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 ~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.

We have examined the transcriptional changes associated with differentiation from villous to extravillous trophoblast using a whole genome microarray. Villous trophoblast (VT) is in contact with maternal blood and mediates nutrient exchange whereas extravillous trophoblast (EVT) invades the decidua and remodels uterine arteries. Using highly purified first trimester trophoblast we identified over 3000 transcripts that are differentially expressed. Many of these transcripts represent novel functions and pathways that show co-ordinated up-regulation in VT or EVT. In addition we identify new players in established functions such as migration, immune modulation and cytokine or angiogenic factor secretion by EVT. The transition from VT to EVT is also characterised by alterations in transcription factors such as STAT4 and IRF9, which may co-ordinate these changes. Transcripts encoding several members of the immunoglobulin-superfamily, which are normally expressed on leukocytes, were highly transcribed in EVT but not expressed as protein, indicating specific control of translation in EVT. Interactions of trophoblast with decidual leukocytes are involved in regulating EVT invasion. We show that decidual T-cells, macrophages and NK cells express the inhibitory collagen receptor LAIR-1 and that EVT secrete LAIR-2, which can block this interaction. This represents a new mechanism by which EVT can modulate leukocyte function in the decidua. Since LAIR-2 is detectable in the urine of pregnant, but not non-pregnant women, trophoblast-derived LAIR-2 may also have systemic effects during pregnancy.

BackgroundPreeclampsia is a hypertensive, multi-system pregnancy disorder whose pathophysiology remains unclear. Elevations in circulating soluble endoglin (sENG) and placental/blood ENG mRNA expression antedate the clinical onset of preeclampsia. This study investigated if endoglin (ENG) pathway genetic variation was also associated with the development of preeclampsia.MethodsWe used a case–control candidate gene association design. Data from 355 white (181 preeclampsia cases/174 controls) and 60 black (30 preeclampsia cases/30 controls) women matched on ancestry, age, and parity were analyzed. Tagging single nucleotide polymorphisms (tSNPs) and potentially functional SNPs in ENG, TGFβ1, TGFβR1, ALK1, and TGFβR2 were genotyped with iPLEX® and TaqMan®. Chi-square or Fisher’s exact tests were used to conduct allele/genotype/haplotype tests in white/black subgroups separately. Odds ratios were computed with binary logistic regression for tSNPs with significant genotype tests.ResultsOf the 49 SNPs evaluated, variation in two ENG tSNPs (rs11792480, rs10121110) and one TGFβR2 tSNP (rs6550005) was associated with preeclampsia in white women (P <0.05, each). In black women, variation in two TGFβ1 tSNPs (rs4803455, rs4803457), one TGFβR1 tSNP (rs10739778), and three TGFβR2 tSNPs (rs6550005, rs1346907, rs877572) was associated with preeclampsia (P <0.05, each). Further evaluation of ENG tSNP rs10121110 revealed that white women inheriting the AA genotype were 2.29 times more likely to develop preeclampsia compared to the GG genotype (P = 0.008, [99% CI: 1.02 to 5.13]). For black women, similar evaluation of TGFβ1 tSNP rs4803457 revealed women inheriting the CT genotype were 7.44 times more likely to develop preeclampsia than those with the CC genotype (P = 0.005, [99% CI: 1.19 to 46.41]).ConclusionsENG pathway genetic variation is associated with preeclampsia. Different ENG pathway genes may be involved in preeclampsia development among white and black women. Additional studies are needed to validate these findings and to determine if genetic variation in ENG pathway genes impacts ENG and sENG levels in preeclampsia.

Objectives: We hypothesized that TNFα would be higher in obese versus lean preeclamptic subjects. Methods:Total plasma TNFα was measured in a nested case-control study of 123 nulliparous lean and obese control and preeclamptic subjects.Results: Adjusted mean TNFα concentrations were 0.97±0.11 (pg/ml ± SEM) in lean controls, 1.01 ±0.10 in obese controls, 1.43±0.11 in lean preeclamptics and 1.16±0.11 in obese preeclamptics. Pregnancy outcome was the single predictor of TNFα concentration in the general linear regression model (p=0.04). Conclusion:TNFα concentration was higher in preeclamptic compared to control subjects. Obesity was not associated with higher TNFα concentrations in preeclamptic or control subjects.