Epigenome-wide study of widespread hypomethylated loci associated with early-onset preeclampsia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE125605 | GEO | 2019/06/30
REPOSITORIES: GEO
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Project description:Introduction. Preeclampsia (PE) carries increased risks of cardiovascular- and metabolic diseases in mothers and offspring during the life course. While the severe early-onset PE (EOPE) phenotype originates from impaired placentation in early pregnancy, late-onset PE (LOPE) is in particular associated with pre-existing maternal cardiovascular- and metabolic risk factors. We hypothesize that PE is associated with altered epigenetic programming of placental and fetal tissues and that these epigenetic changes might elucidate the increased cardiovascular- and metabolic disease susceptibility in PE offspring. Methods. A nested case-control study was conducted in The Rotterdam Periconceptional Cohort comprising 13 EOPE, 16 LOPE, and three control groups of 36 uncomplicated pregnancies, 27 normotensive fetal growth restricted (FGR) and 20 normotensive preterm birth (PTB) complicated pregnancies. Placental tissue, newborn umbilical cord blood leucocytes (UC-WBC) and umbilical vein endothelial cells (HUVEC) were collected and DNA methylation of cytosine-guanine dinucleotides was measured by the Illumina HumanMethylation450K BeadChip. An epigenome-wide analysis was performed by using multiple linear regression models. Results. Epigenome-wide tissue-specific analysis between EOPE and PTB controls revealed 5001 mostly hypermethylated differentially methylated positions (DMPs) in UC-WBC and 869 mostly hypomethylated DMPs in placental tissue, situated in or close to genes associated with cardiovascular-metabolic developmental pathways. Discussion. This study shows differential methylation in UC-WBC and placental tissue in EOPE as compared to PTB, identifying DMPs that are associated with cardiovascular system pathways. Future studies should examine these loci and pathways in more detail to elucidate the associations between prenatal PE exposure and the cardiovascular disease risk in offspring.
2017-09-06 | GSE103253 | GEO
Project description:Preeclampsia (PE), a maternal hypertensive disorder, and intrauterine growth restriction (IUGR), pathologically poor fetal growth, often co-occur and are associated with placental insufficiency (PI). PI is more common in early-onset PE (EOPE) than late-onset PE (LOPE). However, the relationship between these disorders remains unclear. While DNA methylation (DNAm) alterations have been previously identified in PE and IUGR, few studies validated the findings in an independent cohort. This study aims to identify altered DNAm in EOPE, LOPE, and normotensive IUGR, validate these alterations, and use the findings to better understand the relationships between these related disorders. Placental samples from a discovery cohort (43 controls, 22 EOPE, 18 LOPE, 11 IUGR) and validation cohort (15 controls, 22 EOPE, 11 LOPE) were evaluated using the Illumina HumanMethylation450 array. To minimize gestational age (GA) effects, EOPE samples were compared to pre-term controls (GA <37 weeks), while LOPE and IUGR were compared to term controls (GA >37 weeks). Linear regression identified 1703 differentially methylated (DM) sites (FDR<0.05, ∆β>0.1) in EOPE, 5 in LOPE, and 0 in IUGR. Of the 1703 sites associated with EOPE in the discovery cohort, 599 were validated in the second cohort. These sites cluster samples from both cohorts into 3 distinct methylation clusters. Interestingly, LOPE samples diagnosed between 34-36 weeks and had co-occurring IUGR clustered with the EOPE methylation cluster. DNAm profiling may provide an independent tool to refine clinical diagnoses into subgroups with more uniform pathology. The challenges in reproducing genome-wide DNAm studies are also discussed. DNA methylation data of the validation cohort can be found at GSE98224.
