title: The role and interaction of imprinted genes in human fetal growth.
abstract: Identifying the genetic input for fetal growth will help to understand common, serