kristger

• Carson, Alexis Christine; Zidan, Mahmoud; Olstad, Emilie Willoch; Gervin, Kristina; Galesloot, Tessel E. & Scholte, Iris [Vis alle 9 forfattere av denne artikkelen] (2026). Genetically Informed Research Designs in Perinatal Pharmacoepidemiology: A Methodological Overview. Drug Safety. ISSN 0114-5916. 49(7), s. 761–773. doi: 10.1007/s40264-026-01647-9. Fulltekst i vitenarkiv Vis sammendrag

  Despite the widespread use of medications during pregnancy, ethical and methodological barriers to clinical trials make observational studies necessary for evaluating medication safety in this population. Observational studies are prone to biases that often limit their validity due to the lack of randomization; integrating genetic information through discordant sibling designs, polygenic scores, and Mendelian randomization can address several confounding issues. However, application of these three approaches in perinatal pharmacoepidemiology has been limited. Complementing traditional designs with these genetically informed research designs can tackle common biases and strengthen causal inference. This paper focuses on applying genetically informed research designs to child outcomes in perinatal pharmacoepidemiology by reviewing various methods, discussing their strengths and limitations, and examining their application to date, as well as considerations for implementing them in future research. Such considerations include the availability of genetic data, the complexity of integrating genetic data with existing epidemiological data, and selection of appropriate genetic instruments for analyses. Incorporating causal inference in perinatal pharmacoepidemiology can ultimately contribute to enhancing safe medication use during pregnancy.

• Gervin, Kristina; Kverneland, Magnhild; Nakken, Karl Otto; Rudi, Knut; Iversen, Per Ole & Selmer, Kaja Kristine (2026). Epigenetic ageing is accelerated in drug-resistant epilepsy and dynamically modulated during ketogenic diet therapy. EBioMedicine. 131. doi: 10.1016/j.ebiom.2026.106449.
• Zhu, Tianyu; Faragó, Teodóra; Bollepalli, Sailalitha; Heikkinen, Aino; Hukkanen, Mikaela & Raitakari, Olli [Vis alle 18 forfattere av denne artikkelen] (2026). EpiSmokEr2: a robust epigenetic classifier for smoking status inference using Illumina EPIC methylation data. Epigenomics. ISSN 1750-1911. 18(2), s. 205–215. doi: 10.1080/17501911.2026.2630841. Fulltekst i vitenarkiv
• Gervin, Kristina; Kverneland, Magnhild; Nakken, Karl Otto; Rudi, Knut; Iversen, Per Ole & Landmark, Cecilie Johannessen [Vis alle 7 forfattere av denne artikkelen] (2026). DNA methylation of antiseizure medication metabolism genes and pharmacokinetic changes in adult epilepsy patients treated with the modified Atkins diet. Genes & Nutrition. ISSN 1555-8932. 21. doi: 10.1186/s12263-026-00796-x. Fulltekst i vitenarkiv Vis sammendrag

  Background The modified Atkins diet is increasingly used as an adjunctive therapy for drug-resistant epilepsy. Recent evidence suggests that such dietary interventions may affect the pharmacokinetics of antiseizure medications and induce DNA methylation changes. However, it remains unclear whether epigenetic regulation of drug-metabolizing enzymes contributes to variability in medication serum levels. Results We analyzed 58 adults with drug-resistant epilepsy treated with a modified Atkins diet for 12 weeks. DNA methylation was profiled in peripheral blood before diet initiation (baseline) and after 4 weeks and 12 weeks using a genome-wide array. A total of 131 cytosine-phosphate-guanine (CpG) sites mapped to 13 candidate genes involved in antiseizure medication metabolism were assessed. One CpG in the CES1 gene showed significant methylation changes from baseline to 4 weeks, 12 weeks, and across all timepoints (FDR = 0.0018), indicating consistent longitudinal effects. Repeated measures correlation analyses were used to evaluate within-individual associations between DNA methylation and antiseizure medication serum concentrations. Two CpG–drug associations showed strong positive intra-individual correlations: CYP3A5 methylation was significantly associated with carbamazepine serum levels (repeated measures correlation coefficient = 0.81, FDR = 0.023), whereas CYP3A4 methylation showed a similarly strong but borderline association with topiramate (correlation coefficient = 0.76, FDR = 0.051). Conclusions This study finds that a modified Atkins diet may be associated with DNA methylation variation at genes involved in drug metabolism. Furthermore, DNA methylation levels were strongly associated with individual serum concentrations of certain antiseizure medications. These findings are consistent with the concept of a diet–epigenome–drug metabolism axis and warrant further investigation in larger studies to assess clinical implications for personalized dietary and pharmacological management in epilepsy.

• Kinge-Rasmussen, Mathilde; Olstad, Emilie Willoch; Bjørk, Marte-Helene; Nordeng, Hedvig Marie Egeland; Tan, Manuela & Gervin, Kristina [Vis alle 7 forfattere av denne artikkelen] (2026). Genetic susceptibility for neurodevelopmental disorders in children born to women with epilepsy. Brain Communications. 8(2). doi: 10.1093/braincomms/fcag078. Fulltekst i vitenarkiv Vis sammendrag

  Children of women with epilepsy have higher rates of neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), than the general population. This likely reflects a complex gene-environment interplay, but the specific contribution of genetic susceptibility, independent of in utero antiseizure medication exposure, remains unclear. The objective of this study was to evaluate whether polygenic risk scores (PRSs) for ADHD and ASD are elevated in these children compared to the general population and to assess associations with childhood neurodevelopmental traits. We analysed genetic and questionnaire data from the Norwegian Mother, Father and Child Cohort Study (MoBa). We included children born to women with epilepsy (n = 422) and children of mothers without epilepsy (n = 73 300). The parent-reported neurodevelopmental traits hyperactivity, inattention, social difficulties, language difficulties, repetitive behaviour and motor difficulties were measured using z scores at ages 0.5, 1.5, 3, 5 and 8 years. The genetic susceptibility was calculated as PRSs for ADHD and ASD. Children born to women with epilepsy had higher PRSs for ADHD (mean difference = 0.09, P = 0.07), not ASD (mean difference = 0.014, P = 0.78), compared to those without epilepsy. In these children, we observed stronger associations between the ADHD PRSs and neurodevelopmental traits closely linked to ADHD, specifically hyperactivity and inattention for all ages examined with the strongest association at 8 years. For the ASD PRSs, we observed stronger associations with motor development and language difficulties particularly at 5 years in children born to women with epilepsy. Although these associations were in the same direction and statistically significant for all ages in the general population, they did not reach statistical significance in children born to women with epilepsy. Findings from this study show that the ADHD and ASD PRSs were more strongly associated with hyperactivity/inattention, and with language/motor difficulties respectively in children born to women with epilepsy, compared to the general population. However, statistical significance was not reached likely due to limited sample size. These findings underscore the importance of considering genetic predisposition when assessing neurodevelopmental risks in this population.

• Olstad, Emilie Willoch; Nordeng, Hedvig Marie Egeland; Bjørk, Marte-Helene; Selmer, Kaja Kristine & Gervin, Kristina (2025). Paternal valproate use and impact of shared genetic susceptibility on child neurodevelopment. Scientific Reports. 15(1). doi: 10.1038/s41598-025-23377-1. Fulltekst i vitenarkiv
• Reddy, Akhila Srinivas; Gelder, Marleen van; Olstad, Emilie Willoch; Gervin, Kristina; Torkildsen, Janne von Koss & Nordeng, Hedvig Marie Egeland (2025). Prevalence of Neurodevelopmental Disorders in Families of Women Taking Psychotropic Medication During Pregnancy. Paediatric and Perinatal Epidemiology. ISSN 0269-5022. 40(1), s. 97–108. doi: 10.1111/ppe.70075. Fulltekst i vitenarkiv Vis sammendrag

  Background Familial and environmental factors contribute to neurodevelopmental disorders (NDDs). Prenatal psychotropic exposure may influence the risk of NDDs in children. As these medications are prescribed to women with mental disorders, which are genetically and environmentally linked to NDDs, accounting for familial confounding is essential when studying medication safety in pregnancy. Objectives To compare the prevalence of NDDs in pregnant women using psychotropics, their partners, and their previous children, with those not using these medications. Methods We included data from the most recent pregnancy of Norwegian women with mental disorders who gave birth between 2010 and 2018, using Norwegian registries. Maternal psychotropic use included antidepressants, antipsychotics, anxiolytics, hypnotics, and sedatives, as recorded in the Norwegian Prescription Database. NDDs were identified using ICD-10 codes for intellectual disabilities, language/scholastic disorders, pervasive developmental disorders, and attention-deficit hyperactivity disorders (ADHD) from the Norwegian Patient Registry. Modified Poisson regression estimated crude and adjusted relative risks (aRRs) for the association between psychotropic use and family history of NDDs. Results The study included 27,638 women. Among psychotropic users, NDDs prevalence was 9.6% in women, 5.4% in partners, and 10.0% in previous children, compared to 5.7%, 4.6%, and 8.0% in non-users, respectively. ADHD was the most prevalent NDD. Psychotropic use in pregnancy was associated with any NDD, particularly ADHD, in the women [any NDD aRR 1.77 (95% CI 1.60, 1.95); ADHD aRR 1.79 (95% CI 1.61, 1.98)], previous children [any NDD aRR 1.25 (95% CI 1.07, 1.47); ADHD aRR 1.26 (95% CI 1.02, 1.54)], and partners [any NDD aRR 1.21 (95% CI 1.06, 1.37); ADHD aRR 1.22 (95% CI 1.07, 1.39)]. Conclusions Prenatal psychotropic use was associated with a higher prevalence of NDDs in mothers and their previous children, highlighting the need to account for familial neurodevelopmental patterns to distinguish the effects of psychotropics from underlying genetic or familial factors.

