scholarly journals Placental OPRM1 DNA methylation and associations with neonatal opioid withdrawal syndrome, a pilot study

2020 ◽  
Vol 1 (3) ◽  
pp. 124-135
Author(s):  
Elisha M. Wachman ◽  
Alice Wang ◽  
Breanna C. Isley ◽  
Jeffery Boateng ◽  
Jacob A. Beierle ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Pilot Study ◽  
Outcome Measures ◽  
Withdrawal Syndrome ◽  
Placental Tissue ◽  
Epigenetic Variation ◽  
Pharmacologic Treatment ◽  
Cpg Sites ◽  
Opioid Withdrawal Syndrome ◽  
And Control

Aims: Epigenetic variation of DNA methylation of the mu-opioid receptor gene (OPRM1) has been identified in the blood and saliva of individuals with opioid use disorder (OUD) and infants with neonatal opioid withdrawal syndrome (NOWS). It is unknown whether epigenetic variation in OPRM1 exists within placental tissue in women with OUD and whether it is associated with NOWS outcomes. In this pilot study, we aimed to 1) examine the association between placental OPRM1 DNA methylation levels and NOWS outcomes, and 2) compare OPRM1 methylation levels in opioid-exposed versus non-exposed control placentas. Methods: Placental tissue was collected from eligible opioid (n = 64) and control (n = 29) women after delivery. Placental DNA was isolated and methylation levels at six cytosine-phosphate-guanine (CpG) sites within the OPRM1 promoter were quantified. Methylation levels were evaluated for associations with infant NOWS outcome measures: need for pharmacologic treatment, length of hospital stay (LOS), morphine treatment days, and treatment with two medications. Regression models were created and adjusted for clinical co-variates. Methylation levels between opioid and controls placentas were also compared. Results: The primary opioid exposures were methadone and buprenorphine. Forty-nine (76.6%) of the opioid-exposed infants required pharmacologic treatment, 10 (15.6%) two medications, and average LOS for all opioid-exposed infants was 16.5 (standard deviation 9.7) days. There were no significant associations between OPRM1 DNA methylation levels in the six CpG sites and any NOWS outcome measures. No significant differences were found in methylation levels between the opioid and control samples. Conclusions: No significant associations were found between OPRM1 placental DNA methylation levels and NOWS severity in this pilot cohort. In addition, no significant differences were seen in OPRM1 methylation in opioid versus control placentas. Future association studies examining methylation levels on a genome-wide level are warranted.

scholarly journals Morphine Versus Methadone for Neonatal Opioid Withdrawal Syndrome: A Randomized Controlled Pilot Study

2021 ◽  
Author(s):  
Mary Beth Sutter ◽  
Hannah Watson ◽  
Nicole Yonke ◽  
Sherry Weitzen ◽  
Lawrence Leeman
Keyword(s):  
Pilot Study ◽  
Withdrawal Syndrome ◽  
Drug Exposure ◽  
In Utero ◽  
Opioid Withdrawal ◽  
Hospital Length Of Stay ◽  
Public Health Issue ◽  
Clinical Trial Registration ◽  
Randomized Controlled ◽  
Opioid Withdrawal Syndrome

Abstract Background Neonatal Opioid Withdrawal Syndrome (NOWS) is a significant public health issue and while millions of neonates are affected each year, an optimal pharmacologic weaning protocol has yet to be demonstrated. In this study, we compare hospital length of stay (LOS) and length of treatment (LOT) for treatment of neonatal opioid withdrawal (NOWS) with morphine versus methadone. Methods This was a single-site, open-label, randomized controlled pilot study conducted from October 2016-June 2018. Infants were eligible if their primary in-utero drug exposure was heroin, oral opioids, or methadone and they were born at greater than or equal to 34 weeks gestation. Infants were excluded for serious medical comorbidities and primary in-utero exposure to buprenorphine. Results 61 infants were enrolled; 30 were randomized to methadone treatment, and 31 to morphine treatment. Overall 46% of infants required treatment for NOWS. LOS and LOT for infants treated with morphine was 17.9 days and 14.7 days respectively, compared to 16.1 days and 12.8 days for babies treated with methadone (p=0.5, p=0.54). Infants treated with morphine received lower total morphine equivalents than those treated with methadone (9.7 vs. 33, p<0.01). Three treated infants in the methadone group required transfer to the Neonatal Intensive Care Unit, versus no infants in the morphine group. Conclusions Infants treated with morphine versus methadone had no significant differences in LOS or LOT in this pilot study. Infants treated with methadone received up to 3 times the opioid based on morphine equivalents as infants treated with morphine and had more transfers to the NICU for over sedation. Clinical Trial Registration: Morphine Versus Methadone for Opiate Exposed Infants With Neonatal Abstinence Syndrome NCT02851303, initated 01/08/2016 https://clinicaltrials.gov/ct2/show/NCT02851303.

