title: Susceptibility allele-specific loss of miR-1324-mediated silencing of the INO80B chromatin-assembly complex gene in pre-eclampsia.
abstract: In humans, the elucidation of the genetics underlying multifactorial diseases such as pre-eclampsia remains complex. Given the current day availability of genome-wide linkage- and expression data pools, we applied pathway-guided genome-wide meta-analysis guided by the premise that the functional network underlying these multifactorial syndromes is under selective genetic pressure. This approach drastically reduced the genomic region of interest, i.e. 2p13 linked with pre-eclampsia in Icelandic families, from 8 679 641 bp (region with linkage) to 45 264 bp (coding exons of prioritized genes) (0.83%). Mutation screening of the candidate genes (n = 13) rapidly reduced the minimal critical region and showed the INO80B gene, encoding a novel winged helix domain (pfam14465) and part of the chromatin-remodeling complex, to be linked to pre-eclampsia. The functional defect in placental cells involved a susceptibility allele-dependent loss-of-gene silencing due to increased INO80B RNA stability as a consequence of differential binding of miR-1324 to the susceptibility allele of rs34174194. This risk allele is located at position 1 in an absolutely conserved 7-mer (UUGUCUG) in the 3-UTR of INO80B immediately downstream of a variant Pumillio Recognition Element (UGUANAAG). These data support that pre-eclampsia genes affect a conserved fundamental mechanism that evolved as a consequence of hemochorial placentation. Functionally, this involves founder-dependent, placentally expressed paralogous genes that regulate an essential trophoblast differentiation pathway but act at different entry points.
authors.affiliation: Department of Clinical Chemistry Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands cbm.oudejans@vumc.nl.
authors.forename: Cees B M
authors.initials: CB
authors.lastname: Oudejans
authors.affiliation: Department of Clinical Chemistry.
authors.forename: Omar J
authors.initials: OJ
authors.lastname: Michel
authors.affiliation: Department of Physiology Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Janssen
authors.affiliation: Department of Clinical Chemistry.
authors.forename: Rob
authors.initials: R
authors.lastname: Habets
authors.affiliation: Department of Clinical Chemistry.
authors.forename: Ankie
authors.initials: A
authors.lastname: Poutsma
authors.affiliation: Department of Clinical Genetics and.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Sistermans
authors.affiliation: Department of Clinical Genetics and.
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Weiss
authors.affiliation: Human Genetics Foundation (HuGeF), Via Nizza 52, 10126 Torino, Italy Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Danny
authors.initials: D
authors.lastname: Incarnato
authors.affiliation: Human Genetics Foundation (HuGeF), Via Nizza 52, 10126 Torino, Italy Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oliviero
authors.affiliation: Department of Gynecology, Flevo Hospital, Hospitaalweg 1, 1315 RA Almere, The Netherlands and.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Kleiverda
authors.affiliation: Department of Clinical Chemistry Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Marie
authors.initials: M
authors.lastname: Van Dijk
authors.affiliation: Biomedical Center, University of Iceland, Vatnsmýrarvegi 16, 101 Reykjavík, Iceland.
authors.forename: Reynir
authors.initials: R
authors.lastname: Arngrímsson
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007055:Iceland; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010920:Placenta / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy
chemical_list: D018797:Cell Cycle Proteins; C494434:INO80B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; C106907:WBP1 protein, human