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. 2023 May 2;16(1):91.
doi: 10.1186/s12920-023-01522-x.

Placental transcriptome analysis of hypertensive pregnancies identifies distinct gene expression profiles of preeclampsia superimposed on chronic hypertension

Ashley M Hesson  1 , Elizabeth S Langen  2 , Olesya Plazyo  3 , Johann E Gudjonsson  3 , Santhi K Ganesh  4
Affiliations

Placental transcriptome analysis of hypertensive pregnancies identifies distinct gene expression profiles of preeclampsia superimposed on chronic hypertension

Ashley M Hesson et al. BMC Med Genomics. .

Abstract

Background: The pathogenesis of preeclampsia superimposed on chronic hypertension (SI) is poorly understood relative to preeclampsia (PreE) occurring in pregnant people without chronic hypertension. Placental transcriptomes in pregnancies complicated by PreE and SI have not been previously compared.

Methods: We identified pregnant people in the University of Michigan Biorepository for Understanding Maternal and Pediatric Health with hypertensive disorders affecting singleton, euploid gestations (N = 36) along with non-hypertensive control subjects (N = 12). Subjects were grouped as: (1) normotensive (N = 12), (2) chronic hypertensive (N = 13), (3) preterm PreE with severe features (N = 5), (4) term PreE with severe features (N = 11), (5) preterm SI (N = 3), or (6) term SI (N = 4). Bulk RNA sequencing of paraffin-embedded placental tissue was performed. The primary analysis assessed differential gene expression relative to normotensive and chronic hypertensive placentas, where Wald adjusted P values < 0.05 were considered significant. Unsupervised clustering analyses and correlation analyses were performed between conditions of interest, and a gene ontology was constructed.

Results: Comparing samples from pregnant people with hypertensive diseases to non-hypertensive controls, there were 2290 differentially expressed genes. The log2-fold changes in genes differentially expressed in chronic hypertension correlated better with term (R = 0.59) and preterm (R = 0.63) PreE with severe features than with term (R = 0.21) and preterm (R = 0.22) SI. A relatively poor correlation was observed between preterm SI and preterm PreE with severe features (0.20) as well as term SI and term PreE with severe features (0.31). The majority of significant genes were downregulated in term and preterm SI versus normotensive controls (92.1%, N = 128). Conversely, most term and preterm PreE with severe features genes were upregulated compared to the normotensive group (91.8%, N = 97). Many of the upregulated genes in PreE with the lowest adjusted P values are known markers of abnormal placentation (e.g., PAAPA, KISS1, CLIC3), while the downregulated genes with the greatest adjusted P values in SI have fewer known pregnancy-specific functions.

Conclusions: We identified unique placental transcriptional profiles in clinically relevant subgroups of individuals with hypertension in pregnancy. Preeclampsia superimposed on chronic hypertension was molecularly distinct from preeclampsia in individuals without chronic hypertension, and chronic hypertension without preeclampsia, suggesting that preeclampsia superimposed on hypertension may represent a distinct entity.

Keywords: Biomarkers; Hypertension; Inhibin; Preeclampsia; RNASeq.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flow diagram showing the subject-level group comparisons. Shading and bolding represent the final sub-samples included in the analysis
Fig. 2
Fig. 2
Principal component analysis of sample read counts from participants with no-hypertension (controls), chronic hypertension (HTN), preeclampsia with severe features (SF), and preeclampsia superimposed on hypertension (SI). Two dimensions of variance were plotted, PC1 on the X-axis and PC2 on the Y-axis, using the top 500 transcripts with the most variance across samples
Fig. 3
Fig. 3
Heat map of Euclidean sample distances by hypertensive disease state for transcripts with read counts > 10. Individual samples were numbered within each disease state: participants with no hypertension (controls), chronic hypertension (HTN), preeclampsia with severe features (SF), and preeclampsia superimposed on hypertension (SI)
Fig. 4
Fig. 4
A volcano plot showing significantly upregulated (positive log2-fold change) and downregulated (negative log2-fold change) genes by condition. HTN Hypertension, PTSF Preterm PreE with severe features, TSF Term PreE with severe features, PTSI Preterm SI, TSI Term SI
Fig. 5
Fig. 5
Gene ontology results by condition cluster (HTN Hypertension, SF Preeclampsia with severe features, SI Superimposed preeclampsia) and Bonferroni-corrected significance. Node size represents significance. Condition- “specific” genes refer to those driving identification of biologic pathways in the ClueGO gene ontology. Pathways were shaded as red for HTN, green for SF, and blue for SI based on the number of pathway-associated genes significantly differentially expressed in a given condition relative to controls
Fig. 6
Fig. 6
Log2-fold changes in the top twenty most significantly differentially expressed genes in each condition-gestational age grouping (HTN Hypertension, PTSF Preterm PreE with severe features, TSF Term PreE with severe features, PTSI Preterm SI, TSI Term SI) when contrasted with controls. Each differentially expressed gene was annotated with its described function in pregnancy or lack thereof (RPL Recurrent pregnancy loss, FGR Fetal growth restriction, ECM Extracellular matrix). These functional assignments were based on manual review of available data in the DAVID database as well as cited references
Fig. 7
Fig. 7
Log transcript counts of the 50 genes with the most variance in the sample, with full gene names for corresponding transcripts. The counts are given by sample, where the samples were labeled by disease state. HTN Hypertension, SF Preeclampsia with severe features, SI Superimposed preeclampsia
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