• Spildrejorde, Mari Roberts; Dunker, Øystein; Allen, Sara Maria; Kvaløy, Marie Bu; Uglem, Martin & Hjelland, Ina Elen [Vis alle 13 forfattere av denne artikkelen] (2025). Genome-wide association study of neuropathic pain. Pain. ISSN 0304-3959. doi: 10.1097/j.pain.0000000000003848. Fulltekst i vitenarkiv Vis sammendrag

  Neuropathic pain is a complex chronic condition with a multifactorial etiology that includes genetic susceptibility. However, the genetic basis of neuropathic pain remains poorly understood. We aimed to investigate genetic variants associated with the presence and intensity of neuropathic pain using genome-wide association analyses in the GeNeuP cohort, comprised of 1146 deeply phenotyped individuals with peripheral neuropathy from Norway. Genotyping was performed using the Illumina Global Screening Array, and analyses were conducted to test associations with the presence and intensity of neuropathic pain. No significant associations were detected at the genome-wide significance level (P < 5 × 10−8) for either the presence or intensity of neuropathic pain. However, at the subthreshold level (P < 10−6), 3 single nucleotide polymorphisms (annotated to the CHRDL1 and MCF2L gene and a long non-coding RNA) were associated with intensity of neuropathic pain. A targeted candidate gene analysis of 163 genes previously implicated in neuropathic pain and neuropathy did not yield significant associations. These results highlight the complexity of the genetic architecture underlying neuropathic pain and the challenges in identifying common variants with detectable effects. The identification of subthreshold associations of genes involved in synaptic plasticity is intriguing and merits further investigation. Larger studies with refined phenotyping will be essential to validate these signals and to advance understanding of the genetic contributors to neuropathic pain.

• Dagestad, Magnhild Hammersland; Vetti, Nils; Bråten, Lars Christian Haugli; Gjefsen, Elisabeth; Grøvle, Lars & Gervin, Kristina [Vis alle 14 forfattere av denne artikkelen] (2025). Modic Change Edema in Chronic Low Back Pain Treated with Infliximab or Placebo: The BackToBasic Trial. Spine. ISSN 0362-2436. 50(16), s. 1091–1101. doi: 10.1097/BRS.0000000000005391. Fulltekst i vitenarkiv
• Reddy, Akhila Srinivas; Fawad, Fatima; Leite, Mila Apostolova; Olstad, Emilie Willoch; Gervin, Kristina & Kanduri, Chakravarthi [Vis alle 11 forfattere av denne artikkelen] (2025). Prenatal exposure to psychotropics and analgesics on cognitive, linguistic and educational outcomes – a scoping review with focus on validity and reliability of outcome measures. BMC Pregnancy and Childbirth. 25. doi: 10.1186/s12884-025-07235-6. Fulltekst i vitenarkiv Vis sammendrag

  Objective To provide an overview of the observational studies on child’s cognitive, linguistic, and educational outcomes following prenatal exposure to psychotropics and analgesics, including reporting of outcome measure validity and reliability. Study design We searched four databases, MEDLINE, Embase, PsycINFO, and PubMed from inception to September 2023. We included all original studies involving participants less than 18 years old, who were prenatally exposed to psychotropics and/or analgesics with cognitive, linguistic, and/or educational outcomes and excluded those lacking comparison groups. Results 80 studies were identified. Most studies (47%) focused on the effects of prenatal exposure to antiepileptics on child cognition. Valproate was consistently associated with an increased risk of neurodevelopmental disorders, whereas the results for other medications were sparse and conflicting. Neurodevelopmental outcomes were measured by psychometric assessments in 71 studies and by diagnostic codes in health care registries in nine studies. Only 33 of the 71 studies (46.5%) using psychometric measures mentioned the psychometric properties of the instruments used. In studies using diagnostic outcome measures, only one study reported positive predictive values and performed a sensitivity analysis to address outcome misclassification. Conclusion Except for valproate, there is a concerning lack of studies on the impact of prenatal exposure to psychotropics and analgesics on cognitive, linguistic, and educational outcomes with existing studies yielding inconsistent findings. Regardless of whether psychometric measures or diagnostic codes were used, most studies lacked a robust assessment of outcome measures, which threatens their validity and interpretability. Future studies on long-term prenatal medication safety need to focus on the accuracy of neurodevelopmental outcome measures.

• Jones, Meaghan J.; Konwar, Chaini; Asiimwe, Rebecca; Dinh, Louie; Razzaghian, Hamid Reza & Goede, Olivia de [Vis alle 18 forfattere av denne artikkelen] (2025). DNA methylation differences between cord and adult white blood cells reflect postnatal immune cell maturation. Communications Biology. 8. doi: 10.1038/s42003-025-07661-4. Fulltekst i vitenarkiv Vis sammendrag

  Epigenetic modifications such as DNA methylation are both cell type and developmental age specific. Here, we show that the immunological maturation of blood cell types influences DNA methylation changes from naive cord blood to fully functional adult blood. Lymphoid cells in adult blood showed more variability than in cord blood suggesting an antigen-dependent maturation of DNA methylation in lymphoid cells throughout the lifespan. Fewer DNA methylation changes between cord and adult blood were observed in myeloid cells, particularly in monocytes, which demonstrated the least number of DNA methylation changes between cord and adult blood. We also noted differences in epigenetic ages by immune cell types within the same individuals, specifically in cord blood where monocytes were epigenetically oldest compared to the other cell types. In addition, we provide a publicly available resource to the community as an R Shiny web application to interactively explore epigenetic patterns between naive cord white blood cells and fully functional adult white blood cells for six immune cell types.

• Olstad, Emilie Willoch; Nordeng, Hedvig Marie Egeland; Bjørk, Marte-Helene; Selmer, Kaja Kristine & Gervin, Kristina (2025). Agreement Between Parental Self-Reported Antiseizure Medication Use and Dispensed Prescription Records From a National Prescription Database. Pharmacoepidemiology and Drug Safety. ISSN 1053-8569. 34(4). doi: 10.1002/pds.70139. Fulltekst i vitenarkiv
• Spildrejorde, Mari Roberts; Leithaug, Magnus; Samara, Athina; Aass, Hans Christian; Sharma, Ankush & Acharya, Ganesh [Vis alle 9 forfattere av denne artikkelen] (2024). Citalopram exposure of hESCs during neuronal differentiation identifies dysregulated genes involved in neurodevelopment and depression. Frontiers in Cell and Developmental Biology. 12. doi: 10.3389/fcell.2024.1428538. Fulltekst i vitenarkiv Vis sammendrag

  Selective serotonin reuptake inhibitors (SSRIs), including citalopram, are widely used antidepressants during pregnancy. However, the effects of prenatal exposure to citalopram on neurodevelopment remain poorly understood. We aimed to investigate the impact of citalopram exposure on early neuronal differentiation of human embryonic stem cells using a multi-omics approach. Citalopram induced time- and dose-dependent effects on gene expression and DNA methylation of genes involved in neurodevelopmental processes or linked to depression, such as BDNF, GDF11, CCL2, STC1, DDIT4 and GAD2. Single-cell RNA-sequencing analysis revealed distinct clusters of stem cells, neuronal progenitors and neuroblasts, where exposure to citalopram subtly influenced progenitor subtypes. Pseudotemporal analysis showed enhanced neuronal differentiation. Our findings suggest that citalopram exposure during early neuronal differentiation influences gene expression patterns associated with neurodevelopment and depression, providing insights into its potential neurodevelopmental impact and highlighting the importance of further research to understand the long-term consequences of prenatal SSRI exposure.

