RNA sequencing identifies human placentalIL3RAas a potential predictor of adverse cardiovascular outcomes in patients with severe preeclampsia

Abstract

AbstractBackgroundMortality 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. The placenta is central to the etiology of PE. However, how and to what extent the placenta contributes to worse PE outcomes in persons of African ancestry is yet to be fully elucidated.ObjectiveWe aimed to identify molecular pathways that are unique or enriched in placentas of parturient persons of African ancestry with PE with severe features (sPE) compared to those of Asian and European ancestry with sPE.Study designBulk RNA sequencing was performed on 50 placentas from parturient persons with sPE of African (n=9), Asian (n=18) and European (n=23) ancestries and 73 normotensive controls of African (n=9), Asian (n=15) and European (n=49) ancestries.ResultsMetabolism, hormone regulation and hypoxia/angiogenesis genes, previously described to be upregulated in PE, including:LEP,PAPPA2,INHA,FSTL3,FLT1, PHYHIPandENG, were upregulated in sPE across ancestries, with high expression ofFSTL3being additionally associated with intrauterine growth restriction (p = .0047). Notably, the upregulation of,FLT1,LEPandPHYHIPwas significantly higher in sPE placentas from parturient persons of African versus Asian ancestry (p = .0.35, .020 and .012 respectively). Genes associated with allograft rejection and adaptive immune response were upregulated in placentas from parturients of African ancestry but not in those of Asian and European ancestries. Among the allograft rejection/adaptive immune response genes,IL3RAwas of particular interest because the patient with the highest placentalIL3RAlevel, a woman of African ancestry withIL3RAlevels 4.5-fold above the average for African ancestry parturients with sPE, developed postpartum cardiomyopathy, and was the only patient out of 123, that developed this condition. Interestingly, the sPE patients with the highestIL3RAlevels among parturients of Asian and European ancestries developed unexplained tachycardia peripartum, necessitating echocardiography in the European ancestry patient. The association between elevated placentalIL3RAlevels and unexplained tachycardia or peripartum cardiomyopathy was found to be significant in the 50 sPE patients (p = .0005).ConclusionsPlacentas from parturients of African ancestry express higher levels of metabolism (LEP) and hypoxia/angiogenesis (FLT1) genes, as well as allograft rejection/adaptive immune response genes, includingIL3RA. High placental expression ofIL3RAmay predict worse maternal cardiovascular outcomes, including peripartum cardiomyopathy. Studies evaluating placentalIL3RAlevels in peripartum cardiomyopathy cohorts are therefore warranted, as are broader studies evaluating placental factors in maternal cardiovascular outcomes postpartum.