RESUMEN
Preterm labor (PTL) and preterm premature rupture of membranes (PPROM) lead to high perinatal morbidity/mortality rates worldwide. Small extracellular vesicles (sEV) act in cell communication and contain microRNAs that may contribute to the pathogenesis of these complications. We aimed to compare the expression, in sEV from peripheral blood, of miRNAs between term and preterm pregnancies. This cross-sectional study included women who underwent PTL, PPROM, and term pregnancies, examined at the Botucatu Medical School Hospital, SP, Brazil. sEV were isolated from plasma. Western blot used to detect exosomal protein CD63 and nanoparticle tracking analysis were performed. The expression of 800 miRNAs was assessed by the nCounter Humanv3 miRNA Assay (NanoString). The miRNA expression and relative risk were determined. Samples from 31 women-15 preterm and 16 term-were included. miR-612 expression was increased in the preterm groups. miR-612 has been shown to increase apoptosis in tumor cells and to regulate the nuclear factor κB inflammatory pathway, processes involved in PTL/PPROM pathogenesis. miR-1253, miR-1283, miR378e, and miR-579-3p, all associated with cellular senescence, were downregulated in PPROM compared with term pregnancies. We conclude that miRNAs from circulating sEV are differentially expressed between term and preterm pregnancies and modulate genes in pathways that are relevant to PTL/PPROM pathogenesis.
Asunto(s)
Vesículas Extracelulares , Rotura Prematura de Membranas Fetales , MicroARNs , Trabajo de Parto Prematuro , Nacimiento Prematuro , Embarazo , Humanos , Femenino , Recién Nacido , Nacimiento Prematuro/genética , MicroARNs/genética , Estudios Transversales , Rotura Prematura de Membranas Fetales/genética , Trabajo de Parto Prematuro/genética , Trabajo de Parto Prematuro/metabolismo , Vesículas Extracelulares/metabolismoRESUMEN
BACKGROUND: A genetic predisposition to Preterm Labor (PTL) and Preterm Premature Rupture of Membranes (PPROM) has been suggested; however the relevance of polymorphisms and ancestry to susceptibility to PTL and PPROM in different populations remains unclear. The aim of this study was to evaluate the contribution of maternal and fetal SNPs in the IL1B, IL6, IL6R, TNFA, TNFR, IL10, TLR2, TLR4, MMP9, TIMP1 and TIMP2 genes and the influence of ancestry background in the susceptibility to PTL or PPROM in Brazilian women. METHODS: Case-control study conducted at a tertiary hospital in São Paulo State, Brazil. We included women with PTL or PPROM and their babies (PTL: 136 women and 88 babies; PPROM: 65 women and 44 babies). Control group included 402 mother-babies pairs of term deliveries. Oral swabs were collected for identification of AIMs by fragment analysis and SNPs by Taqman® SNP Genotyping Assays and PCR. Linkage Disequilibrium and Hardy-Weinberg proportions were evaluated using Genepop 3.4. Haplotypes were inferred using the PHASE algorithm. Allele, genotype and haplotype frequencies were compared by Fisher's exact test or χ (2) and Odds Ratio. Logistic regression was performed. Clinical and sociodemographic data were analyzed by Fisher's exact test and Mann-Whitney. RESULTS: PTL was associated with European ancestry and smoking while African ancestry was protective. The fetal alleles IL10-592C (rs800872) and IL10-819C (rs1800871) were also associated with PTL and the maternal haplotype TNFA-308G-238A was protective. Maternal presence of IL10-1082G (rs1800896) and TLR2A (rs4696480) alleles increased the risk for PPROM while TNFA-238A (rs361525) was protective. Family history of PTL/PPROM was higher in cases, and time to delivery was influenced by IL1B-31T (rs1143627) and TLR4-299G (rs4986790). CONCLUSION: There is an association between European ancestry and smoking and PTL in our Brazilian population sample. The presence of maternal or fetal alleles that modify the inflammatory response increase the susceptibility to PTL and PPROM. The family history of PTL/PPROM reinforces a role for genetic polymorphisms in susceptibility to these outcomes.
