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Investigating the Role of Fetal Gene Expression in Preterm Birth.

ABSTRACT: Second-trimester amniotic fluid supernatant (AFS) contains cell-free fetal RNA (cffRNA) transcripts that can provide information about fetal gene expression. In a retrospective case-control study, we measured second-trimester fetal gene expression using cffRNA extracted from AFS in women who had spontaneous preterm birth (sPTB) <34 weeks and in women who delivered >37 weeks. We extracted cffRNA from AFS of women with singletons who had second-trimester genetic amniocenteses. Twenty-one gravidas who had sPTB and 21 term controls were matched 1:1 for maternal age, fetal sex, race, gestational age (GA) at the time of amniocentesis, and medication exposure. Cell-free fetal RNA was extracted and hybridized to a customized 65-gene NanoString panel containing genes related to oxidative stress, inflammation, and hypothalamic-pituitary-adrenal (HPA) axis and included 15 housekeeping genes. Two models were run, 1 examining sPTB in relation to case/control status and 1 examining sPTB in relation to GA as a continuous variable. Among cases, the gene expression of nitric oxide synthase 1 ( NOS1), d-aspartate oxidase ( DDO), and Beta-2-microglobulin ( B2M) was higher than controls ( P value < .05; false discovery rate-corrected Q value of ≤0.10). Nitric oxide synthase 1 and DDO are genes associated with oxidative stress; B2M is a marker of the fetal inflammatory response. Fetal HPA gene expression is not associated with GA at delivery or sPTB in second-trimester AFS. Alterations of fetal gene expression related to inflammation and oxidative stress antedate clinical symptoms and may be useful for early identification of patients at risk of having an sPTB.

SUBMITTER: Vora NL

PROVIDER: S-EPMC5933097 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Investigating the Role of Fetal Gene Expression in Preterm Birth.

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