• Vigeland, Maria Dehli; Flåm, Siri Tennebø; Vigeland, Magnus Dehli; Espeland, Ansgar; Zucknick, Manuela & Wigemyr, Monica [Vis alle 14 forfattere av denne artikkelen] (2023). Long-Term Use of Amoxicillin Is Associated with Changes in Gene Expression and DNA Methylation in Patients with Low Back Pain and Modic Changes. Antibiotics. 12(7). doi: 10.3390/antibiotics12071217. Fulltekst i vitenarkiv Vis sammendrag

  Long-term antibiotics are prescribed for a variety of medical conditions, recently including low back pain with Modic changes. The molecular impact of such treatment is unknown. We conducted longitudinal transcriptome and epigenome analyses in patients (n = 100) receiving amoxicillin treatment or placebo for 100 days in the Antibiotics in Modic Changes (AIM) study. Gene expression and DNA methylation were investigated at a genome-wide level at screening, after 100 days of treatment, and at one-year follow-up. We identified intra-individual longitudinal changes in gene expression and DNA methylation in patients receiving amoxicillin, while few changes were observed in patients receiving placebo. After 100 days of amoxicillin treatment, 28 genes were significantly differentially expressed, including the downregulation of 19 immunoglobulin genes. At one-year follow-up, the expression levels were still not completely restored. The significant changes in DNA methylation (n = 4548 CpGs) were mainly increased methylation levels between 100 days and one-year follow-up. Hence, the effects on gene expression occurred predominantly during treatment, while the effects on DNA methylation occurred after treatment. In conclusion, unrecognized side effects of long-term amoxicillin treatment were revealed, as alterations were observed in both gene expression and DNA methylation that lasted long after the end of treatment.

• Olstad, Emilie Willoch; Nordeng, Hedvig Marie Egeland; Sandve, Geir Kjetil Ferkingstad; Lyle, Robert & Gervin, Kristina (2023). Effects of prenatal exposure to (es)citalopram and maternal depression during pregnancy on DNA methylation and child neurodevelopment. Translational Psychiatry. 13(1). doi: 10.1038/s41398-023-02441-2. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Studies assessing associations between prenatal exposure to antidepressants, maternal depression, and offspring DNA methylation (DNAm) have been inconsistent. Here, we investigated whether prenatal exposure to citalopram or escitalopram ((es)citalopram) and maternal depression is associated with differences in DNAm. Then, we examined if there is an interaction effect of (es)citalopram exposure and DNAm on offspring neurodevelopmental outcomes. Finally, we investigated whether DNAm at birth correlates with neurodevelopmental trajectories in childhood. We analyzed DNAm in cord blood from the Norwegian Mother, Father and Child Cohort Study (MoBa) biobank. MoBa contains questionnaire data on maternal (es)citalopram use and depression during pregnancy and information about child neurodevelopmental outcomes assessed by internationally recognized psychometric tests. In addition, we retrieved ADHD diagnoses from the Norwegian Patient Registry and information on pregnancies from the Medical Birth Registry of Norway. In total, 958 newborn cord blood samples were divided into three groups: (1) prenatal (es)citalopram exposed ( n  = 306), (2) prenatal maternal depression exposed ( n  = 308), and (3) propensity score-selected controls ( n  = 344). Among children exposed to (es)citalopram, there were more ADHD diagnoses and symptoms and delayed communication and psychomotor development. We did not identify differential DNAm associated with (es)citalopram or depression, nor any interaction effects on neurodevelopmental outcomes throughout childhood. Trajectory modeling identified subgroups of children following similar developmental patterns. Some of these subgroups were enriched for children exposed to maternal depression, and some subgroups were associated with differences in DNAm at birth. Interestingly, several of the differentially methylated genes are involved in neuronal processes and development. These results suggest DNAm as a potential predictive molecular marker of later abnormal neurodevelopmental outcomes, but we cannot conclude whether DNAm links prenatal (es)citalopram exposure or maternal depression with child neurodevelopmental outcomes.

• Pedersen, Sigrid; Kverneland, Magnhild; Rudi, Knut; Gervin, Kristina; Landmark, Cecilie Johannessen & Iversen, Per Ole [Vis alle 7 forfattere av denne artikkelen] (2023). Decreased serum concentrations of antiseizure medications in children with drug resistant epilepsy following treatment with ketogenic diet. Epilepsia Open. 8(3), s. 858–866. doi: 10.1002/epi4.12746. Fulltekst i vitenarkiv Vis sammendrag

  Objective To examine the potential influence of a ketogenic diet on serum concentrations of antiseizure medications (ASMs) in children with drug resistant epilepsy. Methods We investigated the serum concentrations of ASMs in 25 children with drug resistant epilepsy, 2–13 years of age, treated with a classical ketogenic diet for 12 weeks. The patients were recruited from the National Centre for Epilepsy from August 15th, 2017, to January 24th, 2022. Changes in ASM serum concentrations were analyzed using a mixed effect model analysis. Significance level was set at P < 0.05 for all comparisons. Results The participants used 12 different ASMs during the study. The mean number of ASMs was 2.4 (±SD 0.7). None of the participants changed the type or dose of the ASMs during the intervention period. The serum concentrations of clobazam (n = 9, P = 0.002), desmethylclobazam (n = 9, P = 0.010), and lamotrigine (n = 6, P = 0.016) decreased significantly during the dietary treatment. The analytes with the largest reduction in serum concentration after 12 weeks of dietary treatment were clobazam (mean change −38%) and desmethylclobazam (mean change −37%). We found no significant change in the serum concentrations of levetiracetam, topiramate, and valproic acid. Significance We identified a significant decrease in the serum concentrations of clobazam, desmethylclobazam, and lamotrigine following a 12-week ketogenic diet intervention in children with drug resistant epilepsy. An unintended decrease in the serum concentrations of ASMs may render the patient prone to seizures. Measurements of ASM serum concentrations might be useful in patients on a ketogenic diet, especially in patients with lack of efficacy of the dietary treatment.

• Spildrejorde, Mari; Samara, Athina; Sharma, Ankush; Leithaug, Magnus; Falck, Martin Bengt Alfred & Modafferi, Stefania [Vis alle 12 forfattere av denne artikkelen] (2023). Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol. iScience. 26:107755(10), s. 1–29. doi: 10.1016/j.isci.2023.107755. Fulltekst i vitenarkiv Vis sammendrag

  Prenatal paracetamol exposure has been associated with neurodevelopmental outcomes in childhood. Pharmacoepigenetic studies show differences in cord blood DNA methylation between unexposed and paracetamol-exposed neonates, however, causality and impact of long-term prenatal paracetamol exposure on brain development remain unclear. Using a multi-omics approach, we investigated the effects of paracetamol on an in vitro model of early human neurodevelopment. We exposed human embryonic stem cells undergoing neuronal differentiation with paracetamol concentrations corresponding to maternal therapeutic doses. Single-cell RNA-seq and ATAC-seq integration identified paracetamol-induced chromatin opening changes linked to gene expression. Differentially methylated and/or expressed genes were involved in neurotransmission and cell fate determination trajectories. Some genes involved in neuronal injury and development-specific pathways, such as KCNE3, overlapped with differentially methylated genes previously identified in cord blood associated with prenatal paracetamol exposure. Our data suggest that paracetamol may play a causal role in impaired neurodevelopment.

• Olstad, Emilie Willoch; Nordeng, Hedvig Marie Egeland; Lyle, Robert & Gervin, Kristina (2023). No impact of prenatal paracetamol and folic acid exposure on cord blood DNA methylation in children with attention-deficit/hyperactivity disorder. Frontiers in Genetics. 14, s. 1–6. doi: 10.3389/fgene.2023.1204879. Fulltekst i vitenarkiv Vis sammendrag

  Pharmacoepigenetic studies are important to understand the mechanisms through which medications influence the developing fetus. For instance, we and others have reported associations between prenatal paracetamol exposure and offspring DNA methylation (DNAm). Additionally, folic acid (FA) intake during pregnancy has been associated with DNAm in genes linked to developmental abnormalities. In this study, we aimed to: (i) expand on our previous findings showing differential DNAm associated with long-term prenatal paracetamol exposure in offspring with attention-deficit/hyperactivity disorder (ADHD), and (ii) examine if there is an interaction effect of FA and paracetamol on DNAm in children with ADHD. We used data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway (MBRN). We did not identify any impact of paracetamol or any interaction effect of paracetamol and FA on cord blood DNAm in children with ADHD. Our results contribute to the growing literature on prenatal pharmacoepigenetics, but should be replicated in other cohorts. Replication of pharmacoepigenetic studies is essential to ensure robust findings and to increase the clinical relevance of such studies.