scholarly journals AltumAge: A Pan-Tissue DNA-Methylation Epigenetic Clock Based on Deep Learning

2021 ◽  
Author(s):  
Lucas Paulo de Lima ◽  
Louis R Lapierre ◽  
Ritambhara Singh
Keyword(s):  
Dna Methylation ◽  
Deep Learning ◽  
Placental Tissue ◽  
Training Data ◽  
Data Sets ◽  
Epigenetic Clock ◽  
Neural Network Approach ◽  
Cpg Sites ◽  
Age Related ◽  
Model Predictions

Several age predictors based on DNA methylation, dubbed epigenetic clocks, have been created in recent years. Their accuracy and potential for generalization vary widely based on the training data. Here, we gathered 143 publicly available data sets from several human tissues to develop AltumAge, a highly accurate and precise age predictor based on deep learning. Compared to Horvath's 2013 model, AltumAge performs better across both normal and malignant tissues and is more generalizable to new data sets. Interestingly, it can predict gestational week from placental tissue with low error. Lastly, we used deep learning interpretation methods to learn which methylation sites contributed to the final model predictions. We observed that while most important CpG sites are linearly related to age, some highly-interacting CpG sites can influence the relevance of such relationships. We studied the associated genes of these CpG sites and found literary evidence of their involvement in age-related gene regulation. Using chromatin annotations, we observed that the CpG sites with the highest contribution to the model predictions were related to heterochromatin and gene regulatory regions in the genome. We also found age-related KEGG pathways for genes containing these CpG sites. In general, neural networks are better predictors due to their ability to capture complex feature interactions compared to the typically used regularized linear regression. Altogether, our neural network approach provides significant improvement and flexibility to current epigenetic clocks without sacrificing model interpretability.

537 Racial differences in pharmacologic treatment for newborns with neonatal opioid withdrawal syndrome

2021 ◽  
Vol 224 (2) ◽  
pp. S340
Author(s):  
Allison Akers ◽  
Monique McKiever ◽  
Chelsea Leipold ◽  
Patrick Schneider ◽  
Orman T. Hall ◽  
...  
Keyword(s):  
Racial Differences ◽  
Withdrawal Syndrome ◽  
Opioid Withdrawal ◽  
Pharmacologic Treatment ◽  
Opioid Withdrawal Syndrome

scholarly journals Differential DNA Methylation by Hispanic Ethnicity Among Firefighters in the United States

2021 ◽  
Vol 14 ◽  
pp. 251686572110061
Author(s):  
Jaclyn M Goodrich ◽  
Melissa A Furlong ◽  
Alberto J Caban-Martinez ◽  
Alesia M Jung ◽  
Ken Batai ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Pilot Study ◽  
The United States ◽  
P Value ◽  
Q Value ◽  
Blood Leukocytes ◽  
Cpg Sites ◽  
False Discovery ◽  
Increased Risk ◽  
Hispanic White

Firefighters are exposed to a variety of environmental hazards and are at increased risk for multiple cancers. There is evidence that risks differ by ethnicity, yet the biological or environmental differences underlying these differences are not known. DNA methylation is one type of epigenetic regulation that is altered in cancers. In this pilot study, we profiled DNA methylation with the Infinium MethylationEPIC in blood leukocytes from 31 Hispanic white and 163 non-Hispanic white firefighters. We compared DNA methylation (1) at 12 xenobiotic metabolizing genes and (2) at all loci on the array (>740 000), adjusting for confounders. Five of the xenobiotic metabolizing genes were differentially methylated at a raw P-value <.05 when comparing the 2 ethnic groups, yet were not statistically significant at a 5% false discovery rate ( q-value <.05). In the epigenome-wide analysis, 76 loci exhibited DNA methylation differences at q < .05. Among these, 3 CpG sites in the promoter region of the biotransformation gene SULT1C2 had lower methylation in Hispanic compared to non-Hispanic firefighters. Other differentially methylated loci included genes that have been implicated in carcinogenesis in published studies ( FOXK2, GYLTL1B, ZBTB16, ARHGEF10, and more). In this pilot study, we report differential DNA methylation between Hispanic and non-Hispanic firefighters in xenobiotic metabolism genes and other genes with functions related to cancer. Epigenetic susceptibility by ethnicity merits further study as this may alter risk for cancers linked to toxic exposures.

Placental DNA methylation profiles in opioid-exposed pregnancies and associations with the neonatal opioid withdrawal syndrome

Genomics ◽  
2021 ◽  
Vol 113 (3) ◽  
pp. 1127-1135
Author(s):  
Uppala Radhakrishna ◽  
Sangeetha Vishweswaraiah ◽  
Lavanya V. Uppala ◽  
Marta Szymanska ◽  
Jacqueline Macknis ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Withdrawal Syndrome ◽  
Opioid Withdrawal ◽  
Opioid Withdrawal Syndrome

scholarly journals Placenta DNA Methylation Adaptation to Maternal Glucose Tolerance in Pregnancy

2017 ◽  
Author(s):  
Andres Cardenas ◽  
Valerie Gagné-Ouellet ◽  
Catherine Allard ◽  
Diane Brisson ◽  
Patrice Perron ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Placental Tissue ◽  
Oral Glucose ◽  
Glucose Response ◽  
Glucose Levels ◽  
Cpg Sites ◽  
Glucose Challenge ◽  
Maternal Glucose Levels ◽  
Phosphodiesterase 4B ◽  
Maternal Glucose

ABSTRACTMaternal hyperglycemia during pregnancy is associated with fetal growth and adverse perinatal and developmental outcomes. Placental epigenetic maladaptation may underlie these associations. We performed an epigenome-wide association study of term placentas and prenatal maternal glucose response 2-hour post oral glucose challenge at 24-30 weeks of gestation among 448 mother-infant pairs. Maternal glucose levels post-load were strongly associated with lower DNA methylation of 4 CpGs (FDR q<0.05) within the Phosphodiesterase 4B gene (PDE4B). Additionally, three other CpGs were differentially methylated relative to maternal glucose response within the TNFRSF1B; LDLR; and BLM genes (FDR q<0.05). Methylation levels correlated with expression in placental tissue for all 4 CpG sites in PDE4B (rs: 0.26–0.35, P<0.01), LDLR (rs: 0.22, P=0.03) and at TNFRSF1B (rs: -0.25, P=0.01). Our study provides evidence that maternal glucose response during pregnancy is associated with DNA methylation of genes within the placenta that are partially under epigenetic control.

EPIGENETIC ALTERATIONS ASSOCIATED WITH PREMATURE OVARIAN FAILURE

2008 ◽  
Vol 31 (4) ◽  
pp. 11
Author(s):  
Manda Ghahremani ◽  
Courtney W Hannah ◽  
Maria Peneherrera ◽  
Karla L Bretherick ◽  
Margo R Fluker ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Premature Ovarian Failure ◽  
Promoter Region ◽  
Gene Promoter ◽  
Ovarian Failure ◽  
P Value ◽  
Epigenetic Alterations ◽  
Methylation Array ◽  
Cpg Sites ◽  
Deficient Mice

Background/Purpose: Premature ovarian failure (POF) affects 1% of women with a largely idiopathic and poorly understood etiology. The objective of this study was to identify specific epigenetic alterations by measuring DNA methylation of gene regulatory regions in women with POF vs. controls. Methods: Blood samples were collected from idiopathic POFpatients (Amenorrhea for at least 3 months and 2 serum FSH levels of > 40mIU/ml obtained > 1 month apart prior to age 40) and control women (CW) (healthy pregnancy after age 37 with out a pregnancy loss). Genomic DNA was extracted from EDTA anticoagulated blood and bisulfite converted for analysis using the Illumina Golden Gate Methylation Panel which measures DNA methylation at 1506 CpG sites in the promoter regions of 807 genes in 10 POF and 12 CW. Candidate genes with altered epigenetic marks between POF and CW at a nominal P-value < 0.05 were identified using a t-testcomparison within the Illumina bead studio software. Genes of interest were further analyzed for quantitative methylation at specific CpG sites using pyrosequencing in 30 POF and 30 CW. Results: Comparison of DNA methylation profiles of our initial POF and CW groups identified several genes with statistically significanthyper- or hypo- methylation in the POF group (P < 0.05), including the Androgen Receptor (AR)promoter region, which was significantly hypermethylated. To further validate these results, DNA methylation of the AR gene promoter was quantified bypryosequencing in a larger group of POF and CW. Pyrosequencing further confirmed a significantly higher DNA methylation of the AR promoter region inPOF vs. CW (P=0.007). Conclusions: This is a novel study identifying epigenetic alterations in POF. The hypermethylation of the AR gene in POF patients may cause decreased level of the AR in these women. This is especially interesting given a recent report of induced POF in AR deficient mice^1. Specific epigenetic markers, as identified by DNA methylation array profiling in blood, may serve as useful biomarkers for POF and other fertility disorders. However, it will need to be determined if these methylation changes are present prior to diagnosis, or are a consequence of menopause itself. Reference: 1.Hiroko S. et al. Premature ovarian failure in androgenreceptor deficient mice. PNAS;103:224-9

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