to trauma exposure is posttraumatic stress disorder (PTSD). The biological underpinnings of PTSD, including epigenetic mechanisms of DNA methylation and gene expression, have been studied intensively. However, psychological posttrauma responses vary widely and can include positive outcomes, such as posttraumatic growth (PTG) and, more commonly, resilience. The aim of this systematic review was to summarize the current DNA methylation and gene expression data with respect to three potential posttrauma responses: PTSD, PTG, and resilience. A literature search identified 486 studies, 51 of which were deemed eligible for inclusion (total N = 10,633). All included studies examined PTSD and consistently implicated DNA methylation and gene expression changes in hypothalamic-pituitary-adrenal axis and inflammatory genes. Ten studies acknowledged resilience as a posttrauma response, but only two studies examined epigenetics and gene expression using a scale to measure resilience. Low resilience was associated with gene expression patterns in immune and dopamine genes, and high resilience was associated with a blunted inflammatory response. No studies examined epigenetic or gene expression changes associated with PTG. These findings highlight a focus on pathogenic research, which has failed to adequately acknowledge and measure positive posttrauma outcomes of PTG and resilience. Future research should examine DNA methylation and gene expression changes associated with PTG and resilience in addition to PTSD in order to gain a more comprehensive picture of an individual's well-being following exposure to trauma.
Topics: Adaptation, Psychological; DNA Methylation; Gene Expression Regulation; Humans; Posttraumatic Growth, Psychological; Resilience, Psychological; Stress Disorders, Post-Traumatic; Stress, Physiological
PubMed: 31951051
DOI: 10.1002/jts.22472 -
Journal of Oral Pathology & Medicine :... Feb 2024Aberrant epigenetic modifications significantly develop and progress human malignancies including head and neck squamous cell carcinoma (HNSCC). Taking into account... (Review)
Review
BACKGROUND
Aberrant epigenetic modifications significantly develop and progress human malignancies including head and neck squamous cell carcinoma (HNSCC). Taking into account issues of late diagnosis and poor prognosis associated with HNSCC, this systematic review is designed to provide an up-to-date insight of epigenetic changes in the management of HNSCC.
METHODS
All studies that assessed the diagnostic and prognostic utilities of epigenetic changes (DNA methylation and histone modifications) among patients diagnosed with HNSCC or oral potentially malignant disorders (OPMDs) were considered for inclusion till June 2023. Pre-defined Medical Subject Headings terms were used to search Web of Science, Pubmed, Scopus and Embase Ovid databases.
RESULTS
Twenty-five studies were deemed eligible for inclusion with a total number of 3790 samples (2123 HNSCCs, 334 OPMDs and 1333 as controls). DNA methylation was investigated in 18 studies while the role of histone modifications was assessed in seven studies. The most investigated biomarkers among the studies were H3, DAPK and TIMP3. The diagnostic accuracy of the epigenetic biomarkers in detecting HNSCC was assessed in eight studies where the following biomarkers showed the highest area under the curve values: TIPM3, DCC, DAPK, SEPT9, SHOX9, HOXA9 and TRH. None of the studies assessed the predictability of the epigenetic biomarkers in HNSCC and OPMDs.
CONCLUSION
Although initial promising results were seen using the epigenetic biomarkers in the early detection of HNSCC, the limited number of patients and the absence of well-designed longitudinal studies limit the clinical applicability of the outcomes.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Epigenesis, Genetic; Head and Neck Neoplasms; DNA Methylation; Prognosis; Biomarkers, Tumor
PubMed: 38316046
DOI: 10.1111/jop.13513 -
Molecular Human Reproduction Jul 2022Polycystic ovary syndrome (PCOS) is often associated with aberrant DNA methylation. Despite the advances in diagnostics and treatment of PCOS, the pathophysiological... (Meta-Analysis)
Meta-Analysis
Polycystic ovary syndrome (PCOS) is often associated with aberrant DNA methylation. Despite the advances in diagnostics and treatment of PCOS, the pathophysiological mechanism remains unknown. Several genes are epigenetically dysregulated in PCOS and associated with pathological consequences of PCOS and metabolic comorbidities; however, the methylation status of specific genes and to what extent the genes are deregulated in terms of methylation pattern are unknown. This review aimed to analyse the existing data for specific genes and find conclusive evidence of their involvement in PCOS and associated risks. A comprehensive literature search was conducted in five electronic databases. The case-controlled clinical studies using both PCOS and healthy women and evaluating the methylation pattern without any treatment or intervention were included in the study. A random-effect model was used to extract the data for meta-analysis, and outcomes were expressed as standardized mean difference with a 95% CI. From 541 screened records, 41 studies were included in the review and 21 of them were used for meta-analysis of 20 genes. Meta-analysis revealed a significant global DNA hypomethylation in different tissues and peripheral blood of patients with PCOS compared to healthy controls. Specific gene methylation assessment revealed that genes associated with several functions were significantly hypomethylated and hypermethylated in patients with PCOS. This review provides conclusive evidence of epigenetic deregulation of specific genes in PCOS. These genes can potentially be used to develop diagnostic biomarkers or as targets for personalized therapy.
