Fetal ERAP2 variation is associated with preeclampsia in African Americans in a case-control study

<p>Abstract</p> <p>Background</p> <p>Preeclampsia affects 3-8% of pregnancies and is a major cause of maternal and perinatal morbidity and mortality worldwide. This complex disorder is characterized by alterations in the immune and vascular systems and involves multiple organs. There is strong evidence for a genetic contribution to preeclampsia. Two different single nucleotide polymorphisms (SNPs) in the <it>endoplasmic reticulum aminopeptidase 2 (ERAP2) </it>gene were recently reported to be associated with increased risk for preeclampsia in two different populations. <it>ERAP2 </it>is expressed in placental tissue and it is involved in immune responses, inflammation, and blood pressure regulation; making it is an attractive preeclampsia candidate gene. Furthermore, <it>ERAP2 </it>expression is altered in first trimester placentas of women destined to develop preeclampsia.</p> <p>Methods</p> <p>A case-control design was used to test for associations between two SNPs in <it>ERAP2</it>, rs2549782 and rs17408150, and preeclampsia status in 1103 Chilean maternal-fetal dyads and 1637 unpaired African American samples (836 maternal, 837 fetal).</p> <p>Results</p> <p>We found that the fetal minor allele (G) of rs2549782 was associated with an increased risk for preeclampsia in the African American population (<it>P </it>= 0.009), but not in the Chilean population. We found no association between rs17408150 and risk for preeclampsia in the Chilean population. Association between rs17408150 and risk for preeclampsia was not tested in the African American population due to the absence of the minor allele in this population.</p> <p>Conclusions</p> <p>We report an association between fetal <it>ERAP2 </it>and preeclampsia in an African American population. In conjunction with previous studies, which have found maternal associations with this gene in an Australian/New Zealand population and a Norwegian population, <it>ERAP2 </it>has now been associated with preeclampsia in three populations. This provides strong evidence that <it>ERAP2 </it>plays a role in the development of preeclampsia.</p

Nuclear factor-kappa B localization and function within intrauterine tissues from term and preterm labor and cultured fetal membranes

Abstract Background The objective of this study was to quantify the nuclear localization and DNA binding activity of p65, the major transactivating nuclear factor-kappa B (NF-kappaB) subunit, in full-thickness fetal membranes (FM) and myometrium in the absence or presence of term or preterm labor. Methods Paired full-thickness FM and myometrial samples were collected from women in the following cohorts: preterm no labor (PNL, N = 22), spontaneous preterm labor (PTL, N = 21), term no labor (TNL, N = 23), and spontaneous term labor (STL, N = 21). NF-kappaB p65 localization was assessed by immunohistochemistry, and DNA binding activity was evaluated using an enzyme-linked immunosorbent assay (ELISA)-based method. Results Nuclear p65 labeling was rare in amnion and chorion, irrespective of clinical context. In decidua, nuclear p65 labeling was greater in the STL group relative to the TNL cohort, but there were no differences among the TNL, PTL, and PNL cohorts. In myometrium, diffuse p65 nuclear labeling was significantly associated with both term and preterm labor. There were no significant differences in ELISA-based p65 binding activity in amnion, choriodecidual, and myometrial specimens in the absence or presence of term labor. However, parallel experiments using cultured term fetal membranes demonstrated high levels of p65-like binding even the absence of cytokine stimulation, suggesting that this assay may be of limited value when applied to tissue specimens. Conclusions These results suggest that the decidua is an important site of NF-kappaB regulation in fetal membranes, and that mechanisms other than cytoplasmic sequestration may limit NF-kappaB activation prior to term

Epistasis between COMT and MTHFR in Maternal-Fetal Dyads Increases Risk for Preeclampsia

Preeclampsia is a leading cause of perinatal morbidity and mortality. This disorder is thought to be multifactorial in origin, with multiple genes, environmental and social factors, contributing to disease. One proposed mechanism is placental hypoxia-driven imbalances in angiogenic and anti-angiogenic factors, causing endothelial cell dysfunction. Catechol-O-methyltransferase (Comt)-deficient pregnant mice have a preeclampsia phenotype that is reversed by exogenous 2-methoxyestradiol (2-ME), an estrogen metabolite generated by COMT. 2-ME inhibits Hypoxia Inducible Factor 1α, a transcription factor mediating hypoxic responses. COMT has been shown to interact with methylenetetrahydrofolate reductase (MTHFR), which modulates the availability of S-adenosylmethionine (SAM), a COMT cofactor. Variations in MTHFR have been associated with preeclampsia. By accounting for allelic variation in both genes, the role of COMT has been clarified. COMT allelic variation is linked to enzyme activity and four single nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4680, and rs4818) form haplotypes that characterize COMT activity. We tested for association between COMT haplotypes and the MTHFR 677 C→T polymorphism and preeclampsia risk in 1103 Chilean maternal-fetal dyads. The maternal ACCG COMT haplotype was associated with reduced risk for preeclampsia (P = 0.004), and that risk increased linearly from low to high activity haplotypes (P = 0.003). In fetal samples, we found that the fetal ATCA COMT haplotype and the fetal MTHFR minor “T” allele interact to increase preeclampsia risk (p = 0.022). We found a higher than expected number of patients with preeclampsia with both the fetal risk alleles alone (P = 0.052) and the fetal risk alleles in combination with a maternal balancing allele (P<0.001). This non-random distribution was not observed in controls (P = 0.341 and P = 0.219, respectively). Our findings demonstrate a role for both maternal and fetal COMT in preeclampsia and highlight the importance of including allelic variation in MTHFR

