Molecular subtyping of hypertensive disorders of pregnancy
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.
Authors
- Rory Nolan (ORCID: https://orcid.org/0000-0002-5239-4043)
- Cynthia Gyamfi-Bannerman
- Manfred Lee
- Ai-ris Yonekura Collier (ORCID: https://orcid.org/0000-0002-8539-3960)
- Rupsa C. Boelig (ORCID: https://orcid.org/0000-0002-3705-6943)
- Esther Park-Hwang
- Eugeni Namsaraev
- Hilda L. Collins
- Antonio F. Saad (ORCID: https://orcid.org/0000-0003-0034-3567)
- Ilma Abbas
- Elizabeth F. Sutton (ORCID: https://orcid.org/0000-0002-8807-6434)
- Johnny La
- Daniel Kiefer (ORCID: https://orcid.org/0000-0001-6136-1086)
- Kara M. Rood (ORCID: https://orcid.org/0000-0002-8504-6715)
- Pamela M. Simmons
- Michal A. Elovitz (ORCID: https://orcid.org/0000-0001-7554-7180)
- Thomas F. McElrath (ORCID: https://orcid.org/0000-0003-0857-0107)
- Arun Jeyabalan
- Arkady Khodursky (ORCID: https://orcid.org/0000-0002-4691-2828)
- Nathaniel Delaney-Busch (ORCID: https://orcid.org/0000-0002-2187-6867)
- Joseph Biggio (ORCID: https://orcid.org/0000-0003-3748-7206)
- Elaine P.S. Gee (ORCID: https://orcid.org/0000-0001-7453-4433)
- Ebony B Carter
- Antonina I. Frolova (ORCID: https://orcid.org/0000-0002-6491-6910)
- Carrie Haverty (ORCID: https://orcid.org/0000-0003-1446-4220)
- Maneesh Jain
- Stephen R. Quake (ORCID: https://orcid.org/0000-0002-1613-0809)
- Morten Rasmussen (ORCID: https://orcid.org/0000-0002-2743-5683)
- Vincenzo Berghella
- George R. Saade
- Mark A. DePristo
- William A. Grobman
- Farooq Siddiqui
- Alison Moe (ORCID: https://orcid.org/0000-0003-2857-9037)
- Mitsu Reddy
- Kay Mekaru
- Luis Diego Pacheco
Institutions
- University of North Carolina at Chapel Hill (US)
- Inova Health System (US)
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- MultiCare Health System (US)
- Ochsner Health System (US)
- Harvard University (US)
- College of San Mateo (US)
- Thomas Jefferson University (US)
- Eastern Virginia Medical School (US)
- University of Pittsburgh (US)
- Washington University in St. Louis (US)
- AdventHealth Orlando (US)
- University of California System (US)
- University of California San Diego (US)
- Chan Zuckerberg Initiative (United States) (US)
- Women’s Health Care (US)
- International Women's Health Coalition (US)
- Woman's Hospital (US)
- The Ohio State University (US)
- The University of Texas Medical Branch at Galveston (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1038/s41467-025-58157-y
- Citations
- 17
- Primary Topic
- Pregnancy and preeclampsia studies
- Type
- article
- Field-Weighted Citation Impact
- 34.97