• Gjefsen, Elisabeth; Gervin, Kristina; Bråten, Lars Christian Haugli; Goll, Guro Løvik; Aass, Hans Christian & Schistad, Elina Iordanova [Vis alle 13 forfattere av denne artikkelen] (2023). Longitudinal changes of serum cytokines in patients with chronic low back pain and Modic changes. Osteoarthritis and Cartilage. ISSN 1063-4584. 31(4), s. 543–547. doi: 10.1016/j.joca.2023.01.001. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: To explore serum cytokine levels over time in patients with chronic low back pain (cLBP) and Modic changes (MCs), difference in change between treatment groups in the Antibiotics in Modic Changes (AIM) study and associations between change in cytokines and low back pain. Methods: Serum concentrations of 39 cytokines were measured at baseline and 1 year from 73 partic- ipants in the AIM study; 30 randomized to placebo, 43 to Amoxicillin. Low back pain intensity was measured by numeric rating scale. Change in cytokine levels over time were assessed by paired t-tests. Difference in change in cytokine levels between treatment groups and associations between changes in LBP and cytokine levels were assessed by linear regression models. Networks of cytokine changes in each treatment groups were explored by Pearson's correlations. Results: Five cytokines changed from baseline to 1 year, (mean change, log transformed values with CI) C-X-C motif chemokine ligand (CXCL) 10 (IP-10) (0.11 (0.01e0.20)), CXCL13 (0.61 (0.00e0.12)), C-C motif chemokine ligand (CCL)26 (0.05 (0.01e0.1)), granulocyte macrophage-colony stimulating factor (GM- CSF) ( 0.12 ( 0.23 to 0.00)) and CXCL11 (0.12 (0.03e0.22)). Treatment group only influenced change in CCL21 (b 0.07 (0.01e0.12)), and IL-6 (b 0.17 ( 0.30 to 0.03)). Change in CXCL13 (b 2.43 (0.49e4.38)), CCL27 (b 3.07 (0.46e5.69)), IL-8 (b 1.83 (0.08e3.58)) and CCL19 (b 3.10 (0.86e5.43)) were associated with change in LBP. The correlation networks of cytokine changes demonstrate small differences between treatment groups. Conclusions: Cytokine levels are relatively stable over time in our sample, with little difference between treatment groups. Some cytokines may be associated with LBP intensity. The differences between the correlation networks suggest that long-term Amoxicillin-treatment may have longstanding effects to be further explored.

• Bråten, Lars Christian Haugli; Gjefsen, Elisabeth; Gervin, Kristina; Pripp, Are Hugo; Skouen, Jan Sture & Schistad, Elina Iordanova [Vis alle 16 forfattere av denne artikkelen] (2023). Cytokine Patterns as Predictors of Antibiotic Treatment Effect in Chronic Low Back Pain with Modic Changes: Subgroup Analyses of a Randomized Trial (AIM Study). Journal of Pain Research. 16, s. 1713–1724. doi: 10.2147/JPR.S406079. Fulltekst i vitenarkiv Vis sammendrag

  Objective: Randomized trials testing the effect of antibiotics for chronic low back pain (LBP) with vertebral bone marrow changes on MRI (Modic changes) report inconsistent results. A proposed explanation is subgroups with low grade discitis where antibiotics are effective, but there is currently no method to identify such subgroups. The objective of the present study was to evaluate whether distinct patterns of serum cytokine levels predict any treatment effect of oral amoxicillin at one-year follow-up in patients with chronic low back pain and Modic changes at the level of a previous lumbar disc herniation. Design: We used data from an overpowered, randomized, placebo-controlled trial (the AIM study) that tested 100 days of oral 750 mg amoxicillin vs placebo three times daily in hospital outpatients with chronic (> 6 months) LBP with pain intensity ≥ 5 on a 0– 10 numerical rating scale and Modic changes type 1 (oedema type) or 2 (fatty type). We measured serum levels of 40 inflammatory cytokines at baseline and analysed six predefined potential predictors of treatment effect based on cytokine patterns in 78 randomized patients; three analyses with recursive partitioning, one based on cluster analysis and two based on principal component analyses. The primary outcome was the Roland–Morris Disability Questionnaire score at one-year follow-up in the intention to treat population. The methodology and overall results of the AIM study were published previously. Results: The 78 patients were 25– 62 years old and 47 (60%) were women. None of the three recursive partitioning analyses resulted in any suggested subgroups. Of all main analyses, the largest effect estimate (mean difference between antibiotic and placebo groups) was seen in a subgroup not predefined as of main interest (Cluster category 3+4; − 2.0, 95% CI: − 5.2– 1.3, RMDQ points; p-value for interaction 0.54). Conclusion: Patterns of inflammatory serum cytokine levels did not predict treatment effect of amoxicillin in patients with chronic LBP and Modic changes.

• Husebye, Elisabeth Synnøve Nilsen; Romanowska, Julia; Monsen, Anne-Lise Bjørke; Gilhus, Nils Erik; Selmer, Kaja Kristine & Gervin, Kristina [Vis alle 8 forfattere av denne artikkelen] (2023). Does maternal genetic liability to folate deficiency influence the risk of antiseizure medication-associated language impairment and autistic traits in children of women with epilepsy? American Journal of Clinical Nutrition. ISSN 0002-9165. 118(1), s. 303–313. doi: 10.1016/j.ajcnut.2023.05.023. Fulltekst i vitenarkiv Vis sammendrag

  Background: Prenatal exposure to antiseizure medication (ASM) may lead to low plasma folate concentrations and is associated with impaired neurodevelopment. Objectives: To examine whether maternal genetic liability to folate deficiency interacts with ASM-associated risk of language impairment and autistic traits in children of women with epilepsy. Methods: We included children of women with and without epilepsy and with available genetic data enrolled in the Norwegian Mother, Father, and Child Cohort Study. Information on ASM use, folic acid supplement use and dose, dietary folate intake, child autistic traits, and child language impairment was obtained from parent-reported questionnaires. Using logistic regression, we examined the interaction between prenatal ASM exposure and maternal genetic liability to folate deficiency expressed as polygenic risk score of low folate concentrations or maternal rs1801133 genotype (CC or CT/TT) on risk of language impairment or autistic traits. Results: We included 96 children of women with ASM-treated epilepsy, 131 children of women with ASM-untreated epilepsy, and 37,249 children of women without epilepsy. The polygenic risk score of low folate concentrations did not interact with the ASM-associated risk of language impairment or autistic traits in ASM-exposed children of women with epilepsy compared with ASM-unexposed children aged 1.5–8 y. ASM-exposed children had increased risk of adverse neurodevelopment regardless of maternal rs1801133 genotype {adjusted odds ratio [aOR] for language impairment aged 8 y was 2.88 [95% confidence interval (CI): 1.00, 8.26] if CC and aOR 2.88 [95% CI: 1.10, 7.53] if CT/TT genotypes}. In children of women without epilepsy aged 3 y, those with maternal rs1801133 CT/TT compared with CC genotype had increased risk of language impairment (aOR: 1.18; 95% CI: 1.05, 1.34). Conclusions: In this cohort of pregnant women reporting widespread use of folic acid supplements, maternal genetic liability to folate deficiency did not significantly influence the ASM-associated risk of impaired neurodevelopment.

• Samara, Athina; Spildrejorde, Mari; Sharma, Ankush; Falck, Martin; Leithaug, Magnus & Modafferi, Stefania [Vis alle 11 forfattere av denne artikkelen] (2022). A multi-omics approach to visualize early neuronal differentiation from hESCs in 4D. iScience. 25(11). doi: 10.1016/j.isci.2022.105279. Fulltekst i vitenarkiv Vis sammendrag

  Neuronal differentiation of pluripotent stem cells is an established method to study physiology, disease, and medication safety. However, the sequence of events in human neuronal differentiation and the ability of in vitro models to recapitulate early brain development are poorly understood. We developed a protocol optimized for the study of early human brain development and neuropharmacological applications. We comprehensively characterized gene expression and epigenetic profiles at four timepoints, because the cells differentiate from embryonic stem cells towards a heterogeneous population of progenitors, immature and mature neurons bearing telencephalic signatures. A multi-omics roadmap of neuronal differentiation, combined with searchable interactive gene analysis tools, allows for extensive exploration of early neuronal development and the effect of medications.