Consenso salud materna para Chile en el nuevo milenio

Contexto: Chile presenta una tendencia secular hacia una sostenida mejoría en los principales indicadores materno-infantiles. Su situación constituye una experiencia positiva a nivel de la región de Latino-América y el Caribe. Sin embargo, esta tendencia se ha estancado en los últimos diez años lo que produce una situación inestable y preocupante desde el punto de vista de la salud pública materna. Esto motiva una reunión de expertos a nivel nacional e internacional para proponer estrategias para el alto nivel político orientadas a alcanzar los Objetivos 4 y 5 del Milenio. Conclusión: Este documento de consenso sobre mortalidad materna, sugiere un enfrentamiento en dos ejes: primero, enfrentar la nueva realidad epidemiológica desde la etapa pre-concepcional, esto incluye considerar la alta prevalencia de obesidad, hipertensión arterial, diabetes, hiperlipidemias e hipotiroidismo en la población, y por otro lado reforzar la seguridad de la asistencia del embarazo, parto y puerperio en los lugares más alejados y más vulnerables del país. Es necesario focalizar las intervenciones en los grupos de mayor riesgo vital (edades extremas de la vida fértil y portadoras de enfermedades médico-quirúrgicas severas, que se reflejan en el aumento proporcional de las causas indirectas de muerte materna), reforzar las actividades de auditorías de mortalidad/near miss, así como controlar el aumento alarmante de la tasa de partos por cesáreas

Microbial Prevalence, Diversity and Abundance in Amniotic Fluid During Preterm Labor: A Molecular and Culture-Based Investigation

BACKGROUND: Preterm delivery causes substantial neonatal mortality and morbidity. Unrecognized intra-amniotic infections caused by cultivation-resistant microbes may play a role. Molecular methods can detect, characterize and quantify microbes independently of traditional culture techniques. However, molecular studies that define the diversity and abundance of microbes invading the amniotic cavity, and evaluate their clinical significance within a causal framework, are lacking. METHODS AND FINDINGS: In parallel with culture, we used broad-range end-point and real-time PCR assays to amplify, identify and quantify ribosomal DNA (rDNA) of bacteria, fungi and archaea from amniotic fluid of 166 women in preterm labor with intact membranes. We sequenced up to 24 rRNA clones per positive specimen and assigned taxonomic designations to approximately the species level. Microbial prevalence, diversity and abundance were correlated with host inflammation and with gestational and neonatal outcomes. Study subjects who delivered at term served as controls. The combined use of molecular and culture methods revealed a greater prevalence (15% of subjects) and diversity (18 taxa) of microbes in amniotic fluid than did culture alone (9.6% of subjects; 11 taxa). The taxa detected only by PCR included a related group of fastidious bacteria, comprised of Sneathia sanguinegens, Leptotrichia amnionii and an unassigned, uncultivated, and previously-uncharacterized bacterium; one or more members of this group were detected in 25% of positive specimens. A positive PCR was associated with histologic chorioamnionitis (adjusted odds ratio [OR] 20; 95% CI, 2.4 to 172), and funisitis (adjusted OR 18; 95% CI, 3.1 to 99). The positive predictive value of PCR for preterm delivery was 100 percent. A temporal association between a positive PCR and delivery was supported by a shortened amniocentesis-to-delivery interval (adjusted hazard ratio 4.6; 95% CI, 2.2 to 9.5). A dose-response association was demonstrated between bacterial rDNA abundance and gestational age at delivery (r(2) = 0.42; P<0.002). CONCLUSIONS: The amniotic cavity of women in preterm labor harbors DNA from a greater diversity of microbes than previously suspected, including as-yet uncultivated, previously-uncharacterized taxa. The strength, temporality and gradient with which these microbial sequence types are associated with preterm delivery support a causal relationship

A Signature of Maternal Anti-Fetal Rejection in Spontaneous Preterm Birth: Chronic Chorioamnionitis, Anti-Human Leukocyte Antigen Antibodies, and C4d

