[Show abstract][Hide abstract] ABSTRACT: The potential for developing molecules of interest in preclinical preeclampsia from candidate genes that were discovered on gene expression microarray analysis has been challenged by limited access to additional first trimester trophoblast and decidual tissues. The question of whether these candidates encode secreted proteins that may be detected in maternal circulation early in pregnancy has been investigated using various proteomic methods. Pilot studies utilizing mass spectrometry based proteomic assays, along with enzyme linked immunosorbent assays (ELISAs), and Western immunoblotting in first trimester samples are reported. The novel targeted mass spectrometry methods led to robust multiple reaction monitoring assays. Despite detection of several candidates in early gestation, challenges persist. Future antibody-based studies may lead to a novel multiplex protein panel for screening or detection to prevent or mitigate preeclampsia.
Preview · Article · Nov 2015 · International Journal of Molecular Sciences
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to examine circulating maternal follistatin-like 3 (FSTL-3) by gestational age and obesity in pregnancy and preeclampsia. FSTL-3 was quantified in maternal plasma collected in each trimester from prepregnancy body mass index-determined groups: 15 lean and 24 obese controls and 20 obese women who developed preeclampsia. Repeated measures mixed models and logistic regression were conducted (P ≤ .05). FSTL-3 was not related to maternal adiposity. FSTL-3 changed across pregnancy in lean controls and obese preeclampsia but not in obese controls. FSTL-3 was higher in preeclampsia in the second trimester compared to lean controls and in the third trimester compared to both control groups. Elevated FSTL-3 at mid-gestation was associated with an increased odds of preeclampsia (odds ratio 3.15; 95% confidence interval 1.19-8.36; P = .02). Elevated FSTL-3 concentrations were attributable to preeclampsia and were associated with increased likelihood of later developing preeclampsia, suggesting further study as a biomarker prior to clinically evident disease.
[Show abstract][Hide abstract] ABSTRACT: Current trends in prenatal genetic testing will affect nursing practice, education, research, and policy making. Although fetal genetic testing has been the traditional focus, new technologies open the possibility of acquiring genomic information for both parents and offspring, revealing windows onto individuals' lifelong health. Noninvasive prenatal testing of cell-free fetal DNA also has become a reality. Some of the recent advances in detecting cytogenetic and heritable molecular variants in pregnancy are overviewed. Exemplars of prenatal tests are presented and related ethical, legal, and social implications are considered. Educating clinicians with updated genomic knowledge has been outpaced by new technologies and direct-to-consumer marketing of prenatal tests. Implications for nursing are discussed.
[Show abstract][Hide abstract] ABSTRACT: Although the etiology of preterm birth is incompletely understood, phenotype classifications combined with recent technologies such as genome-wide association studies and next-generation sequencing could lead to discovering genotypes associated with preterm birth. Identifying genetic contributions will allow for genetic screening tests to predict or detect pregnancies with potential for preterm birth. In this article we discuss current knowledge regarding phenotype classifications, genotypes, and their associations with preterm birth.
No preview · Article · Oct 2013 · Journal of Obstetric Gynecologic & Neonatal Nursing
[Show abstract][Hide abstract] ABSTRACT: Background
Preeclampsia 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.
We 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.
Of 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]).
ENG 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.
[Show abstract][Hide abstract] ABSTRACT: Leukocyte-associated immunoglobulin-like receptor 2 (LAIR2) was identified on a global gene expression microarray analysis of surplus chorionic villus sampling (CVS) tissues as down-regulated in the first trimester of preeclampsia pregnancies. LAIR2 is the soluble receptor counterpart to LAIR1, an inhibitory receptor found on multiple immune cell subsets. In situ and immunohistochemical studies have previously shown that placental expression of LAIR2 expression is highly restricted, confined to the more distal portions of extravillous trophoblast (EVT) cell columns. This study examines LAIR2 expression in deeper layers of trophoblasts in the placental implantation site, maternal decidua and maternal spiral arterioles. Immunohistochemical staining detected LAIR2 expression on a subset of EVT within the implantation site. This trophoblast included the invasive EVT infiltrating the maternal decidual vessels and the EVT forming the endovascular trophoblastic plugs. More specifically, LAIR2-positive EVT showed a striking predilection for maternal decidual arterioles and the immediately surrounding decidua. Moreover, the appearance of EVT expressing LAIR2 in these areas was contemporaneous with the process of spiral arteriole remodeling. Based on these findings, we suggest that LAIR2-expressing EVT may play an important role in the remodeling of maternal spiral arterioles.
[Show abstract][Hide abstract] ABSTRACT: Preeclampsia is a common and potentially lethal pregnancy disorder with lifelong increased risk of cardiovascular disease in survivors. Our prior global gene expression microarray analysis led to a novel set of 36 candidates in first trimester placentas of women who subsequently developed preeclampsia. In this report, we present preliminary studies demonstrating biomarkers of genotype and methylation variations in a subset of these candidate genes in maternal leukocyte and fetoplacental DNA of 28 case and 27 control dyads. We tested 84 single nucleotide polymorphisms (SNPs) using MassArray iPLEX and 50 CpG sites using EpiTYPER assays. Promising prediction modeling was identified with 25 SNPs selected using Fisher's exact tests (p ≤ 0.05) and 20 CpG sites selected on fold change. Genotype Distribution Analysis identified SNP variations that differed between nine paired cases versus paired controls. The findings validate the examined candidate genes and support feasibility of methods for further biomarker development. The integrative approach that was implemented begins to translate the 36 candidates toward clinical utility as a screening modality for preeclampsia.
