Altered global gene expression in first trimester placentas of women destined to develop preeclampsia

Abstract

Background: Preeclampsia is a pregnancy-specific disorder that remains a leading cause of maternal, fetal and neonatal morbidity and mortality, and is associated with risk for future cardiovascular disease. There are no reliable predictors, specific preventative measures or treatments other than delivery. A widely held view is that the antecedents of preeclampsia lie with impaired placentation in early pregnancy. Accordingly, we hypothesized dysregulation of global gene expression in first trimester placentas of women who later manifested preeclampsia.

Methods: Surplus chorionic villus sampling (CVS) tissues were collected at 10-12 weeks gestation in 160 patients with singleton fetuses. Four patients developed preeclampsia, and their banked CVS specimens were matched to 8 control samples from patients with unaffected pregnancies. Affymetrix HG-U133 Plus 2.0 GeneChips were utilized for microarray analysis. Naïve Bayes prediction modeling and pathway analysis were conducted. qRT-PCR examined three of the dysregulated genes.

Results: Thirty-six differentially expressed genes were identified in the preeclampsia placentas. qRT-PCR verified the microarray analysis. Thirty-one genes were down-regulated. Many were related to inflammation/immunoregulation and cell motility. Decidual gene dysregulation was prominent. No evidence was found for alterations in hypoxia and oxidative stress regulated genes.

Conclusions: To our knowledge, this is the first study to show dysregulation of gene expression in the early placentas of women approximately 6 months before developing preeclampsia, thereby reinforcing a placental origin of the disorder. We hypothesize that placentation in preeclampsia is compromised in the first trimester by maternal and fetal immune dysregulation, abnormal decidualization, or both, thereby impairing trophoblast invasion. Several of the genes provide potential targets for the development of clinical biomarkers in maternal blood during the first trimester. Supplementary materials are available for this article via the publisher's online edition.

Figure 1

Ingenuity Pathways Analysis Networks 1 and 2. IPA incorporated some of the genes identified in the microarray analysis into potential functional relationships based on human and animal literature. A. Network 1 includes 10 genes from this study related to Cancer, Respiratory Disease, and Cellular Movement. CCK is up-regulated and located in the extracellular space. FSTL3, IGFBP1 and SEMA3 are down-regulated and located in the extracellular space, as is the enzyme MMP12. The genes of interest are in direct (solid arrows) and indirect (dashed arrows) relationships with other molecules depicted in the Network. FN1 is depicted as a down-regulated enzyme in the plasma membrane interacting directly and indirectly with other molecules depicted. None of the genes of interest is located in the cytoplasm in Network 1. ASCL2, ELL2, EPAS1 are down-regulated transcription factors involved in direct and indirect relationships with other molecules. SART3 is a molecule acted upon indirectly by molecules outside the nucleus. B. Network 2 includes 7 genes from this study related to Inflammatory Disease, Cellular Movement, and Hematological System Development and Function. The enzyme MMP12 and molecule PAEP are both down-regulated and located in the extracellular space. The genes of interest are in direct (solid arrows) and indirect (dashed arrows) relationships with other molecules depicted in the Network. SLC16A6 is a down-regulated transporter in the plasma membrane, indirectly related to molecules in other compartments. F11R is a plasma membrane molecule that is down-regulated and related directly and indirectly to other molecules depicted in Network 2. S100A8 is an up-regulated molecule, KRT14 is a down-regulated molecule, and LRAP is an enzyme down-regulated in the cytoplasm. All interact directly and indirectly with other molecules depicted in the Network. None of the genes of interest is located in the nucleus in Network 2.

Figure 1

Ingenuity Pathways Analysis Networks 1 and 2. IPA incorporated some of the genes identified in the microarray analysis into potential functional relationships based on human and animal literature. A. Network 1 includes 10 genes from this study related to Cancer, Respiratory Disease, and Cellular Movement. CCK is up-regulated and located in the extracellular space. FSTL3, IGFBP1 and SEMA3 are down-regulated and located in the extracellular space, as is the enzyme MMP12. The genes of interest are in direct (solid arrows) and indirect (dashed arrows) relationships with other molecules depicted in the Network. FN1 is depicted as a down-regulated enzyme in the plasma membrane interacting directly and indirectly with other molecules depicted. None of the genes of interest is located in the cytoplasm in Network 1. ASCL2, ELL2, EPAS1 are down-regulated transcription factors involved in direct and indirect relationships with other molecules. SART3 is a molecule acted upon indirectly by molecules outside the nucleus. B. Network 2 includes 7 genes from this study related to Inflammatory Disease, Cellular Movement, and Hematological System Development and Function. The enzyme MMP12 and molecule PAEP are both down-regulated and located in the extracellular space. The genes of interest are in direct (solid arrows) and indirect (dashed arrows) relationships with other molecules depicted in the Network. SLC16A6 is a down-regulated transporter in the plasma membrane, indirectly related to molecules in other compartments. F11R is a plasma membrane molecule that is down-regulated and related directly and indirectly to other molecules depicted in Network 2. S100A8 is an up-regulated molecule, KRT14 is a down-regulated molecule, and LRAP is an enzyme down-regulated in the cytoplasm. All interact directly and indirectly with other molecules depicted in the Network. None of the genes of interest is located in the nucleus in Network 2.