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Genome and transcriptome profiling of spontaneous preterm birth phenotypes.

ABSTRACT: Preterm birth (PTB) occurs before 37 weeks of gestation. Risk factors include genetics and infection/inflammation. Different mechanisms have been reported for spontaneous preterm birth (SPTB) and preterm birth following preterm premature rupture of membranes (PPROM). This study aimed to identify early pregnancy biomarkers of SPTB and PPROM from the maternal genome and transcriptome. Pregnant women were recruited at the Liverpool Women's Hospital. Pregnancy outcomes were categorised as SPTB, PPROM (≤ 34 weeks gestation, n = 53), high-risk term (HTERM, ≥ 37 weeks, n = 126) or low-risk (no history of SPTB/PPROM) term (LTERM, ≥ 39 weeks, n = 188). Blood samples were collected at 16 and 20 weeks gestation from which, genome (UK Biobank Axiom array) and transcriptome (Clariom D Human assay) data were acquired. PLINK and R were used to perform genetic association and differential expression analyses and expression quantitative trait loci (eQTL) mapping. Several significant molecular signatures were identified across the analyses in preterm cases. Genome-wide significant SNP rs14675645 (ASTN1) was associated with SPTB whereas microRNA-142 transcript and PPARG1-FOXP3 gene set were associated with PPROM at week 20 of gestation and is related to inflammation and immune response. This study has determined genomic and transcriptomic candidate biomarkers of SPTB and PPROM that require validation in diverse populations.

SUBMITTER: Gupta JK

PROVIDER: S-EPMC8770724 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Long non-coding RNAs (lncRNAs) have a much higher cell- and/or tissue-specificity compared to mRNAs in most cases, making them excellent candidates for therapeutic applications to reduce off-target effects. Placental long non-coding RNAs have been investigated in the pathogenesis of preeclampsia (often causing preterm birth (PTB)), but less is known about their role in preterm birth. Preterm birth occurs in 11% of pregnancies and is the most common cause of death among infants in the world. We recently identified that genes that drive circadian rhythms in cells, termed molecular clock genes, are deregulated in maternal blood of women with spontaneous PTB (sPTB) and in the placenta of women with preeclampsia. Next, we focused on circadian genes-correlated long intergenic non-coding RNAs (lincRNAs, making up most of the long non-coding RNAs), designated as circadian lincRNAs, associated with sPTB. We compared the co-altered circadian transcripts-correlated lincRNAs expressed in placentas of sPTB and term births using two published independent RNAseq datasets (GSE73712 and GSE174415). Nine core clock genes were up- or downregulated in sPTB versus term birth, where the RORA transcript was the only gene downregulated in sPTB across both independent datasets. We found that five circadian lincRNAs (LINC00893, LINC00265, LINC01089, LINC00482, and LINC00649) were decreased in sPTB vs term births across both datasets (p ≤ .0222, FDR≤.1973) and were negatively correlated with the dataset-specific clock genes-based risk scores (correlation coefficient r = -.65 ∼ -.43, p ≤ .0365, FDR≤.0601). Gene set variation analysis revealed that 65 pathways were significantly enriched by these same five differentially expressed lincRNAs, of which over 85% of the pathways could be linked to immune/inflammation/oxidative stress and cell cycle/apoptosis/autophagy/cellular senescence. These findings may improve our understanding of the pathogenesis of spontaneous preterm birth and provide novel insights into the development of potentially more effective and specific therapeutic targets against sPTB.

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Genome and transcriptome profiling of spontaneous preterm birth phenotypes.

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