scholarly journals Polymethylation Scores for Prenatal Maternal Smoke Exposure Persist Until Age 15 and Are Detected in Saliva

2021 ◽  
Author(s):  
Freida A Blostein ◽  
Jonah Fisher ◽  
John Dou ◽  
Lisa Schenper ◽  
Erin B Ware ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Standard Deviation ◽  
Maternal Smoking ◽  
Meta Analysis ◽  
Smoke Exposure ◽  
Receiver Operating Curve ◽  
P Value ◽  
Full Sample ◽  
Clinical Biomarkers ◽  
Prenatal Maternal Smoking

Background: Prenatal maternal smoking has negative implications for child health. DNA methylation signatures can function as biomarkers of prenatal maternal smoking. However little work has assessed how DNA methylation signatures of prenatal maternal smoking vary across ages, ancestry groups, or tissues. In the Fragile Families and Child Wellbeing study, we tested whether prenatal maternal smoking was associated with salivary polymethylation scores for smoking in participants. We assessed the consistency of associations at ages 9 and 15, their portability across participants from African, European, and Hispanic genetic ancestries and the accuracy of exposure classification using area under the curve (AUC) from receiver operating curve analyses. Results: We created saliva polymethylation scores using coefficients from a meta-analysis of prenatal maternal smoke exposure and DNA methylation in newborn cord blood. In the full sample at age 9 (n=753), prenatal maternal smoke exposure was associated with a 0.52 (95%CI: 0.36, 0.67) standard deviation higher polymethylation score for prenatal smoke exposure The direction and magnitude of the association was consistent when stratified by genetic ancestries. In the full sample at age 15 (n=746), prenatal maternal smoke exposure was associated with a 0.46 (95%CI: 0.3, 0.62) standard deviation higher polymethylation score for prenatal smoke exposure, and the effect size was attenuated among the European and Hispanic genetic ancestry samples. The polymethylation score was reasonably accurate at classifying prenatal maternal smoke exposure (AUC age 9=0.77, P value<0.001, age 15=0.77, P value<0.001). The polymethylation score showed higher classification accuracy than using a single a priori site in the AHRR gene (cg05575921 AUC=0.74, P value=0.03; age 15=0.73, P value=0.01). Conclusions: Prenatal maternal smoking was associated with DNA methylation signatures in saliva samples, a clinically practical tissue. Polymethylation scores for prenatal maternal smoking were portable across genetic ancestries and more accurate than individual DNA methylation sites. DNA polymethylation scores from saliva samples could serve as robust and practical clinical biomarkers of prenatal maternal smoke exposure.

scholarly journals P13.15 DNA methylation abnormalities in non-promoter regulatory regions are associated with invasive behavior in pituitary tumors

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii65-iii66
Author(s):  
M Q S Mosella ◽  
T S Sabedot ◽  
T M Malta ◽  
J Rock ◽  
M Felicella ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Target Genes ◽  
Meta Analysis ◽  
Differentially Expressed Gene ◽  
Cell Movement ◽  
Pituitary Tumors ◽  
P Value ◽  
Regulatory Regions ◽  
Cpg Sites ◽  
Invasive Behavior

Abstract BACKGROUND Despite histologically benign, pituitary tumors (PT) may invade important adjacent neurovascular structures which can incur in significant comorbidities preventing a complete surgical resection and contributing to resistance to medical treatment. DNA methylation clearly stratified PT based on their functional status i.e. nonfunctioning PTs (NFPTs) from functioning PT (FPTs). However associations of methylation aberrations with invasive behavior is less clear. MATERIAL AND METHODS In order to evaluate whether DNA methylation alterations in regulatory regions other than promoter and coding regions are associated with invasive behavior we performed a meta-analysis of the genome-wide methylome of three public available PT cohorts plus our own (Illumina HumanMethylation platforms- 450K/EPIC). Pituitary specimens comprised of 43 invasive pituitary tumors (InvPT) and 37 noninvasive (NInvPT); 12 FPT and 68 NFPTs, in addition to 20 non-tumor pituitaries. RNA-seq data were available for one cohort (n=23, 12 InvPT,11NInvPT) and integrated with DNA methylation. Invasiveness criteria was based on Knosp grade >= 2 and/or sphenoid or dural invasion. RESULTS Wilcoxon Rank-sum test; Δβ=0.15; p-value <0.001 identified 58 differentially methylated CpG sites in InvPT that were mainly hypomethylated (95%) in relation to NInvPT. NInvPT methylation profile was similar to non-tumor specimens, despite its heterogeneity. Thirty-four percent (n=20) of the differentially methylated CpG sites were located within predicted enhancer regions distributed in intronic (40%), intergenic (40%) and promoter (20%) regions. Predicted enhancer-target genes were enriched for actin filament cell movement, response to starvation, growth factor stimulus and protein autophosporilation pathways. Among them, ZNF625 and INO80E were found mostly negative correlated among methylation and expression data (-0.50 and -0.48, respectively), besides DOC2A found to be one potentially differentially expressed gene under enhancer control (log2FC > 0.2, pvalue <0.05). CONCLUSION Our results suggest that methylation alterations in predicted regulatory regions, such as enhancers, annotated in non-promoter regions (introns and intergenic) may contribute to the invasive behavior of PT.

