Identifying placental injury pathways in women of African ancestry with severe preeclampsia

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Summary/Abstract Women of African ancestry are 3 to 5-times more likely to die of preeclampsia, a pregnancy-induced hypertensive disorder, or suffer bad outcomes like stroke, pulmonary edema and heart failure, than women of Asian or European ancestries. The placenta plays a central role in the pathology of preeclampsia, as delivery is often curative. However, how the placenta contributes to worse outcomes in women of African ancestry, and which specific placental injury pathways may be targeted for therapy, are not well studied. An exciting evolution in elucidating the underlying pathophysiology of preeclampsia is the concept that the disease has multiple etiologies that manifest differently in the placenta. Therefore, the aim of this study is to identify the specific placental cellular and molecular injury pathways that may account for the disproportionately worse outcomes in women of African ancestry in comparison to women of European and Asian ancestries. The ultimate goal is to identify pathways of placental injury that can be targeted to improve pregnancy outcomes in women of African ancestry. The central hypothesis is that immunologic processes, including non-permissive HLA mismatches and upregulation of genes associated with immune activation underlie the pathophysiology of severe preeclampsia in women of African ancestry compared to women of Asian and European ancestry. This hypothesis will be tested in two specific aims: 1. Identify the region and cell- specific localization of genes and pathways that are differentially expressed/altered in placentas of women with severe preeclampsia versus normotensive women of African ancestry, in contrast to women of Asian and European ancestries, using digital spatial transcriptomics, and evaluate how the placental immune cell milieu changes in these patient populations using immunohistochemistry. 2. Evaluate the role of maternal-fetal HLA mismatches and altered placental expression of HLA molecules in the pathophysiology of severe preeclampsia in women of African ancestry versus women of Asian and European ancestries using comprehensive HLA genotyping, HLA functional prediction analysis and immunohistochemistry. The proposed research is conceptually innovative because it will address the pathophysiology of severe preeclampsia in women of African ancestry (compared to women of Asian and European ancestries) from the context of differential placental manifestations of the disease. It is technically innovative because it will integrate both RNA profiling (via RNA sequencing and digital spatial transcriptomics) and protein expression (via immunohistochemistry) to identify placental cellular processes, genes, and pathways that will potentially be therapeutic targets to modulate the worse outcomes of severe preeclampsia in women of African ancestry. Furthermore, it is innovative in its depth because it will include comprehensive HLA genotyping, HLA functional prediction analysis and HLA immunohistochemistry to better understand the etiologic contribution of non-permissive HLA mismatches to the pathophysiology of severe preeclampsia in women of African ancestry.