• Pedersen, Sigrid; Kverneland, Magnhild; Nakken, Karl Otto; Rudi, Knut; Iversen, Per Ole & Gervin, Kristina [Vis alle 7 forfattere av denne artikkelen] (2022). Genome-wide decrease in DNA methylation in adults with epilepsy treated with modified ketogenic diet: A prospective study. Epilepsia. ISSN 0013-9580. 63(9), s. 2413–2426. doi: 10.1111/epi.17351. Fulltekst i vitenarkiv Vis sammendrag

  Objective The aim of this study was to investigate the impact of the modified ketogenic diet on DNA methylation in adults with epilepsy. Methods In this prospective study, we investigated the genome-wide DNA methylation in whole blood in 58 adults with epilepsy treated with the modified ketogenic for 12 weeks. Patients were recruited from the National Center for Epilepsy, Norway, from March 1, 2011 to February 28, 2017. DNA methylation was analyzed using the Illumina Infinium MethylationEPIC BeadChip array. Analysis of variance and paired t-test were used to identify differentially methylated loci after 4 and 12 weeks of dietary treatment. A false discovery rate approach with a significance threshold of <5% was used to adjust for multiple comparisons. Results We observed a genome-wide decrease in DNA methylation, both globally and at specific sites, after 4 and 12 weeks of dietary treatment. A substantial share of the differentially methylated positions (CpGs) were annotated to genes associated with epilepsy (n = 7), lipid metabolism (n = 8), and transcriptional regulation (n = 10). Furthermore, five of the identified genes were related to inositol phosphate metabolism, which may represent a possible mechanism by which the ketogenic diet attenuates seizures. Significance A better understanding of the modified ketogenic diet's influence at the molecular level may be the key to unraveling the mechanisms by which the diet can ameliorate seizures and possibly to identifying novel therapeutic targets for epilepsy.

• Olstad, Emilie Willoch; Nordeng, Hedvig Marie Egeland; Sandve, Geir Kjetil Ferkingstad; Lyle, Robert & Gervin, Kristina (2022). Low reliability of DNA methylation across Illumina Infinium platforms in cord blood: implications for replication studies and meta-analyses of prenatal exposures. Clinical Epigenetics. 14(1). doi: 10.1186/s13148-022-01299-3. Fulltekst i vitenarkiv Vis sammendrag

  Background: There is an increasing interest in the role of epigenetics in epidemiology, but the emerging research feld 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 Infnium platforms in various tissues. In this study, we have investigated concordance between 450 k and EPIC Infnium platforms in cord blood. We could not replicate our previous fndings on the association of prenatal paracetamol exposure with cord blood DNAm, which prompted an investigation of cross-platform DNAm diferences. 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 signifcant fndings 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 (−R ≈0.99), but low per-CpG correlations (−R≈0.24) between the platforms. 1.7% of the CpGs exhibited a mean DNAm diference across platforms >0.1. Furthermore, only 26.7% of the CpGs exhibited a moderate or better cross-platform reliability (intra-class correlation coefcient ≥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 diferences between platforms. Nevertheless, it emulates the setting in studies using data from multiple Infnium platforms, often analysed several years apart. Therefore, the fndings 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.

• Nustad, Haakon Egdetveit; Steinsland, Ingelin; Ollikainen, Miina; Cazaly, Emma; Kaprio, Jaakko & Benjamini, Yuval [Vis alle 8 forfattere av denne artikkelen] (2022). Modeling dependency structures in 450k DNA methylation data. Bioinformatics. ISSN 1367-4803. 38(4), s. 885–891. doi: 10.1093/bioinformatics/btab774. Fulltekst i vitenarkiv Vis sammendrag

  Motivation: DNA methylation has been shown to be spatially dependent across chromosomes. Previous studies have focused on the influence of genomic context on the dependency structure, while not considering differences in dependency structure between individuals. Results: We modeled spatial dependency with a flexible framework to quantify the dependency structure, focusing on inter-individual differences by exploring the association between dependency parameters and technical and biological variables. The model was applied to a subset of the Finnish Twin Cohort study (N ¼ 1611 individuals). The estimates of the dependency parameters varied considerably across individuals, but were generally consistent across chromosomes within individuals. The variation in dependency parameters was associated with bisulfite conversion plate, zygosity, sex and age. The age differences presumably reflect accumulated environmental exposures and/or accumulated small methylation differences caused by stochastic mitotic events, establishing recognizable, individual patterns more strongly seen in older individuals. Availability and implementation: The twin dataset used in the current study are located in the Biobank of the National Institute for Health and Welfare, Finland. All the biobanked data are publicly available for use by qualified researchers following a standardized application procedure (https://thl.fi/en/web/thl-biobank/for-researchers). A R-script for fitting the dependency structure to publicly available DNA methylation data with the software used in this article is provided in supplementary data.

• Gjefsen, Elisabeth; Gervin, Kristina; Goll, Guro Løvik; Bråten, Lars Christian Haugli; Wigemyr, Monica & Aass, Hans Christian Dalsbotten [Vis alle 13 forfattere av denne artikkelen] (2021). Macrophage migration inhibitory factor: A potential biomarker for chronic low back pain in patients with Modic changes. RMD Open. 7(2), s. 1–10. doi: 10.1136/rmdopen-2021-001726. Fulltekst i vitenarkiv Vis sammendrag

  Background: Low back pain (LBP) is a leading cause of disability worldwide, but the aetiology remains poorly understood. Finding relevant biomarkers may lead to better understanding of disease mechanisms. Patients with vertebral endplate bone marrow lesions visualised on MRI as Modic changes (MCs) have been proposed as a distinct LBP phenotype, and inflammatory mediators may be involved in the development of MCs. Objectives: To identify possible serum biomarkers for LBP in patients with MCs. Methods: In this case control study serum levels of 40 cytokines were compared between patients with LBP and MC type 1 (n=46) or type 2 (n=37) and healthy controls (n=50). Results: Analyses identified significantly higher levels of six out of 40 cytokines in the MC type 1 group (MC1), and five in the MC type 2 group (MC2) compared with healthy controls. Six cytokines were moderately correlated with pain. Principal component analyses revealed clustering and separation of patients with LBP and controls, capturing 40.8% of the total variance, with 10 cytokines contributing to the separation. Macrophage migration inhibitory factor (MIF) alone accounted for 92% of the total contribution. Further, receiver operating characteristics analysis revealed that MIF showed an acceptable ability to distinguish between patients and controls (area under the curve=0.79). Conclusions: These results suggest that cytokines may play a role in LBP with MCs. The clinical significance of the findings is unknown. MIF strongly contributed to clustering of patients with LBP with MCs and controls and might be a biomarker for MCs. Ultimately, these results may guide future research on novel treatments for this patient group.

• Guderud, Kari; Sunde, Line Hagen; Flåm, Siri Tennebø; Mæhlen, Marthe Thoresen; Mjaavatten, Maria Dahl & NORLI, ELLEN SAUAR [Vis alle 13 forfattere av denne artikkelen] (2021). Methotrexate Treatment of Newly Diagnosed RA Patients Is Associated With DNA Methylation Differences at Genes Relevant for Disease Pathogenesis and Pharmacological Action. Frontiers in Immunology. 12, s. 1–11. doi: 10.3389/fimmu.2021.713611. Fulltekst i vitenarkiv Vis sammendrag

  Background: Methotrexate (MTX) is the first line treatment of rheumatoid arthritis (RA), and methylation changes in bulk T cells have been reported after treatment with MTX. We have investigated cell-type specific DNA methylation changes across the genome in naïve and memory CD4+ T cells before and after MTX treatment of RA patients. DNA methylation profiles of newly diagnosed RA patients (N=9) were assessed by reduced representation bisulfite sequencing. Results: We found that MTX treatment significantly influenced DNA methylation levels at multiple CpG sites in both cell populations. Interestingly, we identified differentially methylated sites annotated to two genes; TRIM15 and SORC2, previously reported to predict treatment outcome in RA patients when measured in bulk T cells. Furthermore, several of the genes, including STAT3, annotated to the significant CpG sites are relevant for RA susceptibility or the action of MTX. Conclusion: We detected CpG sites that were associated with MTX treatment in CD4+ naïve and memory T cells isolated from RA patients. Several of these sites overlap genetic regions previously associated with RA risk and MTX treatment outcome.

• Olstad, Emilie Willoch; Nordeng, Hedvig Marie Egeland & Gervin, Kristina (2021). Prenatal medication exposure and epigenetic outcomes: a systematic literature review and recommendations for prenatal pharmacoepigenetic studies. Epigenetics. ISSN 1559-2294. doi: 10.1080/15592294.2021.1903376. Fulltekst i vitenarkiv Vis sammendrag

  When used during pregnancy, analgesics and psychotropics pass the placenta to enter the foetal circulation and may induce epigenetic modifications. Where such modifications occur and whether they disrupt normal foetal developme nt, are currently unanswered questions. This field of prenatal pharmacoepigenetics has received increasing attention, with several studies reporting associations between in utero medication exposure and offspring epigenetic outcomes. Nevertheless, no recent systematic review of the literature is available. Therefore, the objectives of this review were to (i) provide an overview of the literature on the association of prenatal exposure to psychotropics a nd analgesics with epigenetic outcomes, and (ii) suggest recommendations for future studies within prenatal pharmacoepigenetics. We performed systematic literature searches in five databases. The eligible studies assessed human prenatal exposure to psychotropics or analgesics, with epigenetic analyses of offspring tissue as an outcome. We identified 18 eligible studies including 4,419 neonates exposed to either antidepressants, antiepileptic drugs, paracetamol, acetylsalicylic acid, or methadone. The epigenetic outcome in all studies was DNA methylation in cord blood, placental tissue or buccal cells. Although most studies found significant differences in DNA methylation upon medication exposure, almost no differences were persistent across studies for similar medications and sequencing methods. The reviewed studies were challenging to compare due to poor transparency in reporting, and heterogeneous methodology, design, genome coverage, and statistical modelling. We propose 10 recommendations for future prenatal pharmacoepigenetic studies considering both epidemiological and epigenetic perspectives. These recommendations may improve the quality, comparability, and clinical relevance of such studies. PROSPERO registration ID: CRD42020166675.

