scholarly journals Longitudinal Changes of One-Carbon Metabolites and Amino Acid Concentrations during Pregnancy in the Women First Maternal Nutrition Trial

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Stephanie P Gilley ◽  
Nicholas E Weaver ◽  
Evan L Sticca ◽  
Purevsuren Jambal ◽  
Alexandra Palacios ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Amino Acid ◽  
Multiple Testing ◽  
Maternal Nutrition ◽  
Longitudinal Research ◽  
Maternal Blood ◽  
Replication Cohort ◽  
Multiple Testing Correction ◽  
Group A ◽  
Study Sites

ABSTRACT Background Maternal dietary restriction and supplementation of one-carbon (1C) metabolites can impact offspring growth and DNA methylation. However, longitudinal research of 1C metabolite and amino acid (AA) concentrations over the reproductive cycle of human pregnancy is limited. Objective To investigate longitudinal 1C metabolite and AA concentrations prior to and during pregnancy and the effects of a small-quantity lipid-based nutrition supplement (LNS) containing >20 micronutrients and prepregnancy BMI (ppBMI). Methods This study was an ancillary study of the Women First Trial (NCT01883193, clinicaltrials.gov) focused on a subset of Guatemalan women (n = 134), 49% of whom entered pregnancy with a BMI ≥25 kg/m2. Ninety-five women received LNS during pregnancy (+LNS group), while the remainder did not (−LNS group). A subset of women from the Pakistan study site (n = 179) were used as a replication cohort, 124 of whom received LNS. Maternal blood was longitudinally collected on dried blood spot (DBS) cards at preconception, and at 12 and 34 wk gestation. A targeted metabolomics assay was performed on DBS samples at each time point using LC-MS/MS. Longitudinal analyses were performed using linear mixed modeling to investigate the influence of time, LNS, and ppBMI. Results Concentrations of 23 of 27 metabolites, including betaine, choline, and serine, changed from preconception across gestation after application of a Bonferroni multiple testing correction (P < 0.00185). Sixteen of those metabolites showed similar changes in the replication cohort. Asymmetric and symmetric dimethylarginine were decreased by LNS in the participants from Guatemala. Only tyrosine was statistically associated with ppBMI at both study sites. Conclusions Time influenced most 1C metabolite and AA concentrations with a high degree of similarity between the 2 diverse study populations. These patterns were not significantly altered by LNS consumption or ppBMI. Future investigations will focus on 1C metabolite changes associated with infant outcomes, including DNA methylation. This trial was registered at clinicaltrials.gov as NCT01883193.

scholarly journals Epigenome-Wide Study of Brain DNA Methylation Among Opioid Users and Controls

2020 ◽  
Author(s):  
Chang Shu ◽  
David W. Sosnowski ◽  
Ran Tao ◽  
Amy Deep-Soboslay ◽  
Joel E. Kleinman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Multiple Testing ◽  
The United States ◽  
Opioid Abuse ◽  
Current Evidence ◽  
Opioid Use ◽  
Multiple Testing Correction ◽  
Potential Biomarker ◽  
Opioid Intoxication ◽  
Opioid Users

AbstractOpioid abuse poses significant risk to individuals in the United States and epigenetic changes are a leading potential biomarker of abuse. Current evidence, however, is mostly limited to candidate gene analysis in whole blood. To clarify the association between opioid abuse and DNA methylation, we conducted an epigenome-wide analysis (EWAS) of DNA methylation in brains of individuals who died from opioid intoxication and controls. Tissue samples were extracted from the dorsolateral prefrontal cortex of 160 deceased individuals (Mage = 35.15, SD = 9.42 years; 62% male; 78% White). The samples included 73 individuals who died of opioid intoxication, 59 group-matched psychiatric controls, and 28 group-matched normal controls. EWAS was implemented using the Illumina Infinium MethylationEPIC BeadChip; analyses adjusted for sociodemographic characteristics, negative control and ancestry principal components, cellular composition, and surrogate variables. Epigenetic age was calculated using the Horvath and Levine clocks, and gene ontology (GO) analyses were performed. No CpG sites were epigenome-wide significant after multiple testing correction, but 13 sites reached nominal significance (p < 1.0 x 10-5). There was a significant association between opioid use and Levine phenotypic age (b = 2.24, se = 1.11, p = .045). Opioid users were approximately two years phenotypically older compared to controls. GO analyses revealed enriched pathways related to cell function and neuron differentiation, but no terms survived multiple testing correction. Results inform our understanding of the neurobiology of opioid use, and future research with larger samples across stages of opioid use will elucidate the complex genomics of opioid abuse.

