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Human placental-specific epipolymorphism and its association with adverse pregnancy outcomes.

ABSTRACT: Interindividual variation in DNA-methylation level is widespread in the human genome, despite its critical role in regulating gene expression. The nature of this variation, including its tissue-specific nature, and the role it may play in human phenotypic variation and disease is still poorly characterized. The placenta plays a critical role in regulating fetal growth and development in ways that have lifelong effects on health. To identify genes with a high degree of interindividual DNA methylation variation in the human placenta, we surveyed the human genome using the Illumina GoldenGate Methylation Cancer panel targeting 1505 CpG sites of 807 genes. While many sites show a continuous pattern of methylation levels, WNT2, TUSC3 and EPHB4 were identified to have a polymorphic "on-or-off" pattern of DNA methylation variation at their promoter region which was confirmed by pyrosequencing. Methylation of these genes can be found in 7%-25% of over 100 placentas tested. The methylation state at the promoter of these genes is concordant with mRNA allelic expression. In three informative cases TUSC3 was observed to be methylated on the maternal allele, and it is thus possible this represents a polymorphically imprinted gene. Furthermore, TUSC3 promoter methylation showed evidence for association with preeclampsia. A biological significance of these methylation allelic polymorphisms (MAPs) to human placental diversity is further implied by their placental specificity and absence in mouse. An extended study of blood suggests that MAPs may also be found in other tissues, implicating their utility for tissue-specific association with complex disorders. The identification of such "epipolymorphism" in other tissues and their use in association studies, should improve our understanding of interindividual phenotypic variability and complex disease susceptibility.

SUBMITTER: Yuen RK

PROVIDER: S-EPMC2760756 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Human placental-specific epipolymorphism and its association with adverse pregnancy outcomes.

Yuen Ryan K C RK Avila Luana L Peñaherrera Maria S MS von Dadelszen Peter P Lefebvre Louis L Kobor Michael S MS Robinson Wendy P WP

PloS one 20091019 10

Interindividual variation in DNA-methylation level is widespread in the human genome, despite its critical role in regulating gene expression. The nature of this variation, including its tissue-specific nature, and the role it may play in human phenotypic variation and disease is still poorly characterized. The placenta plays a critical role in regulating fetal growth and development in ways that have lifelong effects on health. To identify genes with a high degree of interindividual DNA methyla ...[more]

PMID: 19838307

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Project description:ObjectiveTo evaluate the relationship between acculturation and adverse pregnancy outcomes, and whether these relationships differ across racial or ethnic groups.MethodsThis is a planned secondary analysis of the nuMoM2b study (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be), a prospective observational cohort study of 10,038 pregnant women at eight academic health care centers in the United States. Nulliparous pregnant women with singleton gestations were recruited between 6 0/7 and 13 6/7 weeks of gestation from October 2010-September 2013. Acculturation was defined by birthplace (United States vs non-United States), language used during study visits (English or Spanish), and self-rated English proficiency. The adverse pregnancy outcomes of interest were preterm birth (less than 37 weeks of gestation, both iatrogenic and spontaneous), preeclampsia or eclampsia, gestational hypertension, gestational diabetes, stillbirth, small for gestational age, and large for gestational age. Multivariable regression modeling was performed, as was an interaction analysis focusing on the relationship between acculturation and adverse pregnancy outcomes by maternal race or ethnicity.ResultsOf the 10,006 women eligible for this analysis, 8,100 (80.9%) were classified as more acculturated (eg, born in the United States with high English proficiency), and 1,906 (19.1%) were classified as having less acculturation (eg, born or not born in the United States with low proficiency in English or use of Spanish as the preferred language during study visits). In multivariable logistic regression modeling, more acculturation was significantly associated with higher frequency of preterm birth (odds ratio [OR] 1.46, adjusted odds ratio [aOR] 1.50, 95% CI 1.16-1.95); spontaneous preterm birth (OR 1.54, aOR 1.62, 95% CI 1.14-2.24); preeclampsia or eclampsia (OR 1.39, aOR 1.31, 95% CI 1.03-1.67); preeclampsia without severe features (OR 1.44, aOR 1.43, 95% CI 1.03-2.01); and gestational hypertension (OR 1.68, aOR 1.48, 95% CI 1.22-1.79). These associations did not differ by self-described race or ethnicity.ConclusionIn a large cohort of nulliparous women, more acculturation, regardless of self-described race or ethnicity, was associated with increased odds of several adverse pregnancy outcomes.Clinical trial registrationClinicalTrials.gov, NCT01322529.