• Gomes, Julia do Amaral; Olstad, Emilie Willoch; Kowalski, Thayne Woycinck; Gervin, Kristina; Vianna, Fernanda Sales Luiz & Schüler-Faccini, Lavínia [Vis alle 7 forfattere av denne artikkelen] (2021). Genetic Susceptibility to Drug Teratogenicity: A Systematic Literature Review. Frontiers in Genetics. 12. doi: 10.3389/fgene.2021.645555. Fulltekst i vitenarkiv Vis sammendrag

  Since the 1960s, drugs have been known to cause teratogenic effects in humans. Such teratogenicity has been postulated to be influenced by genetics. The aim of this review was to provide an overview of the current knowledge on genetic susceptibility to drug teratogenicity in humans and reflect on future directions within the field of genetic teratology. We focused on 12 drugs and drug classes with evidence of teratogenic action, as well as 29 drugs and drug classes with conflicting evidence of fetal safety in humans. An extensive literature search was performed in the PubMed and EMBASE databases using terms related to the drugs of interest, congenital anomalies and fetal development abnormalities, and genetic variation and susceptibility. A total of 29 studies were included in the final data extraction. The eligible studies were published between 1999 and 2020 in 10 different countries, and comprised 28 candidate gene and 1 whole-exome sequencing studies. The sample sizes ranged from 20 to 9,774 individuals. Several drugs were investigated, including antidepressants (nine studies), thalidomide (seven studies), antiepileptic drugs (five studies), glucocorticoids (four studies), acetaminophen (two studies), and sex hormones (estrogens, one study; 17-alpha hydroxyprogesterone caproate, one study). The main neonatal phenotypic outcomes included perinatal complications, cardiovascular congenital anomalies, and neurodevelopmental outcomes. The review demonstrated that studies on genetic teratology are generally small, heterogeneous, and exhibit inconsistent results. The most convincing findings were genetic variants in SLC6A4, MTHFR, and NR3C1, which were associated with drug teratogenicity by antidepressants, antiepileptics, and glucocorticoids, respectively. Notably, this review demonstrated the large knowledge gap regarding genetic susceptibility to drug teratogenicity, emphasizing the need for further efforts in the field. Future studies may be improved by increasing the sample size and applying genome-wide approaches to promote the interpretation of results. Such studies could support the clinical implementation of genetic screening to provide safer drug use in pregnant women in need of drugs.

• Guderud, Kari; Sunde, Line Hagen; Flåm, Siri Tennebø; Mæhlen, Marthe Thoresen; Mjaavatten, Maria Dahl & Lillegraven, Siri [Vis alle 16 forfattere av denne artikkelen] (2020). Rheumatoid Arthritis Patients, Both Newly Diagnosed and Methotrexate Treated, Show More DNA Methylation Differences in CD4+ Memory Than in CD4+ Naïve T Cells. Frontiers in Immunology. 11:194, s. 1–14. doi: 10.3389/fimmu.2020.00194. Fulltekst i vitenarkiv Vis sammendrag

  Background: Differences in DNA methylation have been reported in B and T lymphocyte populations, including CD4+ T cells, isolated from rheumatoid arthritis (RA) patients when compared to healthy controls. CD4+ T cells are a heterogeneous cell type with subpopulations displaying distinct DNA methylation patterns. In this study, we investigated DNA methylation using reduced representation bisulfite sequencing in two CD4+ T cell populations (CD4+ memory and naïve cells) in three groups: newly diagnosed, disease modifying antirheumatic drugs (DMARD) naïve RA patients (N = 11), methotrexate (MTX) treated RA patients (N = 18), and healthy controls (N = 9) matched for age, gender and smoking status. Results: Analyses of these data revealed significantly more differentially methylated positions (DMPs) in CD4+ memory than in CD4+ naïve T cells (904 vs. 19 DMPs) in RA patients compared to controls. The majority of DMPs (72%) identified in newly diagnosed and DMARD naïve RA patients with active disease showed increased DNA methylation (39 DMPs), whereas most DMPs (80%) identified in the MTX treated RA patients in remission displayed decreased DNA methylation (694 DMPs). Interestingly, we also found that about one third of the 101 known RA risk loci overlapped (±500 kb) with the DMPs. Notably, introns of the UBASH3A gene harbor both the lead RA risk SNP and two DMPs in CD4+ memory T cells. Conclusion: Our results suggest that RA associated DNA methylation differences vary between the two T cell subsets, but are also influenced by RA characteristics such as disease activity, disease duration and/or MTX treatment.

• Gervin, Kristina; Salas, Lucas A.; Bakulski, Kelly M.; Zelm, Menno C. van; Koestler, Devin C. & Wiencke, John K [Vis alle 14 forfattere av denne artikkelen] (2019). Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data. Clinical Epigenetics. 11(125). doi: 10.1186/s13148-019-0717-y. Fulltekst i vitenarkiv Vis sammendrag

  Background: Umbilical cord blood (UCB) is commonly used in epigenome-wide association studies of prenatal exposures. Accounting for cell type composition is critical in such studies as it reduces confounding due to the cell specificity of DNA methylation (DNAm). In the absence of cell sorting information, statistical methods can be applied to deconvolve heterogeneous cell mixtures. Among these methods, reference-based approaches leverage age-appropriate cell-specific DNAm profiles to estimate cellular composition. In UCB, four reference datasets comprising DNAm signatures profiled in purified cell populations have been published using the Illumina 450 K and EPIC arrays. These datasets are biologically and technically different, and currently, there is no consensus on how to best apply them. Here, we systematically evaluate and compare these datasets and provide recommendations for reference-based UCB deconvolution. Results: We first evaluated the four reference datasets to ascertain both the purity of the samples and the potential cell cross-contamination. We filtered samples and combined datasets to obtain a joint UCB reference. We selected deconvolution libraries using two different approaches: automatic selection using the top differentially methylated probes from the function pickCompProbes in minfi and a standardized library selected using the IDOL (Identifying Optimal Libraries) iterative algorithm. We compared the performance of each reference separately and in combination, using the two approaches for reference library selection, and validated the results in an independent cohort (Generation R Study, n = 191) with matched Fluorescence-Activated Cell Sorting measured cell counts. Strict filtering and combination of the references significantly improved the accuracy and efficiency of cell type estimates. Ultimately, the IDOL library outperformed the library from the automatic selection method implemented in pickCompProbes. Conclusion: These results have important implications for epigenetic studies in UCB as implementing this method will optimally reduce confounding due to cellular heterogeneity. This work provides guidelines for future referencebased UCB deconvolution and establishes a framework for combining reference datasets in other tissues.

• Hjorthaug, Hanne Sagsveen; Gervin, Kristina; Mowinckel, Petter & Munthe-Kaas, Monica Cheng (2018). Exploring the influence from whole blood DNA extraction methods on Infinium 450K DNA methylation. PLOS ONE. 13: e0208699(12). doi: 10.1371/journal.pone.0208699. Fulltekst i vitenarkiv Vis sammendrag

  Genome-wide DNA methylation studies are becoming increasingly important in unraveling the epigenetic basis of cell biology, aging and human conditions. The aim of the present study was to explore whether different methods for extracting DNA from whole blood can affect DNA methylation outcome, potentially confounding DNA methylation studies. DNA was isolated from healthy blood donors (n = 10) using three different extraction methods (i.e. two automatic extractions methods based on magnetic beads or isopropanol precipitation, and manual organic extraction). DNA methylation was analyzed using the Infinium HumanMethylation450 Bead Chip (Infinium 450K) (n = 30 samples in total), which is a frequently used method in genome-wide DNA methylation analyses. Overall, the different extraction methods did not have a significant impact on the global DNA methylation patterns. However, DNA methylation differences between organic extraction and each of the automated methods were in general larger than differences between the two automated extraction methods. No CpG sites or regions reached genome-wide significance when testing for differential methylation between extraction methods. Although this study is based on a small sample, these results suggest that extraction method is unlikely to confound Infinium 450K methylation analysis in whole blood.

