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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 -
Fertility and Sterility Jan 2024Because analytic technologies improve, increasing amounts of data on methylation differences between assisted reproductive technology (ART) and unassisted conceptions... (Review)
Review
IMPORTANCE
Because analytic technologies improve, increasing amounts of data on methylation differences between assisted reproductive technology (ART) and unassisted conceptions are available. However, various studies use different tissue types and different populations in their analyses, making data comparison and integration difficult.
OBJECTIVE
To compare and integrate data on genome-wide analyses of methylation differences due to ART, allowing exposure of overarching themes.
EVIDENCE REVIEW
All studies undertaking genome-wide analysis of human methylation differences due to ART or infertility in any tissue type across the lifespan were assessed for inclusion.
FINDINGS
Seventeen studies were identified that met the inclusion criteria. One study assessed trophectoderm biopsies, 2 first-trimester placenta, 1 first-trimester fetal tissue, 2 term placenta, 7 cord blood, 3 newborn dried blood spots, 1 childhood buccal smears, 1 childhood peripheral blood, and 2 adult peripheral blood. Eleven studies compared tissues from in vitro fertilization (IVF) conceptions with those of unassisted conceptions, 4 compared intracytoplasmic sperm injection with unassisted conceptions, 4 compared non-IVF fertility treatment (NIFT) with unassisted conceptions, 4 compared NIFT with IVF, and 5 compared an infertile population (conceiving via various methods) with an unassisted presumably fertile population. In studies assessing placental tissue, 1 gene with potential methylation changes due to IVF when compared with unassisted conceptions was identified by 2 studies. In blood, 11 potential genes with methylation changes due to IVF compared with unassisted conceptions were identified by 2 studies, 1 of which was identified by 3 studies. Three potentially affected genes were identified by 2 studies involving blood between intracytoplasmic sperm injection and unassisted populations. There were no overlapping genes identified in any tissue type between NIFT and unassisted populations, between NIFT and IVF, or the infertility combined population when compared with the unassisted fertile population.
CONCLUSIONS
Comparing studies is challenging due to differing variables between analyses. However, even in similar tissue types and populations, overlapping methylation changes are limited, suggesting that differences due to ART are minimal.
RELEVANCE
Information from this systematic review is significant for providers and patients who provide and use ART to understand methylation risks that may be associated with the technology.
Topics: Adult; Child; Female; Humans; Infant, Newborn; Male; Pregnancy; DNA Methylation; Fertilization in Vitro; Genome-Wide Association Study; Infertility; Placenta; Reproductive Techniques, Assisted; Semen
PubMed: 37827482
DOI: 10.1016/j.fertnstert.2023.10.007 -
Epigenetics Dec 2023Research has recently begun to examine the potential intergenerational impacts of trauma on obesity. This scoping review examines the literature on the interactions... (Review)
Review
Research has recently begun to examine the potential intergenerational impacts of trauma on obesity. This scoping review examines the literature on the interactions between intergenerational trauma, epigenetics, and obesity in Indigenous populations. The review was conducted to identify what is known from the literature about how intergenerational trauma may epigenetically influence obesity in Indigenous populations. Following the PRISMA-ScR guidelines for scoping reviews, online databases were used to identify studies that included discussion of the four focus topics: trauma, epigenetics, obesity, and Indigeneity. The review resulted in six studies that examined those themes. The focus and findings of the selected studies varied from cultural to biological mechanisms and from discussion regarding trauma, epigenetics, obesity, or Indigeneity, but they support three broad statements. First, they support that obesity has genetic and epigenetic factors. Second, intergenerational trauma is prevalent in Indigenous communities. Finally, intergenerational trauma has cultural and biological influences on obesity. Current literature illustrates that intergenerational trauma has behavioural and epigenetic influences that can lead to increased obesity. This scoping review provides a preliminary map of the current literature and understandings of these topics. This review calls for continued studies regarding the connection between trauma, obesity, and epigenetics in Indigenous communities. Future research is vital for practice and policy surrounding individual and communal healing.
