@article{b362a158d22942f2bc375659adf838a9,
title = "Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth",
abstract = "Background: Preterm birth is defined as live birth before 37 completed weeks of pregnancy, and it is a major problem worldwide. The molecular mechanisms that lead to onset of spontaneous preterm birth are incompletely understood. Prediction and evaluation of the risk of preterm birth is challenging as there is a lack of accurate biomarkers. In this study, our aim was to identify placental proteins that associate with spontaneous preterm birth. Methods: We analyzed the proteomes from placentas to identify proteins that associate with both gestational age and spontaneous labor. Next, rare and potentially damaging gene variants of the identified protein candidates were sought for from our whole exome sequencing data. Further experiments we performed on placental samples and placenta-associated cells to explore the location and function of the spontaneous preterm labor-associated proteins in placentas. Results: Exome sequencing data revealed rare damaging variants in SERPINA1 in families with recurrent spontaneous preterm deliveries. Protein and mRNA levels of alpha-1 antitrypsin/SERPINA1 from the maternal side of the placenta were downregulated in spontaneous preterm births. Alpha-1 antitrypsin was expressed by villous trophoblasts in the placenta, and immunoelectron microscopy showed localization in decidual fibrinoid deposits in association with specific extracellular proteins. siRNA knockdown in trophoblast-derived HTR8/SVneo cells revealed that SERPINA1 had a marked effect on regulation of the actin cytoskeleton pathway, Slit–Robo signaling, and extracellular matrix organization. Conclusions: Alpha-1 antitrypsin is a protease inhibitor. We propose that loss of the protease inhibition effects of alpha-1 antitrypsin renders structures critical to maintaining pregnancy susceptible to proteases and inflammatory activation. This may lead to spontaneous premature birth.",
keywords = "Alpha-1-antitrypsin, Placenta, Preterm birth, Proteomics, SERPINA1, Trophoblast, Whole exome sequencing",
author = "Heli Tiensuu and Haapalainen, {Antti M.} and Pinja Tissarinen and Anu Pasanen and M{\"a}{\"a}tt{\"a}, {Tomi A.} and Huusko, {Johanna M.} and Steffen Ohlmeier and Ulrich Bergmann and Marja Ojaniemi and Muglia, {Louis J.} and Mikko Hallman and Mika R{\"a}met",
note = "Funding Information: We express our sincere thanks to all the families that participated in this study. We would like to thank Maarit Haarala from University of Oulu for sample preparation and laboratory work. Sonja Eeli, Miia Lehto, and Riitta Vikev{\"a}inen from Oulu University Hospital are acknowledged for sample and data collection. The expertise of the Biocenter Oulu Electron Microscopy core facility, a member of Biocenter Finland, is gratefully acknowledged. We thank the Finnish Functional Genomics Centre (supported by University of Turku, {\AA}bo Akademi University, and Biocenter Finland) and the Medical Bioinformatics Centre of Turku Bioscience Centre for the sequencing data analysis. The Medical Bioinformatics Centre is supported by University of Turku, {\AA}bo Akademi University, Biocenter Finland, and Elixir-Finland. Funding Information: This study was supported by the grants from Jane and Aatos Erkko Foundation (MH, MR), Foundation for Pediatric Research (MR), the Sigrid Jus{\'e}lius Foundation (MH), Competitive State Research Financing of the Expert Responsibility Area of Oulu University Hospital (MR), and Stiftellsen Alma och K. A. Snellman foundation (HT, AMH). Funding Information: We express our sincere thanks to all the families that participated in this study. We would like to thank Maarit Haarala from University of Oulu for sample preparation and laboratory work. Sonja Eeli, Miia Lehto, and Riitta Vikev?inen from Oulu University Hospital are acknowledged for sample and data collection. The expertise of the Biocenter Oulu Electron Microscopy core facility, a member of Biocenter Finland, is gratefully acknowledged. We thank the Finnish Functional Genomics Centre (supported by University of Turku, ?bo Akademi University, and Biocenter Finland) and the Medical Bioinformatics Centre of Turku Bioscience Centre for the sequencing data analysis. The Medical Bioinformatics Centre is supported by University of Turku, ?bo Akademi University, Biocenter Finland, and Elixir-Finland. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = apr,
doi = "10.1186/s12916-022-02339-8",
language = "English",
volume = "20",
}