• Gervin, Kristina; Nordeng, Hedvig Marie Egeland; Eskeland, Ragnhild; Paulsen, Ragnhild Elisabeth & Lyle, Robert (2017). Farmakoepigenetikk: Samspillet mellom legemidler og epigenetikk. Norsk Farmaceutisk Tidsskrift (NFT). ISSN 0029-1935. 125(8), s. 30–34. Fulltekst i vitenarkiv Vis sammendrag

  Epigenetikk er læren om arvelige mekanismer som regulerer aktiviteten til genene i ulike celler og vev som ikke involverer en endring i selve DNA-sekvensen. Om gener er skrudd av eller på er bestemt av epigenetiske merkelapper festet til det enkelte genet. Hensikten med denne artikkelen er å gi en kortfattet introduksjon til epigenetikk og farmakoepigenetikk. Epigenetiske faktorer antas å være viktige i utviklingen av en rekke sykdommer, som visse kreftformer og utviklingsforstyrrelser i nervesystemet. Det finnes allerede legemidler på markedet som virker via epigenetiske mekanismer ved å påvirke det epigenetiske maskineriet som fester de epigenetiske merkelappene til DNA-et, eller proteiner som DNA-et er kveilet rundt. Spesielt innen kreftmedisin satses det stort på utvikling av legemidler som kan normalisere avvikende genuttrykk via epigenetiske mekanismer. Lite er kjent om legemidler kan gi opphav til bivirkninger via epigenetiske mekanismer.

• Gervin, Kristina; Nordeng, Hedvig Marie Egeland; Ystrøm, Eivind; Reichborn-Kjennerud, Ted & Lyle, Robert (2017). Long-term prenatal exposure to paracetamol is associated with DNA methylation differences in children diagnosed with ADHD. Clinical Epigenetics. 9. doi: 10.1186/s13148-017-0376-9. Fulltekst i vitenarkiv Vis sammendrag

  Background: Epidemiological studies have shown that long-term exposure to paracetamol during pregnancy is associated with attention-deficit/hyperactivity disorder (ADHD). The mechanism by which paracetamol may modulate the increased risk of developing ADHD is currently unknown. We have conducted an epigenome-wide association study (n = 384 cord blood samples) and investigated whether prenatal exposure to paracetamol is associated with DNA methylation in children diagnosed with ADHD. Results: Analyses identified significant differences in DNA methylation (n = 6211 CpGs) associated with prenatal exposure to paracetamol for more than 20 days in children diagnosed with ADHD compared to controls. In addition, these samples were differentially methylated compared to samples with ADHD exposed to paracetamol for less than 20 days (n = 2089 CpGs) and not exposed to paracetamol (n = 193 CpGs). Interestingly, several of the top genes ranked according to significance and effect size have been linked to ADHD, neural development, and neurotransmission. Gene ontology analysis revealed enrichment of pathways involved in oxidative stress, neurological processes, and the olfactory sensory system, which have previously been implicated in the etiology of ADHD. Conclusions: These initial findings suggest that in individuals susceptible to ADHD, prenatal long-term exposure to paracetamol is associated with DNA methylation differences compared to Controls.

• Gervin, Kristina; Kulle, Bettina; Hjorthaug, Hanne Sagsveen; Carlsen, Karin C. Lødrup; Carlsen, Kai-Håkon & Undlien, Dag Erik [Vis alle 8 forfattere av denne artikkelen] (2016). Intra-individual changes in DNA methylation not mediated by cell-type composition are correlated with aging during childhood. Clinical Epigenetics. 8:110, s. 1–12. doi: 10.1186/s13148-016-0277-3. Fulltekst i vitenarkiv Vis sammendrag

  Background Several studies have reported age-associated changes in DNA methylation in the first few years of life and in adult populations, but the extent of such changes during childhood is less well studied. The goals of this study were to investigate to what degree intra-individual changes in DNA methylation are associated with aging during childhood and dissect the methylation changes directly associated with aging from the effect mediated through variation in cell-type composition (CTC). Results We performed reduced representation bisulfite sequencing (RRBS) in peripheral whole-blood samples collected at 2, 10, and 16 years of age. We identified age-associated longitudinal changes in DNA methylation at 346 CpGs in 178 genes. Analyses separating the effect mediated by CTC variability across age identified 26 CpGs located in 12 genes that associated directly with age. Hence, the CTC changes across age appear to act as a mediator of the observed DNA methylation associated with age. The results were replicated using EpiTYPER in a second sample set selected from the same cohort. Gene ontology analyses revealed enrichment of transcriptional regulation and developmental processes. Further, comparisons of the mean DNA methylation differences between the time points reveal greater differences between 2 to 10 years and 10 to 16 years, suggesting that the identified age-associated DNA methylation patterns manifests in early childhood. Conclusions This study reveals insights into the epigenetic dynamics associated with aging early in life. Such information could ultimately provide clues and point towards molecular pathways that are susceptible to aging-related disease-associated epigenetic dysregulation.

• Gervin, Kristina; Page, Christian; Aass, Hans Christian; Jansen, Michelle A; Fjeldstad, Heidi & Andreassen, Bettina Kulle [Vis alle 17 forfattere av denne artikkelen] (2016). Cell type specific DNA methylation in cord blood: a 450K-reference data set and cell count-based validation of estimated cell type composition. Epigenetics. ISSN 1559-2294. 11(9), s. 690–698. doi: 10.1080/15592294.2016.1214782. Fulltekst i vitenarkiv
• Svendsen, Anders J; Gervin, Kristina; Lyle, Robert; Christiansen, Lene; Kyvik, Kirsten & Junker, Peter [Vis alle 9 forfattere av denne artikkelen] (2016). Differentially methylated DNA regions in monozygotic twin pairs discordant for rheumatoid arthritis: An epigenome-wide study. Frontiers in Immunology. 7. doi: 10.3389/fimmu.2016.00510. Fulltekst i vitenarkiv
• Ollikainen, M; Ismail, K; Gervin, Kristina; Harris, Jennifer; Lyle, Robert & Kyllönen, Anjuska [Vis alle 13 forfattere av denne artikkelen] (2015). Genome-wide blood DNA methylation alterations at regulatory elements and heterochromatic regions in monozygotic twins discordant for obesity and liver fat. Clinical Epigenetics. 7:39, s. 1–13. doi: 10.1186/s13148-015-0073-5. Fulltekst i vitenarkiv Vis sammendrag

  Background: The current epidemic of obesity and associated diseases calls for swift actions to better understand the mechanisms by which genetics and environmental factors affect metabolic health in humans. Monozygotic (MZ) twin pairs showing discordance for obesity suggest that epigenetic influences represent one such mechanism. We studied genome-wide leukocyte DNA methylation variation in 30 clinically healthy young adult MZ twin pairs discordant for body mass index (BMI; average within-pair BMI difference: 5.4 ± 2.0 kg/m2). Results: There were no differentially methylated cytosine-guanine (CpG) sites between the co-twins discordant for BMI. However, stratification of the twin pairs based on the level of liver fat accumulation revealed two epigenetically highly different groups. Significant DNA methylation differences (n = 1,236 CpG sites (CpGs)) between the co-twins were only observed if the heavier co-twins had excessive liver fat (n = 13 twin pairs). This unhealthy pattern of obesity was coupled with insulin resistance and low-grade inflammation. The differentially methylated CpGs included 23 genes known to be associated with obesity, liver fat, type 2 diabetes mellitus (T2DM) and metabolic syndrome, and potential novel metabolic genes. Differentially methylated CpG sites were overrepresented at promoters, insulators, and heterochromatic and repressed regions. Based on predictions by overlapping histone marks, repressed and weakly transcribed sites were significantly more often hypomethylated, whereas sites with strong enhancers and active promoters were hypermethylated. Further, significant clustering of differentially methylated genes in vitamin, amino acid, fatty acid, sulfur, and renin-angiotensin metabolism pathways was observed. Conclusions: The methylome in leukocytes is altered in obesity associated with metabolic disturbances, and our findings indicate several novel candidate genes and pathways in obesity and obesity-related complications.

