Role of Fibronectin-1 polymorphism genes with the pathogenesis of intraventricular hemorrhage in preterm infants.
ABSTRACT: BACKGROUND/INTRODUCTION:Intraventricular hemorrhage (IVH) is a dangerous complication facing a significant proportion of preterm infants. It is multifactorial in nature, and an observed fibronectin deficiency in the germinal matrix basal lamina is among the most prominent factors that influence such rupture. Better understanding of the FN1 gene polymorphisms and their role in IVH may further clarify the presence of a genetic susceptibility of certain babies to this complication. The aim of this study was to assess if 5 single nucleotide polymorphisms of the fibronectin gene may be linked to an increased incidence of IVH. MATERIAL AND METHODS:The study included 108 infants born between 24 and 32 weeks of gestation. IVH was diagnosed using cranial ultrasound performed on the 1st,3rd, and 7th day after birth and classified according to Papile et al. IVH classification. The 5 FN1 gene polymorphisms assessed in the study were the following: rs3796123; rs1968510; rs10202709; rs6725958; and rs35343655. RESULTS:IVH developed in 51 (47.2%) out of the 108 preterm infants. This includes, 18 (35.3%) with stage I IVH, 19 (37.3%) with stage II, 11 (21.6%) with stage III, and 3 (5.9%) with stage IV IVH. Incidence of IVH was higher in infants with lower APGAR scores, low gestational age, and low birthweight. Analysis showed that IVH stage II to IV was approximately seven times more likely to occur in infants with the genotype TT FN1 rs10202709 (OR 7237 (1046-79.59; p =?0,044)). No other significant association was found with the rest of the polymorphisms. CONCLUSION:The results of our study indicate a sevenfold increased genetic susceptibility to IVH in preterm infants with the TT FN1 rs10202709 gene polymorphism. The fibronectin gene polymorphism may therefore be of crucial importance as a genetic risk factor for IVH in preterm infants. Further studies are warranted.
Project description:We aimed to identify specific polymorphisms of genes encoding for vascular endothelial growth factor A (VEGFA), endothelial nitric oxide synthase (eNOS), renin-angiotensin system (angiotensinogen gene [AGT], angiotensinogen type 1 receptor [AGTR1], angiotensin-converting enzyme [ACE]), and heme oxygenase-1 (HMOX-1) in a cohort of preterm infants and correlate their presence with the development of respiratory distress syndrome (RDS) requiring mechanical ventilation (MV), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) and retinopathy of prematurity (ROP).We carried out a retrospective study to evaluate the allele frequency and genotype distribution of polymorphisms of VEGFA, eNOS, AGT, AGTR1, ACE, and HMOX-1 in a population of preterm neonates (n=342) with a gestational age ?28 weeks according to the presence or absence of RDS requiring MV, BPD, IVH, or ROP. Moreover, we evaluated through the haplotype reconstruction analysis whether combinations of the selected polymorphisms are related to the occurrence of RDS, BPD, IVH and ROP.In our population 157 infants developed RDS requiring MV, 71 BPD, 70 IVH, and 43 ROP. We found that TC+CC rs2070744 eNOS (41.7 vs. 25.4%, p=0.01) and GT+TT rs1799983 eNOS (51.8 vs. 35.2%, p=0.01) polymorphisms are independent risk factors for BPD. Haplotype reconstruction showed that haplotypes in VEGF and eNOS are significantly associated with different effects on RDS, BPD, IVH, and ROP in our population.We found that TC+CC rs2070744 eNOS and GT+TT rs1799983 eNOS polymorphisms are independent predictors of an increased risk of developing BPD. Haplotypes of VEGFA and eNOS may be independent protective or risk markers for prematurity complications.
Project description:Intraventricular hemorrhage (IVH) is a significant morbidity seen in very low birth weight infants. Genes related to inflammation may be risk factors for IVH.We examined five polymorphisms for an association with IVH in 100 preterm infants born from singleton pregnancy, before 32 + 0 weeks of gestation, exposed to antenatal steroid therapy, and without congenital abnormalities. These polymorphisms include interleukin-1? 3953 C>T, interleukin-6 -174G>C and -596G>A, tumor necrosis factor -308 G>A, and 86 bp variable number tandem repeat polymorphism of interleukin-1 receptor antagonist (Il?-1RN? 86 bp VNTR).In our study population, 45 (45%) infants developed IVH, including 15 (33.33%) with stage 1, 19 (42.22%) with stage 2, 8 (17.77%) with stage 3, and 3 (6.66%) with stage 4. In contrast to the previously published data, the prevalence of IVH did not vary between infants with different IL-6 and TNF? alleles and genotypes. Our novel investigations in Il-1 +3953 C>T and Il-1RN 86 bp VNTR polymorphism did not show any significant link between those alleles or genotypes and IVH.IVH is a significant problem for preterm infants. In addition to little progress in preventing IVH in preterm babies, substantial research that are focused on understanding the etiology, mechanism and risk factors for IVH are imperative. In the era of personalized medicine, identification of genetic risk factors creates opportunities to generate preventative strategies. Further studies should be performed to confirm the role of genetic factors in etiology and pathogenesis of IVH.
