Tiensuu H, Haapalainen AM, Karjalainen MK, Pasanen A, Huusko JM, Marttila R, et al. (2019) Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2. PLoS Genet 15(6): e1008107. https://doi.org/10.1371/journal.pgen.1008107
Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2
|Author:||Tiensuu, Heli1; Haapalainen, Antti M.1; Karjalainen, Minna K.1;|
1PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
2Division 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 States of America
3Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
|Online Access:||PDF Full Text (PDF, 2.1 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2020041618892
Public Library of Science,
|Publish Date:|| 2020-04-16
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.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
3123 Gynaecology and paediatrics
This work was supported by the Jane and Aatos Erkko Foundation (MH and MR), Sigrid Jusélius Foundation (MH) and Competitive State Research Financing of the Expert Responsibility Area of Oulu University Hospital (MR), March of Dimes Prematurity Research Center Ohio Collaborative, March of Dimes, URL:http://www.marchofdimes.org/, the Bill and Melinda Gates Foundation, URL:http://www.gatesfoundation.org (OPP1113966, LJM) and NIH/The Eunice Kennedy Shriver National Institute of Child Health and Human Development, URL:https://www.nichd.nih.gov/ (HD091527, LJM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
© 2019 Tiensuu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.