Spontaneous preterm birth: the underpinnings in the maternal and fetal genomes.
Ontology highlight
ABSTRACT:
SUBMITTER: Bhattacharjee E
PROVIDER: S-EPMC8187433 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal and fetal genetic factors likely contribute to SPTB. We performed a genome-wide association study (GWAS) on a population of Finnish origin that included 247 infants with SPTB (gestational age [GA] < 36 weeks) and 419 term controls (GA 38-41 weeks). The strongest signal came within the gene encoding slit guidance ligand 2 (SLIT2; rs116461311, minor allele frequency 0.05, p = 1.6×10-6). Pathway analysis revealed the top-ranking pathway was axon guidance, which includes SLIT2. In 172 very preterm-born infants (GA <32 weeks), rs116461311 was clearly overrepresented (odds ratio 4.06, p = 1.55×10-7). SLIT2 variants were associated with SPTB in another European population that comprised 260 very preterm infants and 9,630 controls. To gain functional insight, we used immunohistochemistry to visualize SLIT2 and its receptor ROBO1 in placentas from spontaneous preterm and term births. Both SLIT2 and ROBO1 were located in villous and decidual trophoblasts of embryonic origin. Based on qRT-PCR, the mRNA levels of SLIT2 and ROBO1 were higher in the basal plate of SPTB placentas compared to those from term or elective preterm deliveries. In addition, in spontaneous term and preterm births, placental SLIT2 expression was correlated with variations in fetal growth. Knockdown of ROBO1 in trophoblast-derived HTR8/SVneo cells by siRNA indicated that it regulate expression of several pregnancy-specific beta-1-glycoprotein (PSG) genes and genes involved in inflammation. Our results show that the fetal SLIT2 variant and both SLIT2 and ROBO1 expression in placenta and trophoblast cells may be correlated with susceptibility to SPTB. SLIT2-ROBO1 signaling was linked with regulation of genes involved in inflammation, PSG genes, decidualization and fetal growth. We propose that this receptor-ligand couple is a component of the signaling network that promotes SPTB.
| S-EPMC6563950 | biostudies-literature
Project description:BackgroundAltered neurodevelopment is a major clinical sequela of Preterm Birth (PTB) being currently unexplored in-utero.AimsTo study the link between fetal brain functional (FbF) connectivity and preterm birth, using resting-state functional magnetic resonance imaging (rs-fMRI).Study designProspective single-centre cohort study.SubjectsA sample of 31 singleton pregnancies at 28-34 weeks assigned to a low PTB risk (LR) (n = 19) or high PTB risk (HR) (n = 12) group based on a) the Maternal Frailty Inventory (MaFra) for PTB risk; b) a case-specific PTB risk gradient.MethodsFetal brain rs-fMRI was performed on 1.5T MRI scanner. First, directed causal relations representing fetal brain functional connectivity measurements were estimated using the Greedy Equivalence Search (GES) algorithm. HR vs. LR group differences were then tested with a novel ad-hoc developed Monte Carlo permutation test. Second, a MaFra-only random forest (RF) was compared against a MaFra-Neuro RF, trained by including also the most important fetal brain functional connections. Third, correlation and regression analyses were performed between MaFra-Neuro class probabilities and i) the GA at birth; ii) PTB risk gradient, iii) perinatal clinical conditions and iv) PTB below 37 weeks.ResultsFirst, fewer fetal brain functional connections were evident in the HR group. Second, the MaFra-Neuro RF improved PTB risk prediction. Third, MaFra-Neuro class probabilities showed a significant association with: i) GA at birth; ii) PTB risk gradient, iii) perinatal clinical conditions and iv) PTB below 37 weeks.ConclusionFetal brain functional connectivity is a novel promising predictor of PTB, linked to maternal risk profiles, ahead of birth, and clinical markers of neurodevelopmental risk, at birth, thus potentially "connecting" different PTB phenotypes.
| S-EPMC11002256 | biostudies-literature
Project description:Transcriptome analysis of preterm and term placentas
2021-08-10 | GSE120480 | GEO
Project description:Placental insufficiency is implicated in spontaneous preterm birth (SPTB). We performed RNA-seq study in male and female placentas from women (African American, self-identified) with SPTB (< 36 weeks gestation) compared to normal pregnancies (≥ 38 weeks gestation) to assess the alterations in gene expression profiles.