No preview · Article · Aug 2012 · Clinical and Translational Science
[Show abstract][Hide abstract] ABSTRACT: THE GENOMICS OF ENDOGLIN PATHWAY IN PREECLAMPSIA
Mandy J. Bell, PhD, RN
University of Pittsburgh, 2012
Preeclampsia is a pregnancy disorder that greatly impacts maternal and fetal/neonatal health and wellbeing. This case-control candidate gene association study investigated endoglin pathway genetic variation and its association with preeclampsia. Tagging single nucleotide polymorphisms (tSNPs) in ENG, TGFβ1, TGFβR1, ALK1, and TGFβR2 were genotyped with iPLEX® and TaqMan® in maternal/fetal dyads. The Prenatal Exposures and Preeclampsia Prevention study provided maternal DNA extracted from peripherally collected white blood cell pellets, along with umbilical cord serum we used for fetal DNA extraction. Data on 355 white (181 cases/174 controls) and 60 black (30 cases/30 controls) women matched on ancestry, age, and parity were analyzed. Separate subgroup allele/genotype/haplotype tests were conducted with Chi-square or Fisher’s exact tests. Binary logistic regression provided odds ratios for tSNPs with significant genotype tests. Analysis of maternal/fetal dyads was not conducted, because unlike the maternal samples, the fetal samples did not provide a quality template suitable for iPLEX® data collection. In white women, variation in ENG (rs11792480, rs10121110) and TGFβR2 (rs6550005) was associated with preeclampsia. Allelic frequency distributions in rs11792480, rs10121110, and rs6550005 were significantly different among cases and controls while genotype distributions of rs10121110 and rs6550005 were further associated with preeclampsia (p-values < .05). For rs10121110, women with the AA genotype were 2.290 times more likely to develop preeclampsia compared to the GG genotype (99% CI [1.022, 5.133], p = .008). ENG haplotype TACGA, which contains rs11792480 and rs10121110 risk alleles, was also over-represented in cases (p = .022). In black women, variation in TGFβ1 (rs4803455, rs4803457), TGFβR1 (rs10739778), and TGFβR2 (rs6550005, rs1346907, rs877572) was associated with preeclampsia. Allelic frequency distributions in rs10739778, rs6550005, rs1346907, and rs877572 were significantly different among cases and controls while genotype distributions of rs10739778, rs4803455, and rs4803457 were further associated with preeclampsia (p-values < .05). For rs4803457, women with the CT genotype were 7.437 more times likely to develop preeclampsia compared to the CC genotype (99% CI [1.192, 46.408], p = .005). These results demonstrate that variation in ENG pathway genes is associated with preeclampsia, with different genes from the same pathway contributing to preeclampsia in white compared to black women.
[Show abstract][Hide abstract] ABSTRACT: Preeclampsia is as a leading cause of maternal and perinatal morbidity and mortality. Prevention, early identification, and individualized treatments may become feasible if reliable early biomarkers can be developed. Towards a systems biology framework, this review synthesizes prior linkage studies and genome scans of preeclampsia with candidates identified in a global gene expression microarray analysis of chorionic villus sampling (CVS) specimens from women who subsequently developed preeclampsia. Nearly 40% of these CVS candidate genes occurred in previously identified susceptibility loci for preeclampsia. Integration of genetic epidemiologic and functional gene expression data could help to elucidate preeclampsia as a complex disease resulting from multiple maternal and fetal/placental factors that each contributes a greater or lesser effect. These loci and related candidate genes are set to substantially improve insights into the first trimester pathogenesis of this pregnancy disorder.
No preview · Article · Jun 2011 · Journal of Perinatal Medicine
[Show abstract][Hide abstract] ABSTRACT: High-fidelity simulators offer a teaching tool for nurse educators to provide lifelike simulated clinical experiences for baccalaureate nursing students. A group of faculty teaching a variety of clinical courses followed similar steps within frameworks of the American Association of Colleges of Nursing essentials and education theories to create case scenarios. The benefits of simulation experiences for students are discussed and a template for the nurse educator is provided to help develop simulations. This system is illustrated by an example from a high-risk antepartum obstetric scenario.
No preview · Article · Feb 2011 · Journal of professional nursing: official journal of the American Association of Colleges of Nursing
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: The goal of this study was to further validate eight candidate genes identified in a microarray analysis of first trimester placentas in preeclampsia.
Surplus chorionic villus sampling (CVS) specimens of 4 women subsequently diagnosed with preeclampsia (PE) and 8 control women (C) without preeclampsia analyzed previously by microarray and 24 independent additional control samples (AS) were submitted for confirmatory studies by quantitative real-time polymerase chain reaction (qRT-PCR).