Project description:Congenital thrombophilia is associated with an increased intraventricular hemorrhage (IVH) risk among newborns, but it may also play a protective role. The role of genetic polymorphisms involved in the coagulation pathway of IVH pathogenesis is probably a consequence of an increased risk of thrombosis in the fine blood vessels in the germinal matrix region.The aim of this study was to evaluate the possible relationship between Factor V (FV) 1691G>A, Factor II (FII) 20210G>A mutations and methylenetetrahydrofolate reductase (MTHFR) 677C>T; 1298A>C and Factor XIII (FXIII) 103G>T gene polymorphisms and the occurrence of IVH in 100 infants born from 24 + 0 to 32 + 0 weeks of gestation, born from singleton pregnancy, before 32 + 0 weeks of gestation, exposed to antenatal steroid therapy, and without congenital abnormalities.IVH developed 45 (45%) infants, including 15 (33.33%) diagnosed with IVH stage I, 20 (42.22%) with stage II, 8 (17.77%) with stage III, and 3 (6.66%) with stage IV. Analysis showed a prevalence 4.5 times higher of IVH stages II to IV in infants with the genotype CC (OR 4511 (1147-17.75); p = 0.026) of MTHFR 1298A>C gene polymorphism. Our investigation did not confirm any significant prevalence of IVH development in other studied mutations/polymorphisms.This study confirmed that the MTHFR 1298A>C polymorphism is associated with the risk of IVH. IVH is a significant problem for preterm infants. In addition to little progress in preventing IVH in preterm babies, substantial research that is focused on understanding the etiology, mechanism, and risk factors for IVH is imperative. In the era of personalized medicine, identification of genetic risk factors creates opportunities to generate preventative strategies.
Project description:<h4>Purpose</h4>Very preterm (VPT) infants are at high risk for motor and behavioral deficits. We investigated microstructural differences using diffusion tensor imaging (DTI) among VPT infants with different grades of intraventricular hemorrhage (IVH), their association with early motor function and temperament ratings, and the potential moderating effect of IVH severity on the above structure-function relations.<h4>Methods</h4>Fifty-seven VPT (≤32 weeks gestational age) infants with IVH (Low Grade (Papile grading I/II): 42; High Grade (III/IV): 15) were studied. DTI was acquired between 39 and 44 weeks postmenstrual age and was analyzed using the tract-based spatial statistics approach. Early motor function and temperament were assessed at 3-month corrected age based on the Hammersmith Infant Neurological Examination (HINE) and Infant Behavioral Questionnaire - Revised, Short Version (IBQ-R-S), respectively.<h4>Results</h4>Significantly lower fractional anisotropy and higher mean, axial, and/or radial diffusivity were found in VPT infants with High Grade IVH compared to Low Grade IVH (p < 0.05). Significant associations were found between DTI metrics and motor function in both IVH groups and between DTI and Fear temperament ratings in the High Grade IVH Group (all p < 0.05). IVH severity had a significant moderating effect on the relation between DTI and motor and Fear ratings (p < 0.05).<h4>Conclusion</h4>DTI is a sensitive neuroimaging biomarker providing a refined understanding of the impact and location of differing severities of IVH on the developing white matter of VPT infants. Early motor and behavioral outcomes are associated with microstructural changes that are influenced by severity of IVH.
Project description:<h4>Background</h4>Intraventricular hemorrhage (IVH) is a frequent complication in extreme and very preterm births. Despite a high risk of death and impaired neurodevelopment, the precise prognosis of infants with IVH remains unclear. The objective of this study was to evaluate the rate and predictive factors of evolution to post hemorrhagic hydrocephalus (PHH) requiring a shunt, in newborns with IVH and to report their neurodevelopmental outcomes at 2 years of age.<h4>Methods</h4>Among all preterm newborns admitted to the department of neonatalogy at Rouen University Hospital, France between January 2000 and December 2013, 122 had an IVH and were included in the study. Newborns with grade 1 IVH according to the Papile classification were excluded.<h4>Results</h4>At 2-year, 18% (n?=?22) of our IVH cohort required permanent cerebro spinal fluid (CSF) derivation. High IVH grade, low gestational age at birth and increased head circumference were risk factors for PHH. The rate of death of IVH was 36.9% (n?=?45). The rate of cerebral palsy was 55.9% (n?=?43) in the 77 surviving patients (49.4%). Risk factors for impaired neurodevelopment were high grade IVH and increased head circumference.<h4>Conclusion</h4>High IVH grade was strongly correlated with death and neurodevelopmental outcome. The impact of an increased head circumference highlights the need for early management. CSF biomarkers and new medical treatments such as antenatal magnesium sulfate have emerged and could predict and improve the prognosis of these newborns with PHH.
