Validation of low-coverage whole-genome sequencing for mitochondrial DNA variants suggests mitochondrial DNA as a genetic cause of preterm birth.
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ABSTRACT:
SUBMITTER: Yang Z
PROVIDER: S-EPMC9290920 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The aim of this study was to identify genetic variants contributing to preterm birth (PTB) using a linkage candidate gene approach.We studied 99 single-nucleotide polymorphisms (SNPs) for 33 genes in 257 families with PTBs segregating. Nonparametric and parametric analyses were used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses.Analyses with the infant as the case identified two genes with evidence of linkage: CRHR1 (P = 0.0012) and CYP2E1 (P = 0.0011). Analyses with the mother as the case identified four genes with evidence of linkage: ENPP1 (P = 0.003), IGFBP3 (P = 0.006), DHCR7 (P = 0.009), and TRAF2 (P = 0.01). DNA sequence analysis of the coding exons and splice sites for CRHR1 and TRAF2 identified no new likely etiologic variants.These findings suggest the involvement of six genes acting through the infant and/or the mother in the etiology of PTB.
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Project description:Threatened preterm labour (TPTL) is the most common condition that requires hospitalisation during pregnancy. Most of these symptomatic women continue their pregnancies to term while only an estimated 5% will deliver a premature baby within ten days. Peripheral blood leukocytes are exposed to “activating signals” from reproductive tissues and may indicate the impending onset of labour. Objectives: 1) To investigate differential leukocyte gene expression in women with TPTL; and 2) to develop a gene signature to predict preterm birth (PTB) within 48 hours in symptomatic women. Design, Setting and Participants: Women clinically diagnosed with TPTL were recruited. Peripheral blood was obtained at point of admission prior to medical treatments. mRNA was extracted and microarrays (Affymetrix U133 Plus 2.0) were utilised to determine differential gene expressions between women who did (n=48) and did not (n=106) have a preterm delivery within 48 hours of hospital admission. Results: There were 394 significantly differentially expressed genes (FDR<0.05, Limma); 22 out of 30 genes chosen for qRT-PCR validation were differentially expressed (p<0.05). Total 154; 48 delivered within 48 hours of hospital admission; 106 did not deliver within 48 hours
2014-05-15 | E-GEOD-46510 | biostudies-arrayexpress
Project description:Endocrine factors and signals of fetal organ maturation are reported determinants of birth timing. To test the hypothesis that paracrine signaling by exosomes are key regulators of parturition, maternal plasma exosomes from CD-1 mice were isolated and characterized throughout gestation and the biological pathways associated with differentially-expressed cargo proteins were determined. Results indicate that the shape and size of exosomes remained constant throughout gestation; however, a progressive increase in the quantity of exosomes carrying inflammatory mediators was observed from gestation day (E)5 to E19. In addition, the effects of late-gestation (E18) plasma exosomes derived from feto-maternal uterine tissues on parturition was determined. Intraperitoneal injection of E18 exosomes into E15 mice localized in maternal reproductive tract tissues and in intrauterine fetal compartments. Compared to controls that delivered at term, preterm birth occurred in exosome-treated mice on E18 and was preceded by increased inflammatory mediators on E17 in the cervix, uterus, and fetal membranes but not in the placenta. This effect was not observed in mice injected with early-gestation (E9) exosomes. This study provides evidence that exosomes function as paracrine mediators of labor and delivery.
| S-EPMC6345869 | biostudies-other
Project description:Threatened preterm labor (TPTL) is defined as persistent premature uterine contractions between 20 and 37 weeks of gestation and is the most common condition that requires hospitalization during pregnancy. Most of these TPTL women continue their pregnancies to term while only an estimated 5% will deliver a premature baby within ten days. The aim of this work was to study differential whole blood gene expression associated with spontaneous preterm birth (sPTB) within 48 hours of hospital admission. Peripheral blood was collected at point of hospital admission from 154 women with TPTL before any medical treatment. Microarrays were utilized to investigate differential whole blood gene expression between TPTL women who did (n = 48) or did not have a sPTB (n = 106) within 48 hours of admission. Total leukocyte and neutrophil counts were significantly higher (35% and 41% respectively) in women who had sPTB than women who did not deliver within 48 hours (p<0.001). Fetal fibronectin (fFN) test was performed on 62 women. There was no difference in the urine, vaginal and placental microbiology and histopathology reports between the two groups of women. There were 469 significant differentially expressed genes (FDR<0.05); 28 differentially expressed genes were chosen for microarray validation using qRT-PCR and 20 out of 28 genes were successfully validated (p<0.05). An optimal random forest classifier model to predict sPTB was achieved using the top nine differentially expressed genes coupled with peripheral clinical blood data (sensitivity 70.8%, specificity 75.5%). These differentially expressed genes may further elucidate the underlying mechanisms of sPTB and pave the way for future systems biology studies to predict sPTB.