Childhood exposure to hunger: associations with health outcomes in later life and epigenetic markers

Epigenomics ◽  
2020 ◽  
Vol 12 (21) ◽  
pp. 1861-1870
Author(s):  
Laura Perna ◽  
Yan Zhang ◽  
Beate Wild ◽  
Matthias Kliegel ◽  
Andreas Ihle ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Depressive Symptoms ◽  
Health Outcomes ◽  
Multiple Testing ◽  
Later Life ◽  
Population Based ◽  
German Population ◽  
Multiple Testing Correction ◽  
Childhood Exposure ◽  
Infant Exposure

Aim: To assess associations of early exposure to hunger with depressive symptoms and cardiovascular disease (CVD) and to investigate possible epigenetic pathways. Patients & methods: Data were based on a German population-based cohort of older adults (n = 9631). Regression models were performed for health outcomes in later life. An epigenome-wide association study for early-life exposure to hunger was performed in a subgroup (n = 2221) with whole blood DNA methylation data. Results: Childhood exposure to hunger was associated with CVD and depressive symptoms in later life. Prenatal or infant exposure was strongly associated with depressive symptoms. No CpG reached epigenome-wide significance after multiple testing correction. Conclusion: Childhood hunger is a risk factor for depressive symptoms and CVD at older age. DNA methylation could not explain this association.

scholarly journals Accelerated DNA methylation aging and increased resilience in veterans: the biological cost for soldiering on

2017 ◽  
Author(s):  
Divya Mehta ◽  
Dagmar Bruenig ◽  
Bruce Lawford ◽  
Wendy Harvey ◽  
Tania Carrillo-Roa ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Protective Factors ◽  
Multiple Testing ◽  
Chronological Age ◽  
P Value ◽  
Epigenetic Clock ◽  
Multiple Testing Correction ◽  
Epigenetic Aging ◽  
The Difference ◽  
Biological Cost

AbstractAccelerated epigenetic aging, the difference between the DNA methylation-predicted age (DNAm age) and the chronological age, is associated with a myriad of diseases. This study investigates the relationship between epigenetic aging and risk and protective factors of PTSD. Genome-wide DNA methylation analysis was performed in 211 individuals including combat-exposed Australian veterans (discovery cohort, n = 96 males) and trauma-exposed civilian males from the Grady Trauma Project (replication cohort, n = 115 males). Primary measures included the Clinician Administered PTSD Scale for DSM-5 and the Connor-Davidson Resilience Scale (CDRISC). DNAm age prediction was performed using the validated epigenetic clock calculator. Veterans with PTSD had increased PTSD symptom severity (P-value = 3.75 x 10-34) and lower CDRISC scores (P-value = 7.5 x 10-8) than veterans without PTSD. DNAm age was significantly correlated with the chronological age (P-value = 3.3 x 10-6), but DNAm age acceleration was not different between the PTSD and non-PTSD groups (P-value = 0.24). Evaluating potential protective factors, we found that DNAm age acceleration was significantly associated with CDRISC resilience scores in veterans with PTSD, these results remained significant after multiple testing correction (P-value = 0.023; r = 0.32). This finding was also replicated in an independent trauma-exposed civilian cohort (P-value = 0.02; r = 0.23). Post-hoc factor analyses revealed that this association was driven by “self-efficacy” items within the CDRISC (P-value = 0.015). These results suggest that among individuals already suffering from PTSD, some aspects of increased resilience might come at a biological cost.