scholarly journals DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis

2016 ◽  
Vol 98 (4) ◽  
pp. 680-696 ◽  
Author(s):  
Bonnie R. Joubert ◽  
Janine F. Felix ◽  
Paul Yousefi ◽  
Kelly M. Bakulski ◽  
Allan C. Just ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Maternal Smoking ◽  
Meta Analysis ◽  
Smoking In Pregnancy ◽  
Genome Wide ◽  
In Pregnancy

scholarly journals Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth

2019 ◽  
Author(s):  
Todd M. Everson ◽  
Marta Vives-Usano ◽  
Emie Seyve ◽  
Andres Cardenas ◽  
Marina Lacasaña ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Birth Outcomes ◽  
Fetal Growth ◽  
Maternal Smoking ◽  
Meta Analysis ◽  
Growth Factor Signaling ◽  
Hormone Activity ◽  
Smoking During Pregnancy ◽  
Placental Function ◽  
Maternal Smoking During Pregnancy

AbstractMaternal smoking during pregnancy (MSDP) contributes to poor birth outcomes, in part through disrupted placental functions, which may be reflected in the placental epigenome. We meta-analyzed the associations between MSDP and placental DNA methylation (DNAm) and between DNAm and birth outcomes within the Pregnancy And Childhood Epigenetics (PACE) consortium (7 studies, N=1700, 344 with any MSDP). We identified 1224 CpGs that were associated with MSDP, of which 341 associated with birth outcomes and 141 associated with gene expression. Only 6 of these CpGs were consistent with the findings from a prior meta-analysis of cord blood DNAm, demonstrating substantial tissue-specific responses to MSDP. The placental MSDP associated CpGs were enriched for growth-factor signaling, hormone activity, inflammation, and vascularization, which play important roles in placental function. We demonstrate links between placental DNAm, MSDP and poor birth outcomes, which may better inform the mechanisms through which MSDP impacts placental function and fetal growth.

scholarly journals DNA methylation links prenatal smoking exposure to later life health outcomes in offspring

2018 ◽  
Author(s):  
Petri Wiklund ◽  
Ville Karhunen ◽  
Rebecca C Richmond ◽  
Alina Rodriguez ◽  
Maneka De Silva ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Health Outcomes ◽  
Maternal Smoking ◽  
Psychiatric Morbidity ◽  
Later Life ◽  
Prenatal Smoking ◽  
Smoking During Pregnancy ◽  
Mediation Analyses ◽  
Increased Risk ◽  
Prenatal Maternal Smoking

AbstractMaternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. To test this, we examined the association of prenatal maternal smoking with DNA methylation in 2,821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess, whether methylation markers have causal effects on disease outcomes in the offspring. We identify 69 differentially methylated CpGs in 36 genomic regions (P < 1×10−7), and show that DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

scholarly journals Imputing the Number of Responders from the Mean and Standard Deviation of CGI-Improvement in Clinical Trials Investigating Medications for Autism Spectrum Disorder

2021 ◽  
Vol 11 (7) ◽  
pp. 908
Author(s):  
Spyridon Siafis ◽  
Alessandro Rodolico ◽  
Oğulcan Çıray ◽  
Declan G. Murphy ◽  
Mara Parellada ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Clinical Trials ◽  
Standard Deviation ◽  
Linear Regression ◽  
Meta Analysis ◽  
Autism Spectrum ◽  
Imputation Method ◽  
P Value ◽  
Subgroup Differences ◽  
The Mean