Topics: Humans; Historical Trauma; DNA Methylation; Indigenous Peoples; Obesity; Epigenesis, Genetic; Canada
PubMed: 37752750
DOI: 10.1080/15592294.2023.2260218 -
Clinical Epigenetics Sep 2023Undernutrition in pregnant women is an unfavorable environmental condition that can affect the intrauterine development via epigenetic mechanisms and thus have... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Undernutrition in pregnant women is an unfavorable environmental condition that can affect the intrauterine development via epigenetic mechanisms and thus have long-lasting detrimental consequences for the mental health of the offspring later in life. One epigenetic mechanism that has been associated with mental disorders and undernutrition is alterations in DNA methylation. The effect of prenatal undernutrition on the mental health of adult offspring can be analyzed through quasi-experimental studies such as famine studies. The present systematic review and meta-analysis aims to analyze the association between prenatal famine exposure, DNA methylation, and mental disorders in adult offspring. We further investigate whether altered DNA methylation as a result of prenatal famine exposure is prospectively linked to mental disorders.
METHODS
We conducted a systematic search of the databases PubMed and PsycINFO to identify relevant records up to September 2022 on offspring whose mothers experienced famine directly before and/or during pregnancy, examining the impact of prenatal famine exposure on the offspring's DNA methylation and/or mental disorders or symptoms.
RESULTS
The systematic review showed that adults who were prenatally exposed to famine had an increased risk of schizophrenia and depression. Several studies reported an association between prenatal famine exposure and hyper- or hypomethylation of specific genes. The largest number of studies reported differences in DNA methylation of the IGF2 gene. Altered DNA methylation of the DUSP22 gene mediated the association between prenatal famine exposure and schizophrenia in adult offspring. Meta-analysis confirmed the increased risk of schizophrenia following prenatal famine exposure. For DNA methylation, meta-analysis was not suitable due to different microarrays/data processing approaches and/or unavailable data.
CONCLUSION
Prenatal famine exposure is associated with an increased risk of mental disorders and DNA methylation changes. The findings suggest that changes in DNA methylation of genes involved in neuronal, neuroendocrine, and immune processes may be a mechanism that promotes the development of mental disorders such as schizophrenia and depression in adult offspring. Such findings are crucial given that undernutrition has risen worldwide, increasing the risk of famine and thus also of negative effects on mental health.
Topics: Pregnancy; Adult; Female; Humans; DNA Methylation; Famine; Mental Disorders; Vitamins; Malnutrition
PubMed: 37716973
DOI: 10.1186/s13148-023-01557-y -
Environmental Science & Technology Oct 2023Polycyclic aromatic hydrocarbon (PAH) derivatives constitute a significant class of emerging contaminants that have been ubiquitously detected in diverse environmental... (Review)
Review
Polycyclic aromatic hydrocarbon (PAH) derivatives constitute a significant class of emerging contaminants that have been ubiquitously detected in diverse environmental matrixes, with some even exhibiting higher toxicities than their corresponding parent PAHs. To date, compared with parent PAHs, fewer systematic summaries and reanalyses are available for PAH derivatives with great environmental concerns. This review summarizes the current knowledge on the chemical species, levels, biotransformation patterns, chemical analytical methods, internal exposure routes with representative biomarkers, and toxicity of PAH derivatives, primarily focusing on nitrated PAHs (NPAHs), oxygenated PAHs (OPAHs), halogenated PAHs (XPAHs), and alkylated PAHs (APAHs). A collection of 188 compounds from four categories, 44 NPAHs, 36 OPAHs, 56 APAHs, and 52 XPAHs, has been compiled from 114 studies that documented the environmental presence of PAH derivatives. These compounds exhibited weighted average air concentrations that varied from a lower limit of 0.019 pg/m to a higher threshold of 4060 pg/m. Different analytical methods utilizing comprehensive two-dimensional gas chromatography coupled with high-resolution time-of-flight mass