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

Radhakrishna, Uppala; Vishweswaraiah, Sangeetha; Uppala, Lavanya V.; Szymanska, Marta; Macknis, Jacqueline K.; Kumar, Sandeep; Saleem-Rasheed, Fozia; Aydas, Buket; Forray, Ariadna; Muvvala, Srinivas; Mishra, Nitish K.; Guda, Chittibabu; Carey, David J.; Metpally, Raghu; Crist, Richard C.; Berrettini, Wade H.; Bahado‐Singh, Ray O.

doi:10.1016/j.ygeno.2021.03.006

Cited by 23 publications

(33 citation statements)

References 92 publications

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“…A recent study examined changes to placental DNA methylation that occur in response to maternal OUD and may be predictive of NOWS development 59 . None of the miRNAs identified in our study (Table 4 ) had differential DNA methylation at their genomic loci when comparing placenta from POE neonates who would develop NOWS to neonates who did not develop NOWS.…”

Section: Discussionmentioning

confidence: 99%

Prenatal opioid-exposed infant extracellular miRNA signature obtained at birth predicts severity of neonatal opioid withdrawal syndrome

Mahnke

Roberts

Leeman

et al. 2022

Sci Rep

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Prenatal opioid exposure (POE) is commonly associated with neonatal opioid withdrawal syndrome (NOWS), which is characterized by a broad variability in symptoms and severity. Currently there are no diagnostic tools to reliably predict which infants will develop severe NOWS, while risk stratification would allow for proactive decisions about appropriate clinical monitoring and interventions. The aim of this prospective cohort study was to assess if extracellular microRNAs (miRNAs) in umbilical cord plasma of infants with POE could predict NOWS severity. Participants (n = 58) consisted of pregnant women receiving medications for opioid use disorder and their infants. NOWS severity was operationalized as the need for pharmacologic treatment and prolonged hospitalization (≥ 14 days). Cord blood miRNAs were assessed using semi-quantitative qRT-PCR arrays. Receiver operating characteristic curves and area under the curve (AUC) were estimated. The expression of three miRNAs (miR-128-3p, miR-30c-5p, miR-421) predicted need for pharmacologic treatment (AUC: 0.85) and prolonged hospitalization (AUC: 0.90). Predictive validity improved after two miRNAs (let-7d-5p, miR-584-5p) were added to the need for pharmacologic treatment model (AUC: 0.94) and another two miRNAs (let-7b-5p, miR-10-5p) to the prolonged hospitalization model (AUC: 0.99). Infant cord blood extracellular miRNAs can proactively identify opioid-exposed neonates at high-risk for developing severe NOWS.

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Section: Discussionmentioning

confidence: 99%

Prenatal opioid-exposed infant extracellular miRNA signature obtained at birth predicts severity of neonatal opioid withdrawal syndrome

Mahnke

Roberts

Leeman

et al. 2022

Sci Rep

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“…Details of the methodology were previously published. 26,27 Inclusion and exclusion criteria Patients with HS were prescreened at VS Hospital in Ahmedabad, India using the visual-aided questionnaire for selfassessment of HS 28 and subsequently examined by two independent board-certified dermatologists. The diagnosis was established following the Dessau criteria for HS 29 and samples were carefully assessed and described in line with European Hidradenitis Supurativa Foundation (EHSF) guidance.…”

Section: Methodsmentioning

confidence: 99%

“…Genome-wide DNA methylation profiling was performed using the Infinium MethylationEPIC BeadChip (850 K) array (Illumina Inc., San Diego, CA) with bisulphite-treated genomic DNA according to the manufacturer's protocol. 26,34 This array has 853 307 CpG sites, including 9961 CpG sites of miRNAencoding genes. 35 To achieve successful microarray experiments, the sample placement was randomized in each chip.…”

Section: Illumina Infinium Methylationepic Beadchipmentioning

confidence: 99%

“…The P-value for methylation differences between case and control groups at each locus was calculated as previously described. 26,34 Raw and FDR P-values corrected for multiple testing (Benjamini-Hochberg test) were calculated. AUC for combinations of loci was calculated using the 'R' program 'ROCR' package (v3.5.0).…”

Section: Statistical and Bioinformatic Analysismentioning

confidence: 99%

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Methylated miRNAsmay serve as potential biomarkers and therapeutic targets for hidradenitis suppurativa