2021-08-18 | GSE174415 | GEO
Project description:Spontaneous preterm birth (PTB, <37 weeks gestation) is a major public health concern, and children born preterm have a higher risk of morbidity and mortality throughout their lives. Recent studies suggest that fetal DNA methylation of several genes varies across a range of gestational ages (GA), but it is not yet clear if fetal epigenetic changes associate with PTB. The objective of this study is to interrogate methylation patterns across the genome in fetal leukocyte DNA from African Americans with early PTB (24(1/7)-34(0/7) weeks; N?=?22) or term births (39(0/7)-40(6/7)weeks; N?=?28) and to evaluate the association of each CpG site with PTB and GA. DNA methylation was assessed across the genome with the HumanMethylation450 BeadChip. For each individual sample and CpG site, the proportion of DNA methylation was estimated. The associations between methylation and PTB or GA were evaluated by fitting a separate linear model for each CpG site, adjusting for relevant covariates. Overall, 29 CpG sites associated with PTB (FDR<.05; 5.7×10(-10)<p<2.9×10(-6)) independent of GA. Also, 9637 sites associated with GA (FDR<.05; 9.5×10(-16)<p<1.0×10(-3)), with 61.8% decreasing in methylation with shorter GA. GA-associated CpG sites were depleted in the CpG islands of their respective genes (p<2.2×10(-16)). Gene set enrichment analysis (GSEA) supported enrichment of GA-associated CpG sites in genes that play a role in embryonic development as well as the extracellular matrix. Additionally, this study replicated the association of several CpG sites associated with gestational age in other studies (CRHBP, PIK3CD and AVP). Dramatic differences in fetal DNA methylation are evident in fetuses born preterm versus at term, and the patterns established at birth may provide insight into the long-term consequences associated with PTB.
| S-EPMC3694903 | biostudies-literature
Project description:BACKGROUND:The insulin-like growth factor (IGF) pathway was involved in the occurrence of spontaneous preterm birth (SPTB), but little is known regarding the relationship between genetic variations in IGF pathway and the risk of SPTB. We aimed to investigate the associations of IGF1 rs972936 and IGF1 receptor (IGF1R) rs2229765 polymorphisms with SPTB risk in a Chinese population. METHOD:A total of 114 cases of SPTB and 250 controls of term delivery were included from Guangzhou Women and Children's Medical Center, China. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated using multivariate logistic regression. RESULTS:We found that the GA and GA/AA genotypes of IGF1 rs972936 were associated with an increased risk of SPTB, and the adjusted ORs (95% CI) were 1.74 (1.01-3.02) and 1.75 (1.04-2.93) respectively. Women carrying GA and GA/AA genotypes of IGF1R rs2229765 had a reduced risk compared to those with the GG genotype (0.60 [0.37-0.98] and 0.64 [0.40-1.00] respectively). There were significant interactions between IGF1 rs972936 and GDM status (P for interaction=.02), as well as between IGF1R rs2229765 and pre-pregnancy BMI (P for interaction <.001) on the risk of SPTB. CONCLUSION:Our findings suggest that polymorphisms of IGF1 rs972936 and IGF1R rs2229765 were associated with the risk of SPTB in Chinese pregnant women and these effects depend on the maternal metabolic status.
| S-EPMC6817009 | biostudies-literature
Project description:Preterm birth (PTB) is a major global public health concern. However, little is known about the pathophysiology of spontaneous idiopathic PTB. We tested the hypothesis that rare variants in families would target specific genes and pathways that contribute to PTB risk in the general population. Whole-exome sequencing was performed on 10 PTB mothers from densely affected families including two mother-daughter pairs. We identified novel variants shared between the two mother-daughter pairs when compared to a 1000 Genomes Project background exome file and investigated these genes for pathway aggregation using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Genes in enriched pathways were then surveyed in the other six PTB exomes and tested for association in a larger number of nuclear families. The KEGG complement and coagulation cascade was one of the most enriched pathways in our two mother-daughter pairs. When the six genes found in this pathway (CFH, CR1, F13B, F5, CR2, and C4BPA) were examined for novel missense variants, half of all the exomes harbored at least one. Association analysis of variants in these six gene regions in nuclear families from Finland (237 cases and 328 controls) found statistically significant associations after multiple test corrections in three CR1 SNPs; the strongest in an exonic missense SNP, rs6691117, p value = 6.91e-5, OR = 1.71. Our results demonstrate the importance of the complement and coagulation cascades in the pathophysiology of PTB, and suggest potential screening and intervention approaches to prevent prematurity that target this pathway.
