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. 2023 Dec:144:13-22.
doi: 10.1016/j.placenta.2023.10.008. Epub 2023 Oct 20.

High placental expression of FLT1, LEP, PHYHIP and IL3RA - In persons of African ancestry with severe preeclampsia

Omonigho Aisagbonhi  1 , Tony Bui  2 , Chanond A Nasamran  3 , Hailee St Louis  4 , Donald Pizzo  4 , Morgan Meads  2 , Megan Mulholland  2 , Celestine Magallanes  5 , Leah Lamale-Smith  5 , Louise C Laurent  5 , Robert Morey  6 , Marni B Jacobs  7 , Kathleen M Fisch  8 , Mariko Horii  2
Affiliations

High placental expression of FLT1, LEP, PHYHIP and IL3RA - In persons of African ancestry with severe preeclampsia

Omonigho Aisagbonhi et al. Placenta. 2023 Dec.

Abstract

Introduction: Mortality from preeclampsia (PE) and PE-associated morbidities are 3-to 5-fold higher in persons of African ancestry than in those of Asian and European ancestries.

Methods: To elucidate placental contribution to worse PE outcomes in African ancestry pregnancies, we performed bulk RNA sequencing on 50 placentas from persons with severe PE (sPE) of African (n = 9), Asian (n = 18) and European (n = 23) ancestries and 73 normotensive controls of African (n = 10), Asian (n = 15) and European (n = 48) ancestries.

Results: Previously described canonical preeclampsia genes, involved in metabolism and hypoxia/angiogenesis including: LEP, HK2, FSTL3, FLT1, ENG, TMEM45A, ARHGEF4 and HTRA1 were upregulated sPE versus normotensive placentas across ancestries. LTF, NPR3 and PHYHIP were higher in African vs. Asian ancestry sPE placentas. Allograft rejection/adaptive immune response genes were upregulated in placentas from African but not in Asian or European ancestry sPE patients; IL3RA was of particular interest because the patient with the highest placental IL3RA expression, a person of African ancestry with sPE, developed postpartum cardiomyopathy, and was the only patient out of 123, that developed this condition. Interestingly, the sPE patients with the highest IL3RA expression among persons of Asian and European ancestries developed unexplained tachycardia peripartum, necessitating echocardiography in the European ancestry patient. The association between elevated placental IL3RA levels and unexplained tachycardia or peripartum cardiomyopathy was found to be significant in the 50 sPE patients (p = .0005).

Discussion: High placental upregulation of both canonical preeclampsia and allograft rejection/adaptive immune response genes may contribute to worse PE outcomes in African ancestry sPE patients.

Keywords: African; Cardiomyopathy; IL3RA; Immune; Placenta; Preeclampsia.

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Conflict of interest statement

Declaration of competing interest All authors have no conflict of interests to declare.

Figures

Figure 1:
Figure 1:
Genes and pathways upregulated in common in placentas from severe PE versus normotensive patients of African, Asian and European ancestries. A. Differential gene expression analysis of sPE vs. normotensive controls within each ancestry showing the numbers of protein-coding genes that are significantly upregulated (with DESeq2 calculated adjusted p values of <.05) in sPE versus normotensive placentas of each ancestry. B. Heat map of the 67 protein-coding genes upregulated in patients of all three ancestries with sPE. C. Results of gene set enrichment analysis showing signaling pathways upregulated in sPE versus normotensive placentas.
Figure 2:
Figure 2:
Genes and pathways selectively or more highly upregulated in African ancestry sPE placentas. A. Results of gene set enrichment analysis showing pathways upregulated in African ancestry sPE (vs. normotensive) placentas, but not in Asian or European ancestry sPE (vs. normotensive) placentas. B. Identification of the most significant protein-coding genes upregulated in African ancestry sPE placentas; differentially upregulated genes in: 1. African ancestry sPE vs. normotensive placentas; 2. African sPE vs. Asian sPE placentas and 3. African sPE vs. European sPE placentas were compared. Non-protein-coding genes were excluded. Statistical analysis was performed using DESEq2; adjusted p values <.05 were considered significant. C. Plots of DESeq2-normalized gene expression levels of the most significant genes upregulated in African ancestry sPE placentas in comparison to their levels in Asian and European ancestry sPE placentas. Statistical analysis was performed using DESEq2; adjusted p values <.05 were considered significant.
Figure 3:
Figure 3:
A. Patients with the highest placental DESeq2 normalized IL3RA expression levels for their ancestry developed either unexplained tachycardia or peripartum cardiomyopathy. B. Logarithmic regression analysis of DESeq2 normalized placental IL3RA expression levels in African versus Asian and European ancestry severe preeclampsia parturitions at various gestational ages.
Figure 4:
Figure 4:
CD123 localization in placenta sections; in placentas with CD123 expression, variable expression was seen in chorionic plate vessels (A), decidual vessels (B), stem villous vessels (C) and syncytiotrophoblasts (D). CD123 expression in syncytiotrophoblasts correlated better with DESeq2 normalized IL3RA expression levels than expression in stem villous vessels (E and F).
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