Topics: Case-Control Studies; DNA; DNA Methylation; Female; Genomics; Humans; Polycystic Ovary Syndrome
PubMed: 35789386
DOI: 10.1093/molehr/gaac024 -
Lifestyle Genomics 2023DNA methylation patterns are directly associated with diverse metabolic disorders. The status of methyl-donor micronutrients has been associated with DNA methylation... (Meta-Analysis)
Meta-Analysis
BACKGROUND
DNA methylation patterns are directly associated with diverse metabolic disorders. The status of methyl-donor micronutrients has been associated with DNA methylation levels, and altered ingestion of folate, choline, betaine, B vitamins and methionine may impact genes both globally and at the level of promoter regions. Despite this, the role of methyl-donor micronutrient supplementation on DNA methylation profiles is currently unclear.
OBJECTIVES
The aims of this systematic review and meta-analysis were to identify and synthesize the evidence about methyl-donor nutrient supplementation on DNA methylation.
METHODS
A systematic literature search was performed in Medline, Embase, Scopus, and Web of Science databases with a combination of terms related to DNA methylation assessment, supplementation, and methyl-donor nutrients. Studies (in vitro, animal models, or human clinical trials) were included if DNA methylation levels after any kind of methyl-donor micronutrient supplementation or treatment was investigated. Studies were assessed for bias using Revised Cochrane risk-of-bias tool for randomized trials, risk-of-bias in Non-randomized Studies of Interventions or Systematic Review Centre for Laboratory Animal Experimentation tools. Data were extracted from studies measuring DNA methylation levels in any sample or tissue, following any kind of methyl-donor micronutrient supplementation or treatment. Separate random-effects meta-analyses were performed for animal model studies and human clinical trials that examined the effects of folic acid supplementation on DNA methylation.
RESULTS
Fifty-seven studies were included in this systematic review: 18 human clinical trials, 35 in animal model, and 4 in vitro studies. Concerning overall risk of bias, most of the studies were classified as "high risk" or "some concerns." Meta-analysis with meta-regression from studies in animal models showed that folic acid dose significantly affected DNA methylation and that high and very high doses showed increases in DNA methylation when compared to low doses. However, meta-analysis of human clinical trials showed that folic acid supplementation did not promote significant changes in DNA methylation when compared to placebo.
CONCLUSION
Folic acid supplementation may change global DNA methylation levels in animals supplemented with high, as compared to low, doses. Heterogeneity in studies and supplementation protocols make it difficult to establish clinical recommendations. However, these effects, even if small, might be of clinical importance in the management of patients with diseases related to DNA hypomethylation.
Topics: Humans; Animals; DNA Methylation; Folic Acid; Dietary Supplements; Vitamin B Complex; Micronutrients
PubMed: 37935134
DOI: 10.1159/000533193 -
BMC Genetics Jan 2016Increasing evidence suggests the involvement of epigenetic processes in the development of schizophrenia and bipolar disorder, and recent reviews have focused on...
BACKGROUND
Increasing evidence suggests the involvement of epigenetic processes in the development of schizophrenia and bipolar disorder, and recent reviews have focused on findings in post-mortem brain tissue. A systematic review was conducted to synthesise and evaluate the quality of available evidence for epigenetic modifications (specifically DNA methylation) in peripheral blood and saliva samples of schizophrenia and bipolar disorder patients in comparison to healthy controls.
METHODS
Original research articles using humans were identified using electronic databases. There were 33 included studies for which data were extracted and graded in duplicate on 22 items of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement, to assess methodological precision and quality of reporting.
RESULTS
There were 15 genome-wide and 18 exclusive candidate gene loci investigations for DNA methylation studies. A number of common genes were identified as differentially methylated in schizophrenia/bipolar disorder, which were related to reelin, brain-derived neurotrophic factor, dopamine (including the catechol-O-methyltransferase gene), serotonin and glutamate, despite inconsistent findings of hyper-, hypo-, or lack of methylation at these and other loci. The mean STROBE score of 59% suggested moderate quality of available evidence; however, wide methodological variability contributed to a lack of consistency in the way methylation levels were quantified, such that meta-analysis of the results was not possible.
CONCLUSIONS
Moderate quality of available evidence shows some convergence of differential methylation at some common genetic loci in schizophrenia and bipolar disorder, despite wide variation in methodology and reporting across studies. Improvement in the clarity of reporting clinical and other potential confounds would be useful in future studies of epigenetic processes in the context of exposure to environmental and other risk factors.
Topics: Bipolar Disorder; DNA Methylation; Humans; Reelin Protein; Saliva; Schizophrenia
PubMed: 26809779
DOI: 10.1186/s12863-016-0332-2