Project description:BACKGROUND:Abnormal placental cord insertion (PCI) includes marginal cord insertion (MCI) and velamentous cord insertion (VCI). VCI has been shown to be associated with adverse pregnancy outcomes. This systematic review and meta-analysis aims to determine the association of abnormal PCI and adverse pregnancy outcomes. METHODS:Embase, Medline, CINAHL, Scopus, Web of Science, ClinicalTrials.gov, and Cochrane Databases were searched in December 2016 (from inception to December 2016). The reference lists of eligible studies were scrutinized to identify further studies. Potentially eligible studies were reviewed by two authors independently using the following inclusion criteria: singleton pregnancies, velamentous cord insertion, marginal cord insertion, and pregnancy outcomes. Case reports and series were excluded. The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. Outcomes for meta-analysis were dichotomous and results are presented as summary risk ratios with 95% confidence intervals. RESULTS:Seventeen studies were included in the systematic review, all of which were assessed as good quality. Normal PCI and MCI were grouped together as non-VCI and compared with VCI in seven studies. Four studies compared MCI, VCI, and normal PCI separately. Two other studies compared MCI with normal PCI, and VCI was excluded from their analysis. Studies in this systematic review reported an association between abnormal PCI, defined differently across studies, with preterm birth, small for gestational age (SGA), low birthweight (<?2500 g), emergency cesarean delivery, and intrauterine fetal death. Four cohort studies comparing MCI, VCI, and normal PCI separately were included in a meta-analysis resulting in a statistically significant increased risk of emergency cesarean delivery for VCI (pooled RR 2.86, 95% CI 1.56-5.22, P =?0.0006) and abnormal PCI (pooled RR 1.77, 95% CI 1.33-2.36, P <?0.0001) compared to normal PCI. CONCLUSIONS:The available evidence suggests an association between abnormal PCI and emergency cesarean delivery. However, the number of studies with comparable definitions of abnormal PCI was small, limiting the analysis of other adverse pregnancy outcomes, and further research is required.

Project description:ObjectiveCurrently, no investigations reliably identify placental dysfunction in late pregnancy. To facilitate the development of such investigations we aimed to identify placental features that differ between normal and adverse outcome in late pregnancy in a group of pregnancies with reduced fetal movement.MethodsFollowing third trimester presentation with reduced fetal movement (N = 100), placental structure ex vivo was measured. Placental function was then assessed in terms of (i) chorionic plate artery agonist responses and length-tension characteristics using wire myography and (ii) production and release of placentally derived hormones (by quantitative polymerase chain reaction and enzyme linked immunosorbant assay of villous tissue and explant conditioned culture medium).ResultsPlacentas from pregnancies ending in adverse outcome (N = 23) were ~25% smaller in weight, volume, length, width and disc area (all p<0.0001) compared with those from normal outcome pregnancies. Villous and trophoblast areas were unchanged, but villous vascularity was reduced (median (interquartile range): adverse outcome 10 (10-12) vessels/mm2 vs. normal outcome 13 (12-15), p = 0.002). Adverse outcome pregnancy placental arteries were relatively insensitive to nitric oxide donated by sodium nitroprusside compared to normal outcome pregnancy placental arteries (50% Effective Concentration 30 (19-50) nM vs. 12 (6-24), p = 0.02). Adverse outcome pregnancy placental tissue contained less human chorionic gonadotrophin (20 (11-50) vs. 55 (24-102) mIU/mg, p = 0.007) and human placental lactogen (11 (6-14) vs. 27 (9-50) mg/mg, p = 0.006) and released more soluble fms-like tyrosine kinase-1 (21 (13-29) vs. 5 (2-15) ng/mg, p = 0.01) compared with normal outcome pregnancy placental tissue.ConclusionThese data provide a description of the placental phenotype of adverse outcome in late pregnancy. Antenatal tests that accurately reflect elements of this phenotype may improve its prediction.

Project description:BACKGROUND:Malaria in pregnancy has been associated with maternal morbidity, placental malaria, and adverse birth outcomes. However, data are limited on the relationships between longitudinal measures of malaria during pregnancy, measures of placental malaria, and birth outcomes. METHODS:This is a nested observational study of data from a randomized controlled trial of intermittent preventive therapy during pregnancy among 282 participants with assessment of placental malaria and delivery outcomes. HIV-uninfected pregnant women were enrolled at 12-20 weeks of gestation. Symptomatic malaria during pregnancy was measured using passive surveillance and monthly detection of asymptomatic parasitaemia using loop-mediated isothermal amplification (LAMP). Placental malaria was defined as either the presence of parasites in placental blood by microscopy, detection of parasites in placental blood by LAMP, or histopathologic evidence of parasites or pigment. Adverse birth outcomes assessed included low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) infants. RESULTS:The 282 women were divided into three groups representing increasing malaria burden during pregnancy. Fifty-two (18.4%) had no episodes of symptomatic malaria or asymptomatic parasitaemia during the pregnancy, 157 (55.7%) had low malaria burden (0-1 episodes of symptomatic malaria and < 50% of samples LAMP+), and 73 (25.9%) had high malaria burden during pregnancy (? 2 episodes of symptomatic malaria or ? 50% of samples LAMP+). Women with high malaria burden had increased risks of placental malaria by blood microscopy and LAMP [aRR 14.2 (1.80-111.6) and 4.06 (1.73-9.51), respectively], compared to the other two groups combined. Compared with women with no malaria exposure during pregnancy, the risk of placental malaria by histopathology was higher among low and high burden groups [aRR = 3.27 (1.32-8.12) and aRR = 7.07 (2.84-17.6), respectively]. Detection of placental parasites by any method was significantly associated with PTB [aRR 5.64 (1.46-21.8)], and with a trend towards increased risk for LBW and SGA irrespective of the level of malaria burden during pregnancy. CONCLUSION:Higher malaria burden during pregnancy was associated with placental malaria and together with the detection of parasites in the placenta were associated with increased risk for adverse birth outcomes. Trial Registration Current Controlled Trials Identifier NCT02163447.

Dataset Information

Human placental-specific epipolymorphism and its association with adverse pregnancy outcomes.

Publications

Human placental-specific epipolymorphism and its association with adverse pregnancy outcomes.

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