scholarly journals Epigenome Wide Association and Stochastic Epigenetic Mutation Analysis on Cord Blood of Preterm Birth

2020 ◽  
Vol 21 (14) ◽  
pp. 5044
Author(s):  
Elena Spada ◽  
Luciano Calzari ◽  
Luigi Corsaro ◽  
Teresa Fazia ◽  
Monica Mencarelli ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Preterm Birth ◽  
Cord Blood ◽  
Multiple Testing ◽  
Multiple Testing Correction ◽  
450K Array ◽  
Genome Wide ◽  
Complex Process ◽  
Preterm Group ◽  
Epigenetic Signatures

Preterm birth (PTB) can be defined as the endpoint of a complex process that could be influenced by maternal and environmental factors. Epigenetics recently emerged as an interesting field of investigation since it represents an important mechanism of regulation. This study evaluates epigenetic impact of preterm birth on DNA methylation. Genome-wide DNAm was measured using the Illumina 450K array in cord blood samples obtained from 72 full term and 18 preterm newborns. Lymphocyte composition was calculated based on specific epigenetic markers that are present on the 450k array. Differential methylation analysis was performed both at site and region level; moreover, stochastic epigenetic mutations (SEMs) were also evaluated. The study showed significant differences in blood cell composition between the two groups. Moreover, after multiple testing correction, statistically significant differences in DNA methylation levels emerged between the two groups both at site and region levels. Results obtained were compared to those reported by previous EWAS, leading to a list of more consistent genes associated with PTB. Finally, the SEMs analysis revealed that the burden of SEMs resulted significantly higher in the preterm group. In conclusion, PTB resulted associated to specific epigenetic signatures that involve immune system. Moreover, SEMs analysis revealed an increased epigenetic drift at birth in the preterm group.

scholarly journals Sensitive periods for the effect of childhood adversity on DNA methylation: Results from a prospective, longitudinal study

2018 ◽  
Author(s):  
Erin C. Dunn ◽  
Thomas W. Soare ◽  
Andrew J. Simpkin ◽  
Matthew J. Suderman ◽  
Yiwen Zhu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Longitudinal Study ◽  
Early Life ◽  
Multiple Testing ◽  
Sensitive Period ◽  
Multiple Testing Correction ◽  
Early Life Adversity ◽  
Prospective Longitudinal Study ◽  
Sensitive Periods ◽  
Prospective Longitudinal

AbstractBackgroundExposure to “early life” adversity is known to predict DNA methylation (DNAm) patterns that may be related to prolonged psychiatric risk. However, few studies have investigated whether adversity has time-dependent effects based on the age at exposure.MethodsUsing a two-stage structured life course modeling approach (SLCMA), we tested the hypothesis that there are sensitive periods when adversity induced greater DNAm changes. We tested this hypothesis in relation to two alternative explanations: an accumulation hypothesis, in which the effect of adversity on DNAm increases with the number of occasions exposed, regardless of timing, and a recency model, in which the effect of adversity is stronger for more proximal events. Data came from the Accessible Resource for Integrated Epigenomics Studies (ARIES), a subsample of mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC; n=670-776).ResultsAfter covariate adjustment and multiple testing correction, we identified 40 CpG sites that were differentially methylated at age 7 following exposure to adversity. Most loci (n=32) were predicted by the timing of adversity, namely exposures during infancy. Neither the accumulation nor recency of the adversity explained considerable variability in DNAm. A standard EWAS of lifetime exposure (vs. no exposure) failed to detect these associations.ConclusionsThe developmental timing of adversity explains more variability in DNAm than the accumulation or recency of exposure. Infancy appears to be a sensitive period when exposure to adversity predicts differential DNAm patterns. Classification of individuals as exposed vs. unexposed to “early life” adversity may dilute observed effects.

scholarly journals Modulation of the immune system during postpartum uterine inflammation

