title: ACVR2A promoter polymorphism rs1424954 in the Activin-A signaling pathway in trophoblasts.
abstract: BACKGROUND
  Pre-eclampsia is a pregnancy-specific disorder and characterized by reduced trophoblast invasion and reduced spiral artery remodeling in the first trimester placenta. A polymorphism located in the promoter region of ACVR2A (rs1424954 (A > G)) has previously been shown to be significantly associated with pre-eclampsia.
  
  
  METHODS
  The effects of this variant on ACVR2A expression and its function in the Activin-A signaling pathway were studied by transfections in SGHPL-5 extravillous trophoblasts followed by qRT-PCR.
  
  
  RESULTS
  Here we show that the ACVR2A promoter susceptibility variant causes a downregulation of ACVR2A expression. We also provide evidence for transcription of a so-called PROMPT (PROMoter-uPstream-Transcript) in the opposite direction of ACVR2A, containing the polymorphism, and downregulated when the susceptibility allele is carried, which either shares the same promoter as ACVR2A or is a non-coding RNA that is able to enhance ACVR2A transcription. Furthermore, when the effect of the susceptibility variant is mimicked by knockdown of ACVR2A, physiologic concentrations of Activin-A cause a reduction in NODAL mRNA expression in the SGHPL-5 trophoblasts, indicative of a protective effect as reduction in NODAL expression is associated with an increase in trophoblast invasion. However, at pathologic levels of Activin-A, as found in pre-eclampsia, this effect is no longer seen, and we show this is potentially caused by a lack of downregulation of ACVR2B.
  
  
  CONCLUSIONS
  The combined data suggest a double hit phenomenon in which the first hit, the promoter variant, together with the second hit, pathological levels of Activin-A, lead to high levels of NODAL, associated with reduced trophoblast invasion and observed in pre-eclamptic placentas.
authors: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors: H K
authors: HK
authors: Thulluru
authors: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
authors: O J
authors: OJ
authors: Michel
authors: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors: C B M
authors: CB
authors: Oudejans
authors: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands; Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: m.vdijk@vumc.nl.
authors: M
authors: M
authors: van Dijk
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D028341:Activins / Q000378:metabolism*; D000483:Alleles; D002460:Cell Line; D015536:Down-Regulation; D005091:Exons; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D055457:Nodal Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: C526007:NODAL protein, human; D055457:Nodal Protein; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C422405:activin A; D028341:Activins; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A
keywords: ACVR2A; ACVR2B; Activin-A; Nodal; Pre-eclampsia; Trophoblast