2014-05-15 | GSE46510 | GEO
Project description:Maternal whole blood colected longitudinally were profiled using Affymetrix Human Transcriptome Arrays to evaluate prediction of gestational age in normal and complicated pregnancies and predict preterm birth. LMP is the date at the last menstrual period. Oper_LMP is the date at the last menstrual period with eventual adjustment based on ultrasound determination. Gestational age (GA) (weeks) is defined as (Date at sample - Oper_LMP)/7. For control pregnancies, SubGroup defines those with spontaneous labor at term (TL) as opposed with those delivered by cesarean section (TNL). Train is 1 if the sample was used in sub-challenge 1 in the training set as opposed to test set (0). D2 is 1 if the sample was used in the 2 interval prediction scenario, and if yes, it was assigned to the interval given by column D2Interval. D3 is 1 if the sample was used in the 3 interval prediction scenario, and if yes, it was assigned to the interval given by column D3Interval. DiagnosisGA is the gestational age at diagnosis with any disease indicated by the Group variable, and it is set to NA for normal pregnancies.
2021-05-24 | GSE149437 | GEO
Project description:BackgroundDespite decades of attempts to link infectious agents to preterm birth, an exact causative microbe or community of microbes remains elusive. Culture-independent sequencing of vaginal bacterial communities demonstrates community characteristics are associated with preterm birth, although none are specific enough to apply clinically. Viruses are important components of the vaginal microbiome and have dynamic relationships with vaginal bacterial communities. We hypothesized that vaginal eukaryotic DNA viral communities (the "vaginal virome") either alone or in the context of bacterial communities are associated with preterm birth.ObjectiveThe objective of this study was to use high-throughput sequencing to examine the vaginal eukaryotic DNA virome in a cohort of pregnant women and examine associations between vaginal community characteristics and preterm birth.Study designThis is a nested case-control study within a prospective cohort study of women with singleton pregnancies, not on supplemental progesterone, and without cervical cerclage in situ. Serial midvaginal swabs were obtained at routine prenatal visits. DNA was extracted, bacterial communities were characterized by 16S ribosomal RNA gene sequencing, and eukaryotic viral communities were characterized by enrichment of viral nucleic acid with the ViroCap targeted sequence capture panel followed by nucleic acid sequencing. Viral communities were analyzed according to presence/absence of viruses, diversity, dynamics over time, and association with bacterial community data obtained from the same specimens.ResultsSixty subjects contributed 128 vaginal swabs longitudinally across pregnancy. In all, 24 patients delivered preterm. Participants were predominantly African American (65%). Six families of eukaryotic DNA viruses were detected in the vaginal samples. At least 1 virus was detected in 80% of women. No specific virus or group of viruses was associated with preterm delivery. Higher viral richness was significantly associated with preterm delivery in the full group and in the African American subgroup (P = .0005 and P = .0003, respectively). Having both high bacterial diversity and high viral diversity in the first trimester was associated with the highest risk for preterm birth.ConclusionHigher vaginal viral diversity is associated with preterm birth. Changes in vaginal virome diversity appear similar to changes in the vaginal bacterial microbiome over pregnancy, suggesting that underlying physiology of pregnancy may regulate both bacterial and viral communities.