spectrometry (GC × GC-TOF-MS), gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF-MS), comprehensive two-dimensional gas chromatography coupled to quadrupole mass spectrometry (GC × GC-QQQ-MS), and Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS), that adopted untargeted strategies for the identification of PAH derivatives are also reviewed here. Additionally, an in-depth analysis of biotransformation patterns for each category is provided, including the likelihood of specific biotransformation reaction types. For the toxicity, we primarily summarized key metabolic activation pathways, which could result in the formation of reactive metabolites capable of covalently bonding with DNA and tissue proteins, and potential health outcomes such as carcinogenicity and genotoxicity, oxidative stress, inflammation and immunotoxicity, and developmental toxicity that might be mediated by the aryl hydrocarbon receptor (AhR). Finally, we pinpoint research challenges and emphasize the need for further studies on identifying PAH derivatives, tracking external exposure levels, evaluating internal exposure levels and associated toxicity, clarifying exposure routes, and considering mixture exposure effects. This review aims to provide a broad understanding of PAH derivatives' identification, environmental occurrence, human exposure, biotransformation, and toxicity, offering a valuable reference for guiding future research in this underexplored area.
PubMed: 37703436
DOI: 10.1021/acs.est.3c03170 -
Artificial Intelligence in Medicine Sep 2023DNA methylation biomarkers have great potential in improving prognostic classification systems for patients with cancer. Machine learning (ML)-based analytic techniques... (Review)
Review
BACKGROUND
DNA methylation biomarkers have great potential in improving prognostic classification systems for patients with cancer. Machine learning (ML)-based analytic techniques might help overcome the challenges of analyzing high-dimensional data in relatively small sample sizes. This systematic review summarizes the current use of ML-based methods in epigenome-wide studies for the identification of DNA methylation signatures associated with cancer prognosis.
METHODS
We searched three electronic databases including PubMed, EMBASE, and Web of Science for articles published until 2 January 2023. ML-based methods and workflows used to identify DNA methylation signatures associated with cancer prognosis were extracted and summarized. Two authors independently assessed the methodological quality of included studies by a seven-item checklist adapted from 'A Tool to Assess Risk of Bias and Applicability of Prediction Model Studies (PROBAST)' and from the 'Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK). Different ML methods and workflows used in included studies were summarized and visualized by a sunburst chart, a bubble chart, and Sankey diagrams, respectively.
RESULTS
Eighty-three studies were included in this review. Three major types of ML-based workflows were identified. 1) unsupervised clustering, 2) supervised feature selection, and 3) deep learning-based feature transformation. For the three workflows, the most frequently used ML techniques were consensus clustering, least absolute shrinkage and selection operator (LASSO), and autoencoder, respectively. The systematic review revealed that the performance of these approaches has not been adequately evaluated yet and that methodological and reporting flaws were common in the identified studies using ML techniques.
CONCLUSIONS
There is great heterogeneity in ML-based methodological strategies used by epigenome-wide studies to identify DNA methylation markers associated with cancer prognosis. In theory, most existing workflows could not handle the high multi-collinearity and potentially non-linearity interactions in epigenome-wide DNA methylation data. Benchmarking studies are needed to compare the relative performance of various approaches for specific cancer types. Adherence to relevant methodological and reporting guidelines are urgently needed.
Topics: Humans; DNA Methylation; Epigenome; Prognosis; Neoplasms; Machine Learning
PubMed: 37673571
DOI: 10.1016/j.artmed.2023.102589 -
Biomarkers : Biochemical Indicators of... Sep 2023Colorectal cancer (CRC) poses a substantial health burden, with early detection paramount for improved prognosis. This study aims to evaluate potential CRC biomarkers...