2018-05-11 | GSE100197 | GEO
Project description:Hypertension in pregnancy is the leading cause of morbidity and mortality in pregnancy, affecting up to 10% of all gestations1. Hypertensive disorders of pregnancy include chronic hypertension, gestational hypertension, eclampsia and pre-eclampsia, all of which increase the risk of complications in both mothers and babies during gestation. Preeclampsia, in particular, is characterised by the new-onset of gestational hypertension in the presence of proteinuria or other organ damage. It affects 5-7% of pregnancies and causes approximately 76,000 maternal deaths and 500,000 foetal deaths worldwide each year2. The classification of preeclampsia has been evolving over the last decade. In 2013, American College of Obstetricians and Gynecologists (ACOG) and International Society for the Study of Hypertension in Pregnancy (ISSHP) in the absence of proteinuria included other symptoms/features including liver dysfunction, thrombocytopenia, cerebrovascular events or foetal growth restriction (FGR) in the diagnosis of preeclampsia 1,3,4. Despite the fact that preeclampsia is a multifactorial and heterogeneous disorder, it is now widely accepted that preeclampsia is stratified depending on the time of onset into: i) early-onset PE (EOPE) manifested before 34 weeks of gestation, and ii) late-onset PE (LOPE) manifested from 34 weeks of gestation. Although EOPE and LOPE share the same diagnostic criteria, these two phenotypes of preeclampsia lead to different outcomes. EOPE is commonly associated with FGR, abnormal uterine artery Doppler often leading to preterm birth and higher risk of post-pregnancy morbidities5,6. On the other hand, LOPE appears to be a less severe disorder, often with normal or slightly increased uterine resistance index and a low rate of FGR6,7. Distinct delineation between EOPE and LOPE is still not well understood, with most patients with preeclampsia presenting elements of both pathologies proposing a clinical spectrum for preeclampsia. The lack of untargeted discovery studies involving ‘omics’ analyses has impeded understanding of the molecular differences between these two phenotypes of preeclampsia. Notably, a study from 20058 utilised a proteomics approach using urine samples from a cohort of pregnant women with EOPE and healthy controls, however the differences between EOPE and LOPE were not elucidated. Another more recent bioinformatics study, identified overlapping pathogenic mechanisms between preeclampsia, hypertension and heart disease but could not stratify between EOPE and LOPE due to underreported of data related to individual phenotypes9. In this study, we conducted an unbiased, comprehensive proteomics investigation using plasma samples collected from patients with EOPE (n=17) and LOPE (n=11), compared with age- and BMI-matched normotensive controls (n=18). The use of plasma samples is able to better reflect the pathogenesis of EOPE and LOPE as systemic conditions centred by widespread endothelial dysfunction.
2023-03-11 | PXD026931 | Pride
Project description:Background: A small number of recent reports have suggested that altered placental DNA methylation may be associated with early onset preeclampsia. It is important that further studies be undertaken to confirm and develop these findings. We therefore undertook a systematic analysis of DNA methylation patterns in placental tissue from 24 women with preeclampsia and 24 with uncomplicated pregnancy outcome. Methods: We analyzed the DNA methylation status of approximately 27,000 CpG sites in placental tissues in a massively parallel fashion using an oligonucleotide microarray. Follow up analysis of DNA methylation at specific CpG loci was performed using the Epityper MassArray approach and high-throughput bisulfite sequencing. Results: Preeclampsia-specific DNA methylation changes were identified in placental tissue samples irrespective of gestational age of delivery. In addition, we identified a group of CpG sites within specific gene sequences that were only altered in early onset-preeclampsia (EOPET) although these DNA methylation changes did not correlate with altered mRNA transcription. We found evidence that fetal gender influences DNA methylation at autosomal loci but could find no clear association between DNA methylation and gestational age. Conclusion: Preeclampsia is associated with altered placental DNA methylation. Fetal gender should be carefully considered during the design of future studies in which placental DNA is analyzed at the level of DNA methylation. Further large-scale analyses of preeclampsia-associated DNA methylation are necessary. Bisulphite converted DNA from the 48 samples were hybridized to the Illumina Infinium 27k Human Methylation Beadchip v1.2
2014-07-12 | E-GEOD-59274 | biostudies-arrayexpress
Project description:Early onset preeclampsia (EOPE) affects about 0.4% of pregnancies and is characterized by impaired trophoblast (TB) invasion, resulting in a poorly perfused placenta. Here we have used an in vitro model for mimicking early trophoblast development to determine how early placental development differs between normal pregnancies and those affected by EOPE. Induced pluripotent stem cells (iPSC) were generated from umbilical cords of infants born to mothers who had EOPE and from controls. These iPSC were converted to TB, by exposing them to BMP4 and inhibitors of ACTIVIN A and FGF2 signaling (BAP treatment), under 5 % and 20 % O2, hypothesizing that 20% O2 would act as a stressor. Two embryonic stem cell lines (ESC; H1 and H9), 8 control (CTL) iPSC and 14 EOPE iPSC were tested to assess how well the differentiated TB cells invaded through a Matrigel-coated membrane.
2018-12-31 | GSE119265 | GEO
Project description:Genome wide DNA methylation profiling of normal and preeclampsia placental samples. Illumina Infinium HumanMethylation450 BeadChip (450K array) was used to obtain DNA methylation profiles in placental samples. Samples included 16 samples from healthy uncomplicated pregnancies and 8 samples from pregnancies affected by preeclampsia.