2015 ◽  
Vol 47 (4) ◽  
pp. 89-101 ◽  
Author(s):  
Caroline G. Walker ◽  
Susanne Meier ◽  
Hassan Hussein ◽  
Scott McDougall ◽  
Chris R. Burke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Immune Response ◽  
Multiple Testing ◽  
Expression Profiles ◽  
Gene Set Enrichment Analysis ◽  
Immune Response Gene ◽  
Multiple Testing Correction ◽  
Uterine Inflammation ◽  
Subclinical Endometritis

Postpartum uterine inflammation (endometritis) in the dairy cow is associated with lower fertility at both the time of infection and after the inflammation has resolved. We hypothesized that aberrant DNA methylation may be involved in the subfertility associated with uterine inflammation. The objective of this study was to characterize genome-wide DNA methylation and gene expression in the endometrium of dairy cows with subclinical endometritis (SCE). Endometrial tissues were obtained at 29 days postpartum ( n = 12), and microarrays were used to characterize transcription and DNA methylation. Analyses revealed 1,856 probes differentially expressed in animals with SCE ( n = 6) compared with controls (CON, n = 6, P < 0.05, Storey Multiple testing correction) and 2,976 probes with significant correlation between gene expression and bacteriology score. No significant associations among DNA methylation and gene expression were detected. Analysis of transcription data using the Database for Annotation, Visualization, and Integrated Discovery and Gene Set Enrichment Analysis identified several pathways and processes enriched in SCE cows, with the majority related to the immune response. Furthermore, the top ontology terms enriched in genes that had expression data correlated to bacteriology score were: Defense response, inflammatory response, and innate immune response. Gene expression profiles in cows with subclinical endometritis in this study indicate that the immune response is activated, potentially resulting in a local proinflammatory environment in the uterus. If this period of inflammation is prolonged it could result in tissue damage or failure to complete involution of the uterus, which may create a suboptimal environment for future pregnancy.

scholarly journals Smoking, DNA Methylation, and Breast Cancer: A Mendelian Randomization Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Haibo Tang ◽  
Desong Yang ◽  
Chaofei Han ◽  
Ping Mu
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Multiple Testing ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Cancer Tissue ◽  
Nucleotide Polymorphisms ◽  
Multiple Testing Correction ◽  
Cpg Sites ◽  
Meta Analyses

BackgroundSmoking was strongly associated with breast cancer in previous studies. Whether smoking promotes breast cancer through DNA methylation remains unknown.MethodsTwo-sample Mendelian randomization (MR) analyses were conducted to assess the causal effect of smoking-related DNA methylation on breast cancer risk. We used 436 smoking-related CpG sites extracted from 846 middle-aged women in the ARIES project as exposure data. We collected summary data of breast cancer from one of the largest meta-analyses, including 69,501 cases for ER+ breast cancer and 21,468 cases for ER− breast cancer. A total of 485 single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for smoking-related DNA methylation. We further performed an MR Steiger test to estimate the likely direction of causal estimate between DNA methylation and breast cancer. We also conducted colocalization analysis to evaluate whether smoking-related CpG sites shared a common genetic causal SNP with breast cancer in a given region.ResultsWe established four significant associations after multiple testing correction: the CpG sites of cg2583948 [OR = 0.94, 95% CI (0.91–0.97)], cg0760265 [OR = 1.07, 95% CI (1.03–1.11)], cg0420946 [OR = 0.95, 95% CI (0.93–0.98)], and cg2037583 [OR =1.09, 95% CI (1.04–1.15)] were associated with the risk of ER+ breast cancer. All the four smoking-related CpG sites had a larger variance than that in ER+ breast cancer (all p &lt; 1.83 × 10−11) in the MR Steiger test. Further colocalization analysis showed that there was strong evidence (based on PPH4 &gt; 0.8) supporting a common genetic causal SNP between the CpG site of cg2583948 [with IMP3 expression (PPH4 = 0.958)] and ER+ breast cancer. There were no causal associations between smoking-related DNA methylation and ER− breast cancer.ConclusionsThese findings highlight potential targets for the prevention of ER+ breast cancer. Tissue-specific epigenetic data are required to confirm these results.

scholarly journals Epigenetic DNA methylation changes associated with headache chronification: A retrospective case-control study