INTRODUCTION
Colorectal cancer (CRC) poses a substantial health burden, with early detection paramount for improved prognosis. This study aims to evaluate potential CRC biomarkers and detection techniques.
MATERIALS AND METHODS
This systematic review, reported in adherence to PRISMA Statement 2020 guidelines, collates the latest research on potential biomarkers and detection/prognosis methods for CRC, spanning the last decade.
RESULTS
Out of the 38 included studies, diverse biomarkers and detection methods emerged, with DNA methylation markers like SFRP2 and SDC2, microRNAs including miR-1290, miR-506, and miR-4316, and serum and plasma markers such as NTS levels and U2 snRNA fragments standing out. Methylated cfDNA and m5C methylation alteration in immune cells of the blood, along with circular RNA, showed promise as diagnostic markers. Meanwhile, techniques involving extracellular vesicles and lateral flow immunoassays exhibited potential for swift and effective CRC screening.
DISCUSSION
Our state-of-the-art review identifies potential biomarkers, including SFRP2, SDC2, miR-1290, miR-506, miR-4316, and U2 snRNA fragments, with significant potential in enhancing CRC detection. However, comprehensive validation studies and a rigorous evaluation of clinical utility and cost-effectiveness remain necessary before integration into routine clinical practice.
CONCLUSION
The findings emphasize the need for continued research into biomarkers and detection methods to improve patient outcomes.
Topics: Humans; DNA Methylation; Biomarkers, Tumor; MicroRNAs; Prognosis; Early Detection of Cancer; Colorectal Neoplasms
PubMed: 37585692
DOI: 10.1080/1354750X.2023.2247185 -
Clinical Epigenetics Aug 2023Screening plays a key role in secondary prevention of cervical cancer. High-risk human papillomavirus (hrHPV) testing, a highly sensitive test but with limited... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Screening plays a key role in secondary prevention of cervical cancer. High-risk human papillomavirus (hrHPV) testing, a highly sensitive test but with limited specificity, has become the gold standard frontline for screening programs. Thus, the importance of effective triage strategies, including DNA methylation markers, has been emphasized. Despite the potential reported in individual studies, methylation markers still require validation before being recommended for clinical practice. This systematic review and meta-analysis aimed to evaluate the performance of DNA methylation-based biomarkers for detecting high-grade intraepithelial lesions (HSIL) in hrHPV-positive women.
METHODS
Hence, PubMed, Scopus, and Cochrane databases were searched for studies that assessed methylation in hrHPV-positive women in cervical scrapes. Histologically confirmed HSIL was used as endpoint and QUADAS-2 tool enabled assessment of study quality. A bivariate random-effect model was employed to pool the estimated sensitivity and specificity as well as positive (PPV) and negative (NPV) predictive values.
RESULTS
Twenty-three studies were included in this meta-analysis, from which cohort and referral population-based studies corresponded to nearly 65%. Most of the women analyzed were Dutch, and CADM1, FAM19A4, MAL, and miR124-2 were the most studied genes. Pooled sensitivity and specificity were 0.68 (CI 95% 0.63-0.72) and 0.75 (CI 95% 0.71-0.80) for cervical intraepithelial neoplasia (CIN) 2+ detection, respectively. For CIN3+ detection, pooled sensitivity and specificity were 0.78 (CI 95% 0.74-0.82) and 0.74 (CI 95% 0.69-0.78), respectively. For pooled prevalence, PPV for CIN2+ and CIN3+ detection were 0.514 and 0.392, respectively. Furthermore, NPV for CIN2+ and CIN3+ detection were 0.857 and 0.938, respectively.
CONCLUSIONS
This meta-analysis confirmed the great potential of DNA methylation-based biomarkers as triage tool for hrHPV-positive women in cervical cancer screening. Standardization and improved validation are, however, required. Nevertheless, these markers might represent an excellent alternative to cytology and genotyping for colposcopy referral of hrHPV-positive women, allowing for more cost-effective screening programs.
