Molecular subtyping of hypertensive disorders of pregnancy
Michal A. Elovitz, Elaine P.S. Gee, Nathaniel Delaney-Busch, Alison Moe, Mitsu Reddy, Arkady Khodursky, Johnny La, Ilma Abbas, Kay Mekaru, Hunter Collins, Farooq Siddiqui, Rory Nolan, Rupsa C. Boelig, Daniel Kiefer, Pamela M. Simmons, George R. Saade, Antonio F. Saad, Ebony B Carter, Thomas F. McElrath, Stephen R. Quake, Mark A. DePristo, Carrie Haverty, Manfred Lee, Eugeni Namsaraev, Vincenzo Berghella, Ai‐ris Y. Collier, Antonina I. Frolova, Esther Park-Hwang, Luis D. Pacheco, Elizabeth F. Sutton, Maneesh Jain, Kara M. Rood, William A. Grobman, Joseph Biggio, Cynthia Gyamfi-Bannerman, Arun Jeyabalan, Morten Rasmussen
Abstract
Hypertensive disorders of pregnancy (HDP), including preeclampsia, affect 1 in 6 pregnancies, are major contributors to maternal morbidity and mortality, yet lack precision medicine strategies. Analyzing transcriptomic data from a prospectively-collected diverse cohort (n = 9102), this study reveals distinct RNA subtypes in maternal blood, reclassifying clinical HDP phenotypes like early/late-onset preeclampsia. The placental gene PAPPA2 strongly predicts the most severe forms of preeclampsia in individuals without pre-existing high risk factors, months before symptoms, and its overexpression correlates with earlier delivery in a dose-dependent manner. Further, molecular subtypes characterized by immune genes are upregulated in less severe forms of HDP. These results reclassify HDP clinical phenotypes into two distinct molecular subtypes, placental-associated or immune-associated. Validation performance for placental-associated HDP yields an AUC of 0.88 in the advanced maternal age population without pre-existing high risk factors. Molecular subtypes create new opportunities to apply precision-based medicine in maternal health. The molecular etiology of hypertensive disorders of pregnancy is largely unknown. Here the authors show from a prospective study of diverse pregnancies that the disease can be split into molecular subtypes based on RNA data and validated a classifier for individuals with no preexisting high risk factors.