| S-EPMC3868364 | biostudies-literature
Project description:BACKGROUND: Spontaneous preterm birth (SPB, before 37 gestational weeks) is a major cause of perinatal mortality and morbidity, but its pathogenesis remains unclear. Studies on SPB have been hampered by the limited availability of markers for SPB in predelivery clinical samples that can be easily compared with gestational age-matched normal controls. We hypothesize that SPB involves aberrant placental RNA expression, and that such RNA transcripts can be detected in predelivery maternal plasma samples, which can be compared with gestational age-matched controls. PRINCIPAL FINDINGS: Using gene expression microarray to profile essentially all human genes, we observed that 426 probe signals were changed by >2.9-fold in the SPB placentas, compared with the spontaneous term birth (STB) placentas. Among the genes represented by those probes, we observed an over-representation of functions in RNA stabilization, extracellular matrix binding, and acute inflammatory response. Using RT-quantitative PCR, we observed differences in the RNA concentrations of certain genes only between the SPB and STB placentas, but not between the STB and term elective cesarean delivery placentas. Notably, 36 RNA transcripts were observed at placental microarray signals higher than a threshold, which indicated the possibility of their detection in maternal plasma. Among them, the IL1RL1 mRNA was tested in plasma samples taken from 37 women. It was detected in 6 of 10 (60%) plasma samples collected during the presentation of preterm labor (?32.9 weeks) in women eventually giving SPB, but was detected in only 1 of 27 (4%) samples collected during matched gestational weeks from women with no preterm labor (Fisher exact test, p?=?0.00056). CONCLUSION: We have identified 36 SPB-associated RNA transcripts, which are possibly detectable in maternal plasma. We have illustrated that the IL1RL1 mRNA was more frequently detected in predelivery maternal plasma samples collected from women resulting in SPB than the gestational-age matched controls.
| S-EPMC3320630 | biostudies-literature
Project description:Spontaneous preterm birth (sPTB) is a major pregnancy complication involving biological, social, behavioural and environmental mechanisms. Workload, shift and intensity may play a role in the occurrence of sPTB. This analysis is aimed addressing the effect of occupational activities on the risk for sPTB and the related outcomes. We conducted a secondary analysis of the EMIP study, a Brazilian multicentre cross-sectional study. For this analysis, we included 1,280 singleton sPTB and 1,136 singleton term birth cases. Independent variables included sociodemographic characteristics, clinical complications, work characteristics, and physical effort devoted to household chores. A backward multiple logistic regression analysis was applied for a model using work characteristics, controlled by cluster sampling design. On bivariate analysis, discontinuing work during pregnancy and working until the 7th month of pregnancy were risks for premature birth while working during the 8th - 9th month of pregnancy, prolonged standing during work and doing household chores appeared to be protective against sPTB during pregnancy. Previous preterm birth, polyhydramnios, vaginal bleeding, stopping work during pregnancy, or working until the 7th month of pregnancy were risk factors in the multivariate analysis. The protective effect of variables compatible with exertion during paid work may represent a reverse causality. Nevertheless, a reduced risk associated with household duties, and working until the 8th-9th month of pregnancy support the hypothesis that some sort of physical exertion may provide actual protection against sPTB.
| S-EPMC7297738 | biostudies-literature
Project description:Spontaneous Preterm Delivery (sPTD) is one of the leading causes of perinatal mortality and morbidity worldwide. The present case−control study aims to detect miRNAs differentially expressed in the first trimester maternal plasma with the view to identify predictive biomarkers for sPTD, between 320/7 and 366/7 weeks, that will allow for timely interventions for this serious pregnancy complication. Small RNA sequencing (small RNA-seq) of five samples from women with a subsequent sPTD and their matched controls revealed significant down-regulation of miR-23b-5p and miR-125a-3p in sPTD cases compared to controls, whereas miR-4732-5p was significantly overexpressed. Results were confirmed by qRT-PCR in an independent cohort of 29 sPTD cases and 29 controls. Statistical analysis demonstrated that miR-125a is a promising early predictor for sPTL (AUC: 0.895; 95% CI: 0.814-0.972; p < 0.001), independent of the confounding factors tested, providing a useful basis for the development of a novel non-invasive predictive test to assist clinicians in estimating patient-specific risk.
| S-EPMC9735892 | biostudies-literature