RNA sequencing identifies human placental IL3RA as a potential predictor of adverse cardiovascular outcomes in patients with severe preeclampsia

BackgroundMortality 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, PHYHIP and ENG, were upregulated in sPE across ancestries, with high expression of FSTL3 being additionally associated with intrauterine growth restriction (p = .0047). Notably, the upregulation of, FLT1, LEP and PHYHIP was 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, IL3RA was of particular interest because the patient with the highest placental IL3RA level, a woman of African ancestry with IL3RA levels 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 highest IL3RA levels among parturients 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). 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, including IL3RA. High placental expression of IL3RA may predict worse maternal cardiovascular outcomes, including peripartum cardiomyopathy. Studies evaluating placental IL3RA levels in peripartum cardiomyopathy cohorts are therefore warranted, as are broader studies evaluating placental factors in maternal cardiovascular outcomes postpartum.