Introduction: Response to treatment, according to Clinical Global Impression-Improvement (CGI-I) scale, is an easily interpretable outcome in clinical trials of autism spectrum disorder (ASD). Yet, the CGI-I rating is sometimes reported as a continuous outcome, and converting it to dichotomous would allow meta-analysis to incorporate more evidence. Methods: Clinical trials investigating medications for ASD and presenting both dichotomous and continuous CGI-I data were included. The number of patients with at least much improvement (CGI-I ≤ 2) were imputed from the CGI-I scale, assuming an underlying normal distribution of a latent continuous score using a primary threshold θ = 2.5 instead of θ = 2, which is the original cut-off in the CGI-I scale. The original and imputed values were used to calculate responder rates and odds ratios. The performance of the imputation method was investigated with a concordance correlation coefficient (CCC), linear regression, Bland–Altman plots, and subgroup differences of summary estimates obtained from random-effects meta-analysis. Results: Data from 27 studies, 58 arms, and 1428 participants were used. The imputation method using the primary threshold (θ = 2.5) had good performance for the responder rates (CCC = 0.93 95% confidence intervals [0.86, 0.96]; β of linear regression = 1.04 [0.95, 1.13]; bias and limits of agreements = 4.32% [−8.1%, 16.74%]; no subgroup differences χ2 = 1.24, p-value = 0.266) and odds ratios (CCC = 0.91 [0.86, 0.96]; β = 0.96 [0.78, 1.14]; bias = 0.09 [−0.87, 1.04]; χ2 = 0.02, p-value = 0.894). The imputation method had poorer performance when the secondary threshold (θ = 2) was used. Discussion: Assuming a normal distribution of the CGI-I scale, the number of responders could be imputed from the mean and standard deviation and used in meta-analysis. Due to the wide limits of agreement of the imputation method, sensitivity analysis excluding studies with imputed values should be performed.

scholarly journals Novel DNA methylation sites of glucose and insulin homeostasis: an integrative cross-omics analysis

2018 ◽  
Author(s):  
Jun Liu ◽  
Elena Carnero-Montoro ◽  
Jenny van Dongen ◽  
Samantha Lent ◽  
Ivana Nedeljkovic ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Glucose Level ◽  
In Silico ◽  
Fasting Glucose ◽  
Meta Analysis ◽  
Tissue Expression ◽  
P Value ◽  
Cis Acting ◽  
Functional Relevance ◽  
Meta Analyses

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of the functional relevance of the phenomenon remains limited. Because obesity is the main risk factor for T2D and a driver of methylation from previous study, we aimed to explore the effect of DNA methylation in the early phases of T2D pathology while accounting for body mass index (BMI). We performed a blood-based epigenome-wide association study (EWAS) of fasting glucose and insulin among 4,808 non-diabetic European individuals and replicated the findings in an independent sample consisting of 11,750 non-diabetic subjects. We integrated blood-based in silico cross-omics databases comprising genomics, epigenomics and transcriptomics collected by BIOS project of the Biobanking and BioMolecular resources Research Infrastructure of the Netherlands (BBMRI-NL), the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, and the tissue-specific Genotype-Tissue Expression (GTEx) project. We identified and replicated nine novel differentially methylated sites in whole blood (P-value < 1.27 × 10-7): sites in LETM1, RBM20, IRS2, MAN2A2 genes and 1q25.3 region were associated with fasting insulin; sites in FCRL6, SLAMF1, APOBEC3H genes and 15q26.1 region were associated with fasting glucose. The association between SLAMF1, APOBEC3H and 15q26.1 methylation sites and glucose emerged only when accounted for BMI. Follow-up in silico cross-omics analyses indicate that the cis-acting meQTLs near SLAMF1 and SLAMF1 expression are involved in glucose level regulation. Moreover, our data suggest that differential methylation in FCRL6 may affect glucose level and the risk of T2D by regulating FCLR6 expression in the liver. In conclusion, the present study provided nine new DNA methylation sites associated with glycemia homeostasis and also provided new insights of glycemia related loci into the genetics, epigenetics and transcriptomics pathways based on the integration of cross-omics data in silico.

scholarly journals Exposure to violence, chronic stress, nasal DNA methylation, and atopic asthma in children