Project description:In the pathogenesis of neonatal intraventricular hemorrhage (IVH) in preterm infants, an important role is played by changes in venous and arterial cerebral flows. It has been shown that the ability of autoregulation of cerebral flows in response to variations in arterial blood pressure in preterm infants is impaired. This impaired autoregulation causes an increased risk of germinal matrix rupture and IVH occurrence. We examined three polymorphisms of genes, related to regulation of blood flow, for an association with IVH in 100 preterm infants born from singleton pregnancy, before 32?+?0 weeks of gestation, exposed to antenatal steroids therapy, and without congenital abnormalities. These polymorphisms include: eNOS (894G?>?T and -786T?>?C) and EDN1 (5665G?>?T?) gene. We found that infants with genotype GT eNOS 894G?>?T have 3.4-fold higher risk developing of IVH born before 28?+?6 weeks of gestation. Our investigation did not confirm any significant prevalence for IVH development according to eNOS -786T?>?C genes polymorphism. Our novel investigations in EDN1 5665G?>?T polymorphism did not show any link between alleles or genotypes and IVH. Future investigations of polymorphisms in blood-flow associated genes may provide valuable insight into the pathogenetic mechanisms underlying the development of IVH.
Project description:<h4>Background</h4>Pathogenesis of intraventricular hemorrhage (IVH) in premature infants is multifactorial. Little is known about the impact of genetic variants in the vitamin K-dependent coagulation system on the development of IVH.<h4>Methods</h4>Polymorphisms in the genes encoding vitamin K epoxide reductase complex 1 (VKORC1 -1639G>A) and coagulation factor 7 (F7 -323Ins10) were examined prospectively in 90 preterm infants <32 weeks gestational age with respect to coagulation profile and IVH risk.<h4>Results</h4>F7-323Ins10 was associated with lower factor VII levels, but not with individual IVH risk. In VKORC1-wildtype infants, logistic regression analysis revealed a higher IVH risk compared to carriers of the -1639A allele. Levels of the vitamin K-dependent coagulation parameters assessed in the first hour after birth did not differ between VKORC1-wildtype infants and those carrying -1639A alleles.<h4>Conclusions</h4>Our data support the assumption that genetic variants in the vitamin K-dependent coagulation system influence the coagulation profile and the IVH risk in preterm infants. Further studies focussing on short-term changes in vitamin K-kinetics and the coagulation profile during the first days of life are required to further understand a possible link between development of IVH and genetic variants affecting the vitamin K-metabolism.
Project description:Intraventricular hemorrhage (IVH) remains a major cause of white matter injury in preterm infants with no viable therapeutic strategy to restore myelination. Maturation of oligodendrocytes and myelination is influenced by thyroid hormone (TH) signaling, which is mediated by TH receptor ? (TR?) and TR?. In the brain, cellular levels of TH are regulated by deiodinases, with deiodinase-2 mediating TH activation and deiodinase-3 TH inactivation. Therefore, we hypothesized that IVH would decrease TH signaling via changes in the expression of deiodinases and/or TRs, and normalization of TH signaling would enhance maturation of oligodendrocytes and myelination in preterm infants with IVH. These hypotheses were tested using both autopsy materials from human preterm infants and a rabbit model of IVH. We found that deiodinase-2 levels were reduced, whereas deiodinase-3 levels were increased in brain samples of both humans and rabbits with IVH compared with controls without IVH. TR? expression was also increased in human infants with IVH. Importantly, treatment with TH accelerated the proliferation and maturation of oligodendrocytes, increased transcription of Olig2 and Sox10 genes, augmented myelination, and restored neurological function in pups with IVH. Consistent with these findings, the density of myelinating oligodendrocytes was almost doubled in TH-treated human preterm infants compared with controls. Thus, in infants with IVH the combined elevation in deiodinase-3 and reduction in deiodinase-2 decreases TH signaling that can be worsened by an increase in unliganded TR?. Given that TH promotes neurological recovery in IVH, TH treatment might improve the neurodevelopmental outcome of preterm infants with IVH.
