(435) APOE4 genotype increases susceptibility to fetal growth restriction in the context of preeclampsia

Thursday, January 30, 2025

4:00 PM – 6:00 PM

Submitting Author and Presenting Author(s)

Bani Medegan Fagla, BS

MD/PhD Student
University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States

Coauthor(s)

CD

Cielo Dela Rosa, BS, MSc

University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States
SS

Savita Sundar, BS

University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States
EW

Erykah Walton, BS

University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States
JY

Jason York, PhD

University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States
GZ

Guomao Zhao, BS

Laboratory Manager, Perinatal Research
University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States
AJ

Aswathi Jayaram, MD, MS

Fellow, MFM
University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States
LT

Leon M. Tai, PhD

University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States
MB

Mert Ozan Bahtiyar, MD

Yale University
New Haven, Connecticut, United States
Catalin S. Buhimschi, MBA, MD

Professor and Division Director Maternal Fetal Medicine
University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States
IB

Irina A. Buhimschi, MD, MSc

Professor and Director, Perinatal Research
University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States

Objective: APOE4, one of three alleles of the lipid regulating gene APOE, is the greatest genetic risk factor for sporadic Alzheimer’s disease (AD) particularly in females. Preeclampsia (PE), a pregnancy-specific disorder, is characterized by abnormal deposition of misfolded proteins in the placenta, analogous to the hallmark protein aggregates in AD brain. We sought to investigate in a human cohort the association between APOE genotype and risk of PE with or without fetal growth restriction (FGR; EFW < 10%). Additionally, the effect of APOE4 was investigated mechanistically in a transgenic mouse model where the mouse ApoE gene was substituted by either human APOE4 or APOE3 (the common allele).

Study Design: We genotyped 181 consecutively enrolled maternal-fetal dyads divided by pregnancy phenotype in three clinical groups: 1) PE without FGR (n=56), 2) PE with FGR (n=21), and 3) non-PE pregnancies (n=104). DNA was extracted from maternal or cord blood and subjected to PCR. Risk association was determined by logistic regression. For mechanistic studies, we induced a PE-like syndrome in pregnant APOE4^+/+ and APOE3^+/+ mice using the reduced uteroplacental perfusion pressure (RUPP) procedure. Control mice underwent sham surgeries (n=6-7/group/genotype). Endpoints consisted of kidney morphology (glomerular size), fetal weights, placental efficiency, and placental ApoE mRNA expression by RT-qPCR.

Results:
1) In the human cohort, fetal carriage of at least one APOE4 allele was associated with increased odds of PE with FGR (p=0.043, Fig. 1); 2) An interaction of APOE4 with female fetal sex was further identified (p=0.024); 3) In mice, placental efficiency was reduced post-RUPP in both genotypes (Fig. 2A) but only APOE4^+/+ had decreased fetal weights (Fig. 2B) and kidney injury (p=0.014, Fig. 2C); 4) RT-qPCR of mouse placenta indicated significantly upregulated ApoE mRNA in response to RUPP in both genotypes.

Conclusion: ApoE participates to placental homeostasis during pregnancy. APOE4 may have a reduced capacity to maintain optimal fetal growth in the context of PE-associated placental dysfunction compared to APOE3.