Molecular subtyping of hypertensive disorders of pregnancy

Michal A. Elovitz, Elaine P. S. Gee, Nathaniel Delaney-Busch, Alison B. Moe, Mitsu Reddy, Arkady Khodursky, Johnny La, Ilma Abbas, Kay Mekaru, Hunter Collins, Farooq Siddiqui, Rory Nolan, Rupsa C. Boelig, Daniel G. Kiefer, Pamela M. Simmons, George R. Saade, Antonio 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, Antonia I. Frolova, Esther Park-Hwang, Luis D. Pacheco, Elizabeth F. Sutton, Maneesh Jain, Kara Rood, William A. Grobman, Joseph R. Biggio, Cynthia Gyamfi-Bannerman, Arun Jeyabalan and Morten Rasmussen ()
Additional contact information
Michal A. Elovitz: Mirvie Inc.
Elaine P. S. Gee: Mirvie Inc.
Nathaniel Delaney-Busch: Mirvie Inc.
Alison B. Moe: Mirvie Inc.
Mitsu Reddy: Mirvie Inc.
Arkady Khodursky: Mirvie Inc.
Johnny La: Mirvie Inc.
Ilma Abbas: Mirvie Inc.
Kay Mekaru: Mirvie Inc.
Hunter Collins: Mirvie Inc.
Farooq Siddiqui: Mirvie Inc.
Rory Nolan: Mirvie Inc.
Rupsa C. Boelig: Thomas Jefferson University
Daniel G. Kiefer: Women’s Care Florida
Pamela M. Simmons: Woman’s Hospital
George R. Saade: Eastern Virginia Medical School
Antonio Saad: Inova Health
Ebony B. Carter: University of North Carolina at Chapel Hill
Thomas F. McElrath: Mirvie Inc.
Stephen R. Quake: Stanford University
Mark A. DePristo: BigHat Biosciences Inc.
Carrie Haverty: Mirvie Inc.
Manfred Lee: Mirvie Inc.
Eugeni Namsaraev: Mirvie Inc.
Vincenzo Berghella: Thomas Jefferson University
Ai-ris Y. Collier: Beth Israel Deaconess Medical Center
Antonia I. Frolova: Washington University School of Medicine
Esther Park-Hwang: MultiCare Health System
Luis D. Pacheco: Univerity of Texas Medical Branch
Elizabeth F. Sutton: Woman’s Hospital
Maneesh Jain: Mirvie Inc.
Kara Rood: The Ohio State University
William A. Grobman: The Ohio State University
Joseph R. Biggio: Ochsner Health
Cynthia Gyamfi-Bannerman: University of California San Diego
Arun Jeyabalan: University of Pittsburgh
Morten Rasmussen: Mirvie Inc.

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58157-y

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