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222: Global transcriptomic analysis of human placenta in the setting of intrauterine growth restriction (IUGR) using RNA sequencing (RNA-Seq)

      Objective

      Appropriate fetal growth is linked to normal placental development and function. Identification of key pathogenic pathways that may be responsible for the increased morbidity and mortality of fetuses with IUGR is critical. We performed a genome-wide transcriptome RNA-seq analysis to discover placental villous trophoblast transcripts differentially expressed in the setting of preeclampsia (PE) as opposed to idiopathic IUGR.

      Study Design

      Total RNA was extracted from 25 placental villous tissue samples of women with: 1) idiopathic PTB (iPTB, n=5, GA: 32±1wks; 2) idiopathic IUGR (n=5, GA: 29±1 wks); 3) severe PE & normal fetal growth (sPE, n=8, GA: 30±1 wks); 4) sPE & IUGR (n=7, GA: 30±1 wks). All IUGR fetuses had birthweights <10% (85% were at <3%) and abnormal Dopplers. Cord blood Insulin-like growth factor 1 (IGF-1) was measured as a marker of IUGR. RNA-seq was performed using the Illumina platform. Following data curation and quality control, statistical analyses were performed using ‘DESeq2’ and ‘edgeR’ (FDR<0.1).

      Results

      Relative to iPTB, idiopathic IUGR resulted in altered expression of 3,908 placental transcripts. Relative to iPTB, placentas of sPE & IUGR exhibited altered expression of 1,639 genes. This group profile was consistent with significantly lower cord blood IGF-1 levels in idiopathic IUGR vs. iPTB newborns (P<0.001). Conversely, 576 genes were differentially expressed in the setting of sPE alone. Overall, the global transcriptional profiles of sPE and sPE & IUGR placentas were highly similar, with differential expression of <10 genes. In contrast, idiopathic IUGR differed from sPE & IUGR by 91 transcripts and from sPE & normal fetal growth by 543 transcripts. Idiopathic IUGR was associated with dysregulation of gene sets related to cell cycle regulation, oxidative phosphorylation, and insulin growth factor regulation. sPE was linked to pathways associated with altered adipokine signaling, lipid and sugar metabolism, and amyloid precursor processing.

      Conclusion

      The transcriptome of villous trophoblasts of pregnancies complicated by sPE and sPE & IUGR is remarkably similar, implying that in sPE, IUGR cannot be linked to a markedly different gene expression profile. The large variability of placental transcriptome in idiopathic IUGR emphasizes again the heterogeneity of the growth restricted phenotype.