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Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2.
Tiensuu, Heli; Haapalainen, Antti M; Karjalainen, Minna K; Pasanen, Anu; Huusko, Johanna M; Marttila, Riitta; Ojaniemi, Marja; Muglia, Louis J; Hallman, Mikko; Rämet, Mika.
Afiliação
  • Tiensuu H; PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
  • Haapalainen AM; PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
  • Karjalainen MK; PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
  • Pasanen A; PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
  • Huusko JM; PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
  • Marttila R; Division of Human Genetics, Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio, United Stat
  • Ojaniemi M; PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
  • Muglia LJ; PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
  • Hallman M; Division of Human Genetics, Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, Ohio, United Stat
  • Rämet M; PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
PLoS Genet ; 15(6): e1008107, 2019 06.
Article em En | MEDLINE | ID: mdl-31194736
Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal and fetal genetic factors likely contribute to SPTB. We performed a genome-wide association study (GWAS) on a population of Finnish origin that included 247 infants with SPTB (gestational age [GA] < 36 weeks) and 419 term controls (GA 38-41 weeks). The strongest signal came within the gene encoding slit guidance ligand 2 (SLIT2; rs116461311, minor allele frequency 0.05, p = 1.6×10-6). Pathway analysis revealed the top-ranking pathway was axon guidance, which includes SLIT2. In 172 very preterm-born infants (GA <32 weeks), rs116461311 was clearly overrepresented (odds ratio 4.06, p = 1.55×10-7). SLIT2 variants were associated with SPTB in another European population that comprised 260 very preterm infants and 9,630 controls. To gain functional insight, we used immunohistochemistry to visualize SLIT2 and its receptor ROBO1 in placentas from spontaneous preterm and term births. Both SLIT2 and ROBO1 were located in villous and decidual trophoblasts of embryonic origin. Based on qRT-PCR, the mRNA levels of SLIT2 and ROBO1 were higher in the basal plate of SPTB placentas compared to those from term or elective preterm deliveries. In addition, in spontaneous term and preterm births, placental SLIT2 expression was correlated with variations in fetal growth. Knockdown of ROBO1 in trophoblast-derived HTR8/SVneo cells by siRNA indicated that it regulate expression of several pregnancy-specific beta-1-glycoprotein (PSG) genes and genes involved in inflammation. Our results show that the fetal SLIT2 variant and both SLIT2 and ROBO1 expression in placenta and trophoblast cells may be correlated with susceptibility to SPTB. SLIT2-ROBO1 signaling was linked with regulation of genes involved in inflammation, PSG genes, decidualization and fetal growth. We propose that this receptor-ligand couple is a component of the signaling network that promotes SPTB.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores Imunológicos / Predisposição Genética para Doença / Peptídeos e Proteínas de Sinalização Intercelular / Nascimento Prematuro / Desenvolvimento Fetal / Proteínas do Tecido Nervoso Tipo de estudo: Etiology_studies / Risk_factors_studies Limite: Female / Humans / Pregnancy País/Região como assunto: Europa Idioma: En Revista: PLoS Genet Assunto da revista: GENETICA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Finlândia

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores Imunológicos / Predisposição Genética para Doença / Peptídeos e Proteínas de Sinalização Intercelular / Nascimento Prematuro / Desenvolvimento Fetal / Proteínas do Tecido Nervoso Tipo de estudo: Etiology_studies / Risk_factors_studies Limite: Female / Humans / Pregnancy País/Região como assunto: Europa Idioma: En Revista: PLoS Genet Assunto da revista: GENETICA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Finlândia