Chronic chorioamnionitis is found in more than one-third of spontaneous preterm births. Chronic chorioamnionitis and villitis of unknown etiology represent maternal anti-fetal cellular rejection. Antibody-mediated rejection is another type of transplantation rejection. We investigated whether there was evidence for antibody-mediated rejection against the fetus in spontaneous preterm birth.This cross-sectional study included women with (1) normal pregnancy and term delivery (n = 140) and (2) spontaneous preterm delivery (n = 140). We analyzed maternal and fetal sera for panel-reactive anti-HLA class I and class II antibodies, and determined C4d deposition on umbilical vein endothelium by immunohistochemistry. Maternal anti-HLA class I seropositivity in spontaneous preterm births was higher than in normal term births (48.6% vs. 32.1%, p = 0.005). Chronic chorioamnionitis was associated with a higher maternal anti-HLA class I seropositivity (p<0.01), significant in preterm and term birth. Villitis of unknown etiology was associated with increased maternal and fetal anti-HLA class I and II seropositivity (p<0.05, for each). Fetal anti-HLA seropositivity was closely related to maternal anti-HLA seropositivity in both groups (p<0.01, for each). C4d deposition on umbilical vein endothelium was more frequent in preterm labor than term labor (77.1% vs. 11.4%, p<0.001). Logistic regression analysis revealed that chronic chorioamnionitis (OR = 6.10, 95% CI 1.29–28.83), maternal anti-HLA class I seropositivity (OR = 5.90, 95% CI 1.60–21.83), and C4d deposition on umbilical vein endothelium (OR = 36.19, 95% CI 11.42–114.66) were associated with preterm labor and delivery.A major subset of spontaneous preterm births has a signature of maternal anti-fetal cellular and antibody-mediated rejections with links to fetal graft-versus-host disease and alloimmune reactions

Urgencias en obstetricia

Tradicionalmente, el embarazo es considerado un evento fisiológico. Sin embargo, cerca de un 20% de las embarazadas desarrolla patologías obstétricas que se asocian a mortalidad materna y perinatal. A nivel mundial, cada año medio millón de mujeres fallece durante el embarazo y parto debido a estas complicaciones. Desafortunadamente, un número significativo de las urgencias obstétricas ocurre en pacientes sin factores de riesgo, por lo que la prevención, identificación precoz e intervención a tiempo de estos eventos juegan un rol fundamental para contrarrestar un resultado perinatal adverso. En el presente capítulo hemos seleccionado las emergencias que concentran la mayor morbimortalidad de nuestra especialidad. Si bien algunas han quedado fuera, creemos que los temas aquí presentados representan las urgencias obstétricas más importantes que enfrentamos a diario, para las cuales debemos estar preparados con el fin de realizar un manejo óptimo del embarazo y parto para la obtención de un resultado perinatal favorable

Periodontitis and placental growth factor in oral fluids are early pregnancy predictors of gestational diabetes mellitus

Gestational Diabetes Mellitus (GDM) affects around 7-10% of all pregnancies. Early detection of predisposition to GDM is the first step in developing efficacious preventive treatment. The objective of the present study was to establish the utility of placental proteins presents in oral fluids (gingival crevicular fluid [GCF] and saliva), and periodontal disease status as early pregnancy predictors of GDM.A nested case control within a prospective cohort was conducted. Pregnant systemically healthy women, aged between 18 and 40 years at 11-14\ua0weeks gestation were included. Samples of oral fluids were collected and a complete maternal/obstetric and periodontal history was obtained. The concentration of Placental Growth Factor (PlGF) and soluble Fms-like tyrosine kinase 1 (sFlt-1) were measured by ELISA assay in a nested case control sample of the prospective cohort. Multiple logistic regression models assessed the association. The evaluation of the diagnostic accuracy of the biomarkers was performed through ROC curves by calculating the area under the curve (AUC).There were recruited 212 pregnant women at 11-14\ua0weeks of pregnancy, of these, 14 women (i.e. 6.6%) developed GDM, and displayed significant greater bleeding on probing (BOP) [p\ua0=\ua00.0003]; periodontal probing depth (PPD) [p\ua0=\ua00.0028]; clinical attachment level (CAL) [p\ua0=\ua00.0008] and periodontal inflamed surface area (PISA) [p\ua0=\ua00.0001]. Similarly, initial glycaemia and GCF-PlGF concentrations were significantly greater in women with GDM [p\ua0=\ua00.0012, and p\ua0=\ua00.0019, respectively]. When data were subjected to ROC curve analysis, the combination of initial glycaemia and GCF-PlGF concentration delivered an area under the ROC curve of 0.897. Multiple logistic regression analyses demonstrate an association between glycaemia [OR 1.21, 95% CI 1.06-1.38; p\ua0=\ua00.005] and GCF-PlGF concentrations in women who developed GDM [OR 1.68, CI 1.05-2.68 p\ua0=\ua00.03].Within the limitations of the present study, the results support that first trimester maternal glycaemia combined with GCF-PlGF concentrations could be a surrogate biomarker for the future development of GDM in pre-symptomatic women. This article is protected by copyright. All rights reserved