| S-EPMC6066425 | biostudies-literature
Project description:Mitochondria are small double-membraned organelles responsible for the generation of energy used in the body in the form of ATP. Mitochondria are unique in that they contain their own circular mitochondrial genome termed mtDNA. mtDNA codes for 37 genes, and together with the nuclear genome (nDNA), dictate mitochondrial structure and function. Not surprisingly, pathogenic variants in the mtDNA or nDNA can result in mitochondrial disease. Mitochondrial disease primarily impacts tissues with high energy demands, including the heart. Mitochondrial cardiomyopathy is characterized by the abnormal structure or function of the myocardium secondary to genetic defects in either the nDNA or mtDNA. Mitochondrial cardiomyopathy can be isolated or part of a syndromic mitochondrial disease. Common manifestations of mitochondrial cardiomyopathy are a phenocopy of hypertrophic cardiomyopathy, dilated cardiomyopathy, and cardiac conduction defects. The underlying pathophysiology of mitochondrial cardiomyopathy is complex and likely involves multiple abnormal processes in the cell, stemming from deficient oxidative phosphorylation and ATP depletion. Possible pathophysiology includes the activation of alternative metabolic pathways, the accumulation of reactive oxygen species, dysfunctional mitochondrial dynamics, abnormal calcium homeostasis, and mitochondrial iron overload. Here, we highlight the clinical assessment of mtDNA-related mitochondrial cardiomyopathy and offer a novel hypothesis of a possible integrated, multivariable pathophysiology of disease.
| S-EPMC9496904 | biostudies-literature
Project description:Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) encompass a clinically and etiologically heterogenous group of mitochondrial disorders caused by impaired mtDNA maintenance. Among the most frequent causes of MDDS are defects in nucleoside/nucleotide metabolism, which is critical for synthesis and homeostasis of the deoxynucleoside triphosphate (dNTP) substrates of mtDNA replication. A central enzyme for generating dNTPs is ribonucleotide reductase, a critical mediator of de novo nucleotide synthesis composed of catalytic RRM1 subunits in complex with RRM2 or p53R2. Here, we report 5 probands from 4 families who presented with ptosis and ophthalmoplegia as well as other clinical manifestations and multiple mtDNA deletions in muscle. We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381, which has evolutionarily conserved interactions with the specificity site. Atomistic molecular dynamics simulations indicate mechanisms by which RRM1 variants affect protein structure. Cultured primary skin fibroblasts of probands manifested mtDNA depletion under cycling conditions, indicating impaired de novo nucleotide synthesis. Fibroblasts also exhibited aberrant nucleoside diphosphate and dNTP pools and mtDNA ribonucleotide incorporation. Our data reveal that primary RRM1 deficiency and, by extension, impaired de novo nucleotide synthesis are causes of MDDS.
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Project description:Transcriptome analysis of preterm and term placentas
2021-08-10 | GSE120480 | GEO
Project description:BackgroundThe pathogenesis of late-onset sepsis (LOS) in preterm infants is poorly understood and knowledge about risk factors, especially prenatal risk factors, is limited. This study aimed to assess the association between the cause of preterm birth and LOS in very preterm infants.Methods2052 very preterm singletons from a national population-based cohort study alive at 72 h of life were included. Survival without LOS was compared by cause of preterm birth using survival analysis and Cox regression models.Results437 (20.1%) had at least one episode of LOS. The frequency of LOS varied by cause of preterm birth: 17.1% for infants born after preterm labor, 17.9% after preterm premature rupture of membranes, 20.3% after a placental abruption, 20.3% after isolated hypertensive disorders, 27.5% after hypertensive disorders with fetal growth restriction (FGR), and 29.4% after isolated FGR. In multivariate analysis, when compared to infants born after preterm labor, the risk remained higher for infants born after hypertensive disorders (hazard ratio HR = 1.7, 95% CI = 1.2-2.5), hypertensive disorders with FGR (HR = 2.6, 95% CI = 1.9-3.6) and isolated FGR (HR = 2.9, 95% CI = 1.9-4.4).ConclusionVery preterm infants born after hypertensive disorders or born after FGR had an increased risk of LOS compared to those born after preterm labor.ImpactLate-onset sepsis risk differs according to the cause of preterm birth. Compared with those born after preterm labor, infants born very preterm because of hypertensive disorders of pregnancy and/or fetal growth restriction display an increased risk for late-onset sepsis. Antenatal factors, in particular the full spectrum of causes leading to preterm birth, should be taken into consideration to better prevent and manage neonatal infectious morbidity and inform the parents.
| S-EPMC7903216 | biostudies-literature