Topics: Female; Humans; Pregnancy; Uterine Cervical Neoplasms; DNA Methylation; Early Detection of Cancer; Colposcopy; Triage; Papillomavirus Infections; Referral and Consultation; Papillomaviridae; Cell Adhesion Molecule-1
PubMed: 37533074
DOI: 10.1186/s13148-023-01537-2 -
Psychosomatic Medicine Oct 2023Functional somatic syndromes (FSS) are highly prevalent across all levels of health care. The fact that they are characterized by medically unexplained symptoms, such as...
OBJECTIVE
Functional somatic syndromes (FSS) are highly prevalent across all levels of health care. The fact that they are characterized by medically unexplained symptoms, such as fatigue and pain, raises the important question of their underlying pathophysiology. Psychosocial stress represents a significant factor in the development of FSS and can induce long-term modifications at the epigenetic level. The aim of this review was to systematically review, for the first time, whether individuals with FSS are characterized by specific alterations in DNA methylation.
METHODS
MEDLINE and PsycINFO were searched from the first available date to September 2022. The inclusion criteria were as follows: a) adults fulfilling the research diagnostic criteria for chronic fatigue syndrome, fibromyalgia syndrome, and/or irritable bowel syndrome; b) healthy control group; and c) candidate-gene or genome-wide study of DNA methylation.
RESULTS
Sixteen studies ( N = 957) were included. In candidate-gene studies, specific sites within NR3C1 were identified, which were hypomethylated in individuals with chronic fatigue syndrome compared with healthy controls. In genome-wide studies in chronic fatigue syndrome, a hypomethylated site located to LY86 and hypermethylated sites within HLA-DQB1 were found. In genome-wide studies in fibromyalgia syndrome, differential methylation in sites related to HDAC4 , TMEM44 , KCNQ1 , SLC17A9 , PRKG1 , ALPK3 , TFAP2A , and LY6G5C was found.
CONCLUSIONS
Individuals with chronic fatigue syndrome and fibromyalgia syndrome seem to be characterized by altered DNA methylation of genes regulating cellular signaling and immune functioning. In chronic fatigue syndrome, there is preliminary evidence for these to be implicated in key pathophysiological alterations, such as hypocortisolism and low-grade inflammation, and to contribute to the debilitating symptoms these individuals experience.
PREREGISTRATION
PROSPERO identifier: CRD42022364720.
Topics: Adult; Humans; Fatigue Syndrome, Chronic; Fibromyalgia; DNA Methylation; Genome-Wide Association Study; Irritable Bowel Syndrome
PubMed: 37531610
DOI: 10.1097/PSY.0000000000001237 -
Environmental and Molecular Mutagenesis Aug 2023Individual differences in drug response have always existed in clinical treatment. Many non-genetic factors show non-negligible impacts on personalized medicine.... (Review)
Review
Individual differences in drug response have always existed in clinical treatment. Many non-genetic factors show non-negligible impacts on personalized medicine. Emerging studies have demonstrated epigenetic could connect non-genetic factors and individual treatment differences. We used systematic retrieval methods and reviewed studies that showed individual factors' impact on DNA methylation of drug metabolism genes. In total, 68 studies were included, and half (n = 36) were cohort studies. Six aspects of individual factors were summarized from the perspective of personalized medicine: parental exposure, environmental pollutants exposure, obesity and diet, drugs, gender and others. The most research (n = 11) focused on ABCG1 methylation. The majority of studies showed non-genetic factors could result in a significant DNA methylation alteration in drug metabolism genes, which subsequently affects the pharmacokinetic processes. However, the underlying mechanism remained unknown. Finally, some viewpoints were presented for future research.
Topics: Humans; DNA Methylation; Epigenesis, Genetic; Diet
PubMed: 37522536
DOI: 10.1002/em.22567