2016-04-12 | GSE75196 | GEO
Project description:Background: A small number of recent reports have suggested that altered placental DNA methylation may be associated with early onset preeclampsia. It is important that further studies be undertaken to confirm and develop these findings. We therefore undertook a systematic analysis of DNA methylation patterns in placental tissue from 24 women with preeclampsia and 24 with uncomplicated pregnancy outcome. Methods: We analyzed the DNA methylation status of approximately 27,000 CpG sites in placental tissues in a massively parallel fashion using an oligonucleotide microarray. Follow up analysis of DNA methylation at specific CpG loci was performed using the Epityper MassArray approach and high-throughput bisulfite sequencing. Results: Preeclampsia-specific DNA methylation changes were identified in placental tissue samples irrespective of gestational age of delivery. In addition, we identified a group of CpG sites within specific gene sequences that were only altered in early onset-preeclampsia (EOPET) although these DNA methylation changes did not correlate with altered mRNA transcription. We found evidence that fetal gender influences DNA methylation at autosomal loci but could find no clear association between DNA methylation and gestational age. Conclusion: Preeclampsia is associated with altered placental DNA methylation. Fetal gender should be carefully considered during the design of future studies in which placental DNA is analyzed at the level of DNA methylation. Further large-scale analyses of preeclampsia-associated DNA methylation are necessary.
2014-07-12 | GSE59274 | GEO
Project description:Dysregulated RNA editing is well documented in several diseases such as cancer. The extent to which RNA editing might be involved in diseases originated in the placenta such as preeclampsia remains unknown, because RNA editing has rarely been studied in the placenta. Here, the RNA editome is systematically profiled on placentae from 9 patients with early-onset severe preeclampsia (EOSPE) and 32 normal controls, and a widespread RNA editing dysregulation in EOSPE has been identified. The mis-edited gene set is enriched with known preeclampsia-associated genes and differentially expressed genes in EOSPE. The “RNA editing events” at two microRNA binding sites in 3’-UTR of the LEP mRNA have been generated, which leads to increased expression level of LEP in trophoblast cells. Upregulation of LEP is also observed in the placentae of PE patients. These results suggest that widespread placental RNA editing may be involved in placental development and dysregulation of RNA editing in the placenta may contribute to the pathogenesis of preeclampsia.
2020-04-20 | GSE148241 | GEO
Project description:Preeclampsia is one of the leading causes of maternal death worldwide. While the root cause is still unknown, the underlying biology of the disorder is becoming more clear. We recently published a study showing large, significant differences in DNA methylation in 3rd trimester placental samples associated with early-onset preeclampsia (EOPET) compared to controls. In this study, to identify DNA methylation differences associated with preeclampsia that occur early in pregnancy and to further delineate common EOPET-associated differences, we utilized a genetic defect, trisomy 16 (T16), that is predisposing to preeclampsia. We ran T16 placental samples from the 1st trimester (n=5) and 3rd trimester (n=10) against gestational age matched controls on the Illumina Infinium HumanMethylation450 BeadChip. Third trimester samples were from pregnancies with T16 confined to the placenta (confined placental mosaicism 16;CPM16), and consisted of samples that were and were not associated with EOPET (n=5 each). We identified a large number of DNA methylation differences in CPM16 samples compared to controls using stringent criteria (n=2254;False Discovery Rate <0.01, ->0.15). Several of these differences (11%) overlapped differences observed in chromosomally normal EOPET using similarly stringent criteria (FDR<0.01;->0.125). Isolating EOPET-associated probes produced a similar - distribution amongst CPM16 samples, although samples associated with EOPET showed a tendency towards larger DNA methylation differences. We also identified 262 DNA methylation differences between 1st trimester T16 and 1st trimester controls. Of these, 77 overlapped differences seen in 3rd trimester CPM16. Investigating these 77 T16/CPM16 specific DNA methylation differences, we identified three probes near two genes (ARGHEF37 and JUNB) that were also present as EOPET-associated methylation differences. In summary, we identified significant overlapping DNA methylation profiles of placentas with T16 and chromosomally normal placentas associated with EOPET. Specific DNA methylation marks within these profiles may be of future clinical utility in early identification of pregnancies susceptible to EOPET. Bisulfite converted DNA from 5 1st trimester trisomy 16 placentas, 5 chromosomally normal 1st trimester placentas, 10 third trimester placentas from confined placental mosaicism placentas and 10 chromosomally normal 3rd trimester placentas
2014-01-15 | E-GEOD-49343 | biostudies-arrayexpress
Project description:Early onset preeclampsia (EOPE) in a model for early stage human placental trophoblast
| PRJNA488631 | ENA