2020 ◽  
Author(s):  
Qi Yan ◽  
Erick Forno ◽  
Andres Cardenas ◽  
Cancan Qi ◽  
Yueh-Ying Han ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Chronic Stress ◽  
Perceived Stress ◽  
Puerto Ricans ◽  
Meta Analysis ◽  
Exposure To Violence ◽  
Gun Violence ◽  
Atopic Asthma ◽  
P Value ◽  
Using Data

ABSTRACTBackgroundExposure to violence (ETV) or stress may cause asthma through unclear mechanisms.MethodsEpigenome-wide association study (EWAS) of DNA methylation in nasal epithelium and four ETV or chronic stress measures in 487 Puerto Ricans aged 9-20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study [EVA-PR]). We assessed measures of ETV or chronic stress in children (ETV scale, gun violence, and perceived stress) and their mothers (perceived stress). Each EWAS was conducted using linear regression, with CpGs as dependent variables and the stress/violence measure as a predictor, adjusting for age, sex, the top five principal components, and SVA latent factors. We then selected the top 100 CpGs (by P-value) associated with each stress/violence measure in EVA-PR and conducted a meta-analysis of the selected CpGs and atopic asthma using data from EVA-PR and two additional cohorts (Project Viva and PIAMA).ResultsIn the EWAS of stress/violence in EVA-PR, gun violence was associated with methylation of cg18961589 in LINC01164 (β=0.03, P=1.28×10−7), and maternal stress was associated with methylation of cg03402351 in SNN (β=0.04, P=1.69×10−7) and cg19064846 in PTPRN2 (β=0.03, P=3.36×10−7). In a meta-analysis of three cohorts, which included the top CpGs associated with stress/violence in EVA-PR, CpGs in STARD3NL, SLC35F4, TSR3, CDC42SE2, KLHL25, PLCB1, BUD13, OR2B3, GALR1, TMEM196, TEAD4 and ANAPC13 were associated with atopic asthma at FDR-P < 0.05.ConclusionsETV and chronic stress may increase the risk of atopic asthma through DNA methylation in airway epithelium, though this needs confirmation in future longitudinal studies.

scholarly journals Interaction of prenatal maternal smoking, interleukin 13 genetic variants and DNA methylation influencing airflow and airway reactivity

2013 ◽  
Vol 5 (1) ◽  
Author(s):  
Veeresh K Patil ◽  
John W Holloway ◽  
Hongmei Zhang ◽  
Nelis Soto-Ramirez ◽  
Susan Ewart ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genetic Variants ◽  
Maternal Smoking ◽  
Airway Reactivity ◽  
Interleukin 13 ◽  
Prenatal Maternal Smoking

scholarly journals Chained Risk Assessment for Life-Long Disease Burden of Early Exposures–Demonstration of Concept Using Prenatal Maternal Smoking

2020 ◽  
Vol 17 (5) ◽  
pp. 1472 ◽  
Author(s):  
Isabell K. Rumrich ◽  
Kirsi Vähäkangas ◽  
Matti Viluksela ◽  
Otto Hänninen
Keyword(s):  
Risk Factors ◽  
Risk Assessment ◽  
Maternal Smoking ◽  
Disease Burden ◽  
Communicable Disease ◽  
Meta Analysis ◽  
Intermediate Risk ◽  
Traditional Risk Factors ◽  
Prenatal Maternal Smoking ◽  
Meta Analyses

Traditional risk factors and environmental exposures only explain less than half of the disease burden. The developmental origin of the health and disease (DOHaD) concept proposes that prenatal and early postnatal exposures increase disease susceptibility throughout life. The aim of this work is to demonstrate the application of the DOHaD concept in a chained risk assessment and to provide an estimate of later in life burden of disease related to maternal smoking. We conducted three systematic literature searches for meta-analysis and reviewed the literature reporting meta-analyses of long-term health outcomes associated with maternal smoking and intermediate risk factors (preterm birth, low birth weight, childhood overweight). In the chained model the three selected risk factors explained an additional 2% (34,000 DALY) of the total non-communicable disease burden (1.4 million DALY) in 2017. Being overweight in childhood was the most important risk factor (28,000 DALY). Maternal smoking was directly associated with 170 DALY and indirectly via the three intermediate risk factors 1000 DALY (1200 DALY in total). The results confirm the potential to explain a previously unattributed part of the non-communicable diseases by the DOHAD concept. It is likely that relevant outcomes are missing, resulting in an underestimation of disease burden.

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