Project description:<h4>Importance</h4>No trials to date have demonstrated the benefits of tocolysis on death and/or neonatal morbidity in preterm infants; tocolytics may affect the fetal blood-brain barrier.<h4>Objectives</h4>To assess the risks associated with tocolysis in women delivering prematurely as measured by death and/or intraventricular hemorrhage (IVH) in preterm infants and to compare the association of calcium channel blockers (CCBs) nifedipine and nicardipine hydrochloride vs atosiban used for tocolysis with death and/or IVH.<h4>Design, settings, and participants</h4>The French 2011 EPIPAGE-2 (Enquête Épidémiologique sur les Petits Âges Gestationnels) cohort was limited to mothers admitted for preterm labor without fever, who delivered from 24 to 31 weeks of gestation from April 1 through December 31, 2011. Groups of preterm infants with vs without tocolytic exposure and groups with atosiban vs CCB exposure were compared. Data analysis was performed from June 7, 2014, through September 3, 2017.<h4>Exposures</h4>Tocolytics.<h4>Main outcomes and measures</h4>The primary outcome was a composite of death and/or IVH in preterm infants. Secondary outcomes included death, IVH, and a composite of death and/or grades III to IV IVH.<h4>Results</h4>A total of 1127 mothers (mean [SD] age, 25.5 [6.0] years) experienced preterm labor and gave birth to 1343 preterm infants with a male to female ratio of 1.23 and mean (SD) gestational age of 27?(2.5) weeks. Of these, 789 mothers (70.0%) received tocolytics; 314 (39.8%) received only atosiban, and 118 (15.0%) received only a CCB. In the first analysis, the primary outcome (death and/or IVH) was not significantly different in preterm infants with vs without tocolytic exposure (183 of 363 [50.4%] vs 207 of 363 [57.0%]; relative risk [RR], 0.88; 95% CI, 0.77-1.01; P?=?.07). The secondary outcome (death and/or grades III-IV IVH) was significantly lower in preterm infants with vs without tocolytic exposure (92 of 363 [25.3%] vs 118 of 363 [32.5%]; RR, 0.78; 95% CI, 0.62-0.98; P?=?.03). Other outcomes did not differ significantly. In the secondary analysis, death and/or IVH was not significantly different in preterm infants with atosiban vs CCB exposure (96 of 214 [44.9%] vs 62 of 121 [51.2%]; RR, 0.88; 95% CI, 0.70-1.10; P?=?.26), nor was IVH (77 of 197 [39.1%] vs 48 of 106 [45.3%]; RR, 0.86; 95% CI, 0.66-1.13; P?=?.29).<h4>Conclusions and relevance</h4>In this population-based study, findings suggest that tocolytics were associated with a reduction of death and severe IVH. Other studies are necessary to compare perinatal outcomes after use of atosiban vs CCBs.
Project description:We hypothesized that activation of PPARg would enhance myelination, reduce hydrocephalus, and promote neurological recovery in newborns with IVH. These hypotheses were tested in preterm rabbit model of IVH; autopsy brain samples from premature infants with and without IVH were analyzed. We found that IVH augmented PPARg expression in microglia of both preterm human infants and rabbit kits. The treatment with PPARg agonist or PPARg overexpression by adenovirus delivery further elevated PPARg levels in microglia, reduced pro-inflammatory cytokines, increased microglial phagocytosis, and improved oligodendrocyte progenitor cell (OPC) maturation in kits with IVH. Transcriptomic analyses of OPCs identified previously unrecognized PPARg-induced novel genes for purinergic signaling, cAMP generation, and antioxidant production, which would reprogram these progenitors toward promoting myelination. RNA-seq analyses of microglia revealed PPARg-triggered downregulation of several pro-inflammatory genes and transcripts having roles in Parkinson’s disease and amyotrophic lateral sclerosis, contributing to neurological recovery in kits with IVH. Accordingly, PPARg activation enhanced myelination and neurological function in kits with IVH. Overall design: We performed two sets of RNA-seq: a) To address the effect of PPARg overexpression on microglial transcriptome, we performed a RNA-seq analysis on CD45Low/CD11b+ microglia isolated from the cerebral hemispheres of Ad-PPARg or Ad-GFP treated kits with IVH by FACS at D7; b) To determine the effect of PPARg overexpression on OPC transcriptome, we performed a RNA-seq analysis on O4+ OPC isolated from the cerebral hemispheres of Ad-PPARg and Ad-GFP treated preterm kits with IVH at D7.