Cephalalgia ◽  
2017 ◽  
Vol 38 (2) ◽  
pp. 312-322 ◽  
Author(s):  
Bendik S Winsvold ◽  
Priit Palta ◽  
Else Eising ◽  
Christian M Page ◽  
Arn MJM van den Maagdenberg ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Multiple Testing ◽  
Chronic Headache ◽  
Meta Analysis ◽  
Linear Regression Analysis ◽  
Enrichment Analysis ◽  
Functional Enrichment ◽  
Multiple Testing Correction ◽  
Retrospective Case ◽  
Cpg Sites

Background The biological mechanisms of headache chronification are poorly understood. We aimed to identify changes in DNA methylation associated with the transformation from episodic to chronic headache. Methods Participants were recruited from the population-based Norwegian HUNT Study. Thirty-six female headache patients who transformed from episodic to chronic headache between baseline and follow-up 11 years later were matched against 35 controls with episodic headache. DNA methylation was quantified at 485,000 CpG sites, and changes in methylation level at these sites were compared between cases and controls by linear regression analysis. Data were analyzed in two stages (Stages 1 and 2) and in a combined meta-analysis. Results None of the top 20 CpG sites identified in Stage 1 replicated in Stage 2 after multiple testing correction. In the combined meta-analysis the strongest associated CpG sites were related to SH2D5 and NPTX2, two brain-expressed genes involved in the regulation of synaptic plasticity. Functional enrichment analysis pointed to processes including calcium ion binding and estrogen receptor pathways. Conclusion In this first genome-wide study of DNA methylation in headache chronification several potentially implicated loci and processes were identified. The study exemplifies the use of prospectively collected population cohorts to search for epigenetic mechanisms of disease.

scholarly journals Genetic biomarkers in the VEGF pathway predicting response to anti-VEGF therapy in age-related macular degeneration

2019 ◽  
Vol 4 (1) ◽  
pp. e000273
Author(s):  
Irina Balikova ◽  
Laurence Postelmans ◽  
Brigitte Pasteels ◽  
Pascale Coquelet ◽  
Janet Catherine ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Macular Degeneration ◽  
Treatment Response ◽  
Multiple Testing ◽  
Age Related Macular Degeneration ◽  
Patient Specific ◽  
Multiple Testing Correction ◽  
Anti Vegf ◽  
Age Related ◽  
Vegf Pathway

ObjectiveAge-related macular degeneration (ARMD) is a leading cause of visual impairment. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) are the standard treatment for wet ARMD. There is however, variability in patient responses, suggesting patient-specific factors influencing drug efficacy. We tested whether single nucleotide polymorphisms (SNPs) in genes encoding VEGF pathway members contribute to therapy response.Methods and analysisA retrospective cohort of 281 European wet ARMD patients treated with anti-VEGF was genotyped for 138 tagging SNPs in the VEGF pathway. Per patient, we collected best corrected visual acuity at baseline, after three loading injections and at 12 months. We also registered the injection number and changes in retinal morphology after three loading injections (central foveal thickness (CFT), intraretinal cysts and serous neuroepithelium detachment). Changes in CFT after 3 months were our primary outcome measure. Association of SNPs to response was assessed by binomial logistic regression. Replication was attempted by associating visual acuity changes to genotypes in an independent Japanese cohort.ResultsAssociation with treatment response was detected for seven SNPs, including in FLT4 (rs55667289: OR=0.746, 95% CI 0.63 to 0.88, p=0.0005) and KDR (rs7691507: OR=1.056, 95% CI 1.02 to 1.10, p=0.005; and rs2305945: OR=0.963, 95% CI 0.93 to 1.00, p=0.0472). Only association with rs55667289 in FLT4 survived multiple testing correction. This SNP was unavailable for testing in the replication cohort. Of six SNPs tested for replication, one was significant although not after multiple testing correction.ConclusionIdentifying genetic variants that define treatment response can help to develop individualised therapeutic approaches for wet ARMD patients and may point towards new targets in non-responders.

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