Asunto(s)
Citocinas/genética , Rotura Prematura de Membranas Fetales/genética , Trabajo de Parto Prematuro/genética , Linaje , Polimorfismo de Nucleótido Simple , Adulto , Alelos , Población Negra/genética , Brasil , Estudios de Casos y Controles , Femenino , Marcadores Genéticos , Haplotipos , Humanos , Recién Nacido , Interleucina-10/genética , Embarazo , Fumar/efectos adversos , Receptor Toll-Like 2/genética , Factor de Necrosis Tumoral alfa/genética , Población Blanca/genética , Adulto JovenRESUMEN
OBJECTIVE: The purpose of this study was to determine whether maternal/fetal single nucleotide polymorphisms (SNPs) in candidate genes are associated with spontaneous preterm labor/delivery. STUDY DESIGN: A genetic association study was conducted in 223 mothers and 179 fetuses (preterm labor with intact membranes who delivered <37 weeks of gestation [preterm birth (PTB)]), and 599 mothers and 628 fetuses (normal pregnancy); 190 candidate genes and 775 SNPs were studied. Single locus/haplotype association analyses were performed; the false discovery rate was used to correct for multiple testing. RESULTS: The strongest single locus associations with PTB were interleukin-6 receptor 1 (fetus; P=.000148) and tissue inhibitor of metalloproteinase 2 (mother; P=.000197), which remained significant after correction for multiple comparisons. Global haplotype analysis indicated an association between a fetal DNA variant in insulin-like growth factor F2 and maternal alpha 3 type IV collagen isoform 1 (global, P=.004 and .007, respectively). CONCLUSION: An SNP involved in controlling fetal inflammation (interleukin-6 receptor 1) and DNA variants in maternal genes encoding for proteins involved in extracellular matrix metabolism approximately doubled the risk of PTB.
Asunto(s)
Estudios de Asociación Genética , Trabajo de Parto Prematuro/genética , Polimorfismo de Nucleótido Simple , Receptores de Interleucina-6/genética , Adulto , Estudios de Casos y Controles , Chile , Corioamnionitis/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Femenino , Rotura Prematura de Membranas Fetales/genética , Predisposición Genética a la Enfermedad , Variación Genética , Haplotipos , Humanos , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional/fisiología , Preeclampsia/genética , Embarazo , Nacimiento Prematuro/genética , Adulto JovenRESUMEN
Preterm birth (PTB) is a worldwide health problem and remains the leading cause of perinatal morbidity and mortality. Systemic and local intrauterine infections have been implicated in the pathogenesis of preterm labor and delivery. Common pathways between PTB, premature rupture of ovular membranes (PROM) and altered molecular routes of inflammation have been proposed. There is evidence to support a genetic component in these conditions. Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, is thought to play a key role in eliciting an inflammatory response. LPS is recognized by proteins of the innate immune system, including Toll-like receptor 4 (TLR4). Individuals from some European countries carrying the variant alleles resulting in an amino acid substitution (Asp299Gly) are at increased risk of Gram-negative infections and premature birth. The objective of this study was to determine if preterm newborns have different allele frequency of the Asp299Gly TLR4 variant from healthy term neonates in Uruguay. The impact of PROM was also examined. There was an increase in the risk for fetuses carrying the Asp299Gly substitution in TLR4 of being severely premature (<33 weeks) and to present PROM at the same time.
Asunto(s)
Rotura Prematura de Membranas Fetales/genética , Polimorfismo Genético , Nacimiento Prematuro/genética , Receptor Toll-Like 4/genética , Adulto , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Recién Nacido , Modelos Logísticos , Embarazo , UruguayRESUMEN
Se ha demostrado una importante asociación entre U. urealyticum y enfermedades materno-infantiles tales como rotura prematura de membranas, parto prematuro y enfermedad respiratoria en niños de muy bajo peso. Debido a que el cultivo de este microorganismo es un procedimiento costoso que requiere de hasta 5 días para descartar una muestra como negativa, se evaluó la sensibilidad y especificidad de la RPC para detectar U. urealyticum en líquido anmiótico. Los resultados indican que la RPC posee alta especificidad (100 por ciento) y sensibilidad (95,8 por ciento). Aunque se requiere de mayor evaluación clínica, este método rápido de detección de la bacteria (menos de 24 horas) es de particular importancia en el manejo y prevención de la morbimortalidad en recién nacidos y embarazadas