Downregulation was significant in FSTL3 in PE as compared to C and AS (p = .04). PAEP was downregulated, but the difference was only significant between C and AS (p = .002) rather than between PE and either of the control groups. Expression levels for CFH, EPAS1, IGFBP1, MMP12, and SEMA3C were not statistically different among groups, but trends were consistent with microarray results; there was no anti-correlation. S100A8 was not measurable in all samples, probably because different probes and primers were needed.
This study corroborates reduced FSTL3 expression in the first trimester of preeclampsia. Nonsignificant trends in the other genes may require follow-up in studies powered for medium or medium/large effect sizes. qRT-PCR verification of the prior microarray of CVS may support the placental origins of preeclampsia hypothesis. Replication is needed for the candidate genes as potential biomarkers of susceptibility, early detection, and/or individualized care of maternal-infant preeclampsia.
Full-text · Article · Nov 2010 · Biological Research for Nursing
[Show abstract][Hide abstract] ABSTRACT: A global gene expression microarray analysis of surplus chorionic villus sampling (CVS) tissues identified leukocyte-associated immunoglobulin-like receptor 2 (LAIR2) as down-regulated in the first trimester of pregnancies destined for preeclampsia. Neither the localization nor the function of LAIR2 has been examined in the placenta. Localization studies were conducted in placental tissues to determine the precise sites of LAIR2 mRNA production and protein binding.
Quantitative real time polymerase chain reaction (qRT-PCR) indicated LAIR2 expression in CVS, but none in breast, lymph node, kidney, skin, uterus, or third trimester placentas. In situ hybridization (ISH) revealed a highly restricted LAIR2 localization. LAIR2 mRNA was found only in the more distal portions of trophoblast anchoring cell columns, adjacent to the invading extravillous trophoblast (EVT). Immunohistochemistry (IHC) detected intracellular LAIR2 staining in these same cells. Extracellular staining of this soluble receptor was found in the acellular material between invasive EVT cells distal to the anchoring cell columns.
ISH and IHC staining for LAIR2 detected specific, highly localized expression at the leading edge of EVT anchoring cell columns in first trimester placentas. This staining likely identifies the site of production for this soluble receptor. Following secretion, the receptor appears to bind extracellular material among the invasive EVT. The precise restriction of this protein only to the sites of EVT invasion strongly suggests that it functions to regulate this invasion. The decreased LAIR2 expression noted in first trimester placentas that ultimately developed preeclampsia further suggests that alterations in LAIR2 may play an etiologic role in preeclampsia.
[Show abstract][Hide abstract] ABSTRACT: This article reports on a workshop conducted for the purpose of teaching culturally competent communication through the use of high fidelity patient simulation (HFPS). The workshop was held at the 9th International Meeting on Simulation in Healthcare, organized by the Society for Simulation in Healthcare and held at Lake Buena Vista, Florida, in January 2009. The objective of the workshop was to stimulate discussion among health care educators about state-of-the-art methods of incorporating cultural awareness and sensitivity into communication skill development through the use of HFPS scenarios. Introductory background and significance information, workshop materials, interactions from the workshop groups, and a summary of the themes that emerged from the workshop experience are presented.
No preview · Article · Sep 2010 · Clinical Simulation in Nursing
[Show abstract][Hide abstract] ABSTRACT: To examine whether high insulin resistance versus high inflammation identifies subtypes of preeclampsia.
A cytokine panel, glucose and insulin were measured in 37 preeclampsia plasma samples. Wilcoxon rank sum assessed median concentration of HOMA(IR) by pro-inflammatory:anti-inflammatory ratio. Regression stratifying by BMI and preterm birth was conducted.
There was no difference in median HOMA(IR) by the pro-inflammatory:anti-inflammatory ratio (p = 0.16). No subsets scatterplot clusters emerged. A positive correlation between HOMAlog and the ratio was significant (p = 0.04).
No dichotomous subsets of preeclampsia by inflammation versus insulin resistance were detected. Contrary to our hypothesis, insulin resistance was higher as inflammation increased in preeclampsia.
Full-text · Article · May 2010 · Hypertension in Pregnancy
[Show abstract][Hide abstract] ABSTRACT: Systems biology expands on general systems theory as the "omics'' era rapidly progresses. Although systems biology has been institutionalized as an interdisciplinary framework in the biosciences, it is not yet apparent in nursing. This article introduces systems biology for nursing science by presenting an overview of the theory. This framework for the study of organisms from molecular to environmental levels includes iterations of computational modeling, experimentation, and theory building. Synthesis of complex biological processes as whole systems rather than isolated parts is emphasized. Pros and cons of systems biology are discussed, and relevance of systems biology to nursing is described. Nursing research involving molecular, physiological, or biobehavioral questions may be guided by and contribute to the developing science of systems biology. Nurse scientists can proactively incorporate systems biology into their investigations as a framework for advancing the interdisciplinary science of human health care. Systems biology has the potential to advance the research and practice goals of the National Institute for Nursing Research in the National Institutes of Health Roadmap initiative.
No preview · Article · Mar 2009 · Biological Research for Nursing
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.