• Nilsen, Thomas Sevenius; Knudsen, Gun Peggy; Gervin, Kristina; Brandt, Ingunn; Røysamb, Espen & Tambs, Kristian [Vis alle 11 forfattere av denne artikkelen] (2013). The Norwegian twin registry from a public health perspective: a research update. Twin Research and Human Genetics. ISSN 1832-4274. 16(1), s. 285–295. doi: 10.1017/thg.2012.117. Fulltekst i vitenarkiv
• Gilfillan, Gregor Duncan; Hughes, Timothy; Sheng, Ying; Hjorthaug, Hanne Sagsveen; Straub, Tobias & Gervin, Kristina [Vis alle 9 forfattere av denne artikkelen] (2012). Limitations and possibilities of low cell number ChIP-seq. BMC Genomics. 13. doi: 10.1186/1471-2164-13-645. Fulltekst i vitenarkiv Vis sammendrag

  Background Chromatin immunoprecipitation coupled with high-throughput DNA sequencing (ChIP-seq) offers high resolution, genome-wide analysis of DNA-protein interactions. However, current standard methods require abundant starting material in the range of 1–20 million cells per immunoprecipitation, and remain a bottleneck to the acquisition of biologically relevant epigenetic data. Using a ChIP-seq protocol optimised for low cell numbers (down to 100,000 cells / IP), we examined the performance of the ChIP-seq technique on a series of decreasing cell numbers. Results We present an enhanced native ChIP-seq method tailored to low cell numbers that represents a 200-fold reduction in input requirements over existing protocols. The protocol was tested over a range of starting cell numbers covering three orders of magnitude, enabling determination of the lower limit of the technique. At low input cell numbers, increased levels of unmapped and duplicate reads reduce the number of unique reads generated, and can drive up sequencing costs and affect sensitivity if ChIP is attempted from too few cells. Conclusions The optimised method presented here considerably reduces the input requirements for performing native ChIP-seq. It extends the applicability of the technique to isolated primary cells and rare cell populations (e.g. biobank samples, stem cells), and in many cases will alleviate the need for cell culture and any associated alteration of epigenetic marks. However, this study highlights a challenge inherent to ChIP-seq from low cell numbers: as cell input numbers fall, levels of unmapped sequence reads and PCR-generated duplicate reads rise. We discuss a number of solutions to overcome the effects of reducing cell number that may aid further improvements to ChIP performance.

• Gervin, Kristina; Vigeland, Magnus Dehli; Mattingsdal, Morten; Hammerø, Martin; Nygård, Heidi & Olsen, Anne Olaug [Vis alle 10 forfattere av denne artikkelen] (2012). DNA Methylation and Gene Expression Changes in Monozygotic Twins Discordant for Psoriasis: Identification of Epigenetically Dysregulated Genes. PLoS Genetics. ISSN 1553-7390. 8(1). doi: 10.1371/journal.pgen.1002454. Fulltekst i vitenarkiv
• Munthe-Kaas, Monica Cheng; Bertelsen, Randi Jacobsen; Torjussen, Tale Mæhre; Hjorthaug, Hanne Sagsveen; Undlien, Dag Erik & Lyle, Robert [Vis alle 11 forfattere av denne artikkelen] (2012). Pet keeping and tobacco exposure influence CD14 methylation in childhood. Pediatric Allergy and Immunology. ISSN 0905-6157. 23(8), s. 746–753. doi: 10.1111/pai.12021. Fulltekst i vitenarkiv
• Hekman, Katherine E.; Yu, Guo-Yun; Brown, C.; Zhu, Haipeng; Du, Xiaofei & Gervin, Kristina [Vis alle 14 forfattere av denne artikkelen] (2012). A conserved eEF2 coding variant in SCA26 leads to loss of translational fidelity and increased susceptibility to proteostatic insult. Human Molecular Genetics. ISSN 0964-6906. 21(26), s. 5472–5483. doi: 10.1093/hmg/dds392. Fulltekst i vitenarkiv
• Skinningsrud, Beate; Lie, Benedicte Alexandra; Lavant, Ewa; Carlson, Joyce A.; Erlich, Henry & Akselsen, Hanne Elisabeth [Vis alle 12 forfattere av denne artikkelen] (2011). Multiple loci in the HLA complex are associated with Addison's Disease. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 96(10), s. E1703–E1708. doi: 10.1210/jc.2011-0645. Fulltekst i vitenarkiv
• Gervin, Kristina; Hammerø, Martin; Akselsen, Hanne Elisabeth; Moe, Rune; Nygård, Heidi & Brandt, Ingunn [Vis alle 10 forfattere av denne artikkelen] (2011). Extensive variation and low heritability of DNA methylation identified in a twin study. Genome Research. ISSN 1088-9051. 21(11), s. 1813–1821. doi: 10.1101/gr.119685.110. Fulltekst i vitenarkiv
• Munthe-Kaas, Monica Cheng; Torjussen, Tale Mæhre; Gervin, Kristina; Carlsen, Karin C. Lødrup; Carlsen, Kai-Håkon & Granum, Berit [Vis alle 9 forfattere av denne artikkelen] (2010). CD14 polymorphisms and serum CD14 levels through childhood: A role for gene methylation? Journal of Allergy and Clinical Immunology. ISSN 0091-6749. 125(6), s. 1361–1368. doi: 10.1016/j.jaci.2010.02.010. Fulltekst i vitenarkiv
• Skinningsrud, Beate; Husebye, Einar; Husebye, Eystein Sverre; Gilfillan, Gregor D; Frengen, Eirik & Erichsen, Aage [Vis alle 13 forfattere av denne artikkelen] (2009). X-Linked Congenital Adrenal Hypoplasia with Hypogonadotropic Hypogonadism Caused by an Inversion Disrupting a Conserved Noncoding Element Upstream of the NR0B1 (DAX1) Gene. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 94(10), s. 4086–4093. doi: 10.1210/jc.2009-0923. Fulltekst i vitenarkiv
• Bjørnvold, Marit; Munthe-Kaas, Monica Cheng; Egeland, Thore; Joner, Geir; Dahl-Jørgensen, Knut & Njølstad, Pål Rasmus [Vis alle 11 forfattere av denne artikkelen] (2009). A TLR2 polymorphism is associated with type 1 diabetes and allergic asthma. Genes and Immunity. ISSN 1466-4879. 10(2), s. 181–187. doi: 10.1038/gene.2008.100. Fulltekst i vitenarkiv
• Munthe-Kaas, Monica Cheng; Carlsen, Kai-Håkon; Håland, Geir; Devulapalli, Chandra S.; Gervin, Kristina & Egeland, Thore [Vis alle 8 forfattere av denne artikkelen] (2008). T cell–specific T-box transcription factor haplotype is associated with allergic asthma in children. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. 121. doi: 10.1016/j.jaci.2007.07.068. Fulltekst i vitenarkiv Vis sammendrag

  BACKGROUND: T cell-specific T-box transcription factor (T-bet) is a member of the T-box family of transcription factors regulating lineage commitment of T(H) lymphocytes toward a predominant T(H)1 phenotype. Asthma and allergy are common complex diseases characterized by T(H)2-mediated inflammation. OBJECTIVE: We aimed to assess possible relationships between the T-bet gene (TBX21) and asthma and allergy in children. METHOD: Twelve single nucleotide polymorphisms (SNPs) in the TBX21 region were genotyped in 948 children from the Environment and Childhood Asthma study. Allele and haplotype frequencies were compared in children with and without asthma (by 10 years) and allergy (>/=1 positive skin prick test response), as well as for the quantitative traits bronchial hyperresponsiveness determined by means of methacholine bronchial challenge testing, lung function determined by means of forced flow volume loops, fractional exhaled nitric oxide measurement, eosinophil count, and serum total IgE level. RESULTS: Allergic asthma was significantly associated with 2 of the tested SNPs (rs11650354 and rs16947078) and further associated with the particular haplotype including these SNPs, with homozygote status resulting in an odds ratio of 8.3 (95% CI, 2.5-26.9) for allergic asthma. Neither nonallergic asthma or "allergy alone" nor the remaining quantitative variables were associated with TBX21 SNPs or haplotypes. CONCLUSION: An association between a specific TBX21 haplotype and allergic asthma in children is demonstrated for the first time and might explain previously detected associations between SNPs within TBX21 and asthma and bronchial hyperresponsiveness. CLINICAL IMPLICATIONS: T-bet genetics might identify individuals at risk for allergic asthma

• Bjørnvold, Marit; Undlien, DE; Joner, Geir; Dahl-Jørgensen, Knut; Njølstad, Pål Rasmus & Akselsen, HE [Vis alle 9 forfattere av denne artikkelen] (2008). Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes. Diabetologia. ISSN 0012-186X. 51(4), s. 589–596. doi: 10.1007/s00125-008-0932-0. Fulltekst i vitenarkiv
• Tjeldhorn, L; Hendriksen, Svend Rand.; Gervin, Kristina; Brandal, Kristin; Inderhaug, E & Geiran, Odd [Vis alle 7 forfattere av denne artikkelen] (2006). Rapid and efficient FBN1 mutation detetction using automated sample preparation and direct sequencing as the primary strategy. Genetic Testing. ISSN 1090-6576. 10, s. 258–264. Fulltekst i vitenarkiv

Se alle arbeider i NVA

• Nordeng, Hedvig Marie Egeland; Lyle, Robert & Gervin, Kristina (2015). Use of paracetamol during pregnancy: adverse epigenetic side-effects and development of ADHD. Fulltekst i vitenarkiv
• Nordeng, Hedvig Marie Egeland; Lyle, Robert & Gervin, Kristina (2015). Medications during pregnancy: effects on neurodevelopmental disorders in childhood and epigenetic outcomes. Fulltekst i vitenarkiv

Se alle arbeider i NVA