Radhakrishna

Uppala

Jhala

et al. 2022

Acad Dermatol Venereol

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Background Hidradenitis suppurativa (HS) is a chronic inflammatory disease influenced by genetics, non‐genetic and environmental factors that modulate miRNA expression. Currently, no miRNA data are available for HS. In this study, we profiled DNA methylation patterns of miRNA genes associated with HS susceptibility. Objectives Identify miRNA gene methylation profiles associated with HS susceptibility. This study examined the methylation patterns of DNAs from 24 healthy controls and 24 patients with HS using Illumina Infinium MethylationEPIC BeadChip array analysis. Methylation patterns of miRNA genes were analysed using KEGG pathway analysis to explore the inversely correlated pathways regulated by miRNAs. Results We identified 60 CpG sites representing 65 unique microRNA genes including 54 hypomethylated and 6 hypermethylated CpGs as potentially associated with HS. Some of these CpGs were found to be critical for skin function, such as miR‐29, miR‐200, miR‐205, miR‐548 and miR‐132. The miR‐192 is implicated in non‐alcoholic fatty liver disease. The miR‐200c gene was identified as a vital determinant in regulating skin repair after injury and may contribute to age‐associated alterations in wound repair. miR‐132 was significantly upregulated during the inflammation phase of wound repair, enhancing the activity of STAT3 and ERK pathways that promote keratinocyte proliferation. Conclusions Epigenetically altered microRNA genes are implicated in wound healing, inflammation, keratinocyte proliferation and wound modulation. This is the first study to analyse methylation profiles of miRNA genes in the HS population, highlighting the unique role that miRNAs might play in diagnosing and treating HS.

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“…Furthermore, multiple epigenome-wide association studies (EWASs) have identified DNAm changes associated with medication exposure during pregnancy (e.g. valproic acid, antidepressants and paracetamol) [14][15][16][17][18][19][20]. Recently, we found an association between cord blood DNAm and prenatal long-term exposure to paracetamol in children with attentiondeficit/hyperactivity disorder (ADHD) [21].…”

Section: Introductionmentioning

confidence: 99%

Low reliability of DNA methylation across Illumina Infinium platforms in cord blood: implications for replication studies and meta-analyses of prenatal exposures

et al. 2022

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Background There is an increasing interest in the role of epigenetics in epidemiology, but the emerging research field faces several critical biological and technical challenges. In particular, recent studies have shown poor correlation of measured DNA methylation (DNAm) levels within and across Illumina Infinium platforms in various tissues. In this study, we have investigated concordance between 450 k and EPIC Infinium platforms in cord blood. We could not replicate our previous findings on the association of prenatal paracetamol exposure with cord blood DNAm, which prompted an investigation of cross-platform DNAm differences. Results This study is based on two DNAm data sets from cord blood samples selected from the Norwegian Mother, Father and Child Cohort Study (MoBa). DNAm of one data set was measured using the 450 k platform and the other data set was measured using the EPIC platform. Initial analyses of the EPIC data could not replicate any of our previous significant findings in the 450 k data on associations between prenatal paracetamol exposure and cord blood DNAm. A subset of the samples (n = 17) was included in both data sets, which enabled analyses of technical sources potentially contributing to the negative replication. Analyses of these 17 samples with repeated measurements revealed high per-sample correlations ($$\stackrel{\mathrm{-}}{\text{R}}\hspace{0.17em}\approx$$ R - ≈ 0.99), but low per-CpG correlations ($$\stackrel{\mathrm{-}}{\text{R}}$$ R - ≈ 0.24) between the platforms. 1.7% of the CpGs exhibited a mean DNAm difference across platforms > 0.1. Furthermore, only 26.7% of the CpGs exhibited a moderate or better cross-platform reliability (intra-class correlation coefficient ≥ 0.5). Conclusion The observations of low cross-platform probe correlation and reliability corroborate previous reports in other tissues. Our study cannot determine the origin of the differences between platforms. Nevertheless, it emulates the setting in studies using data from multiple Infinium platforms, often analysed several years apart. Therefore, the findings may have important implications for future epigenome-wide association studies (EWASs), in replication, meta-analyses and longitudinal studies. Cognisance and transparency of the challenges related to cross-platform studies may enhance the interpretation, replicability and validity of EWAS results both in cord blood and other tissues, ultimately improving the clinical relevance of epigenetic epidemiology.

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

Cited by 23 publications

References 92 publications

Prenatal opioid-exposed infant extracellular miRNA signature obtained at birth predicts severity of neonatal opioid withdrawal syndrome

Prenatal opioid-exposed infant extracellular miRNA signature obtained at birth predicts severity of neonatal opioid withdrawal syndrome

Methylated miRNAsmay serve as potential biomarkers and therapeutic targets for hidradenitis suppurativa

Low reliability of DNA methylation across Illumina Infinium platforms in cord blood: implications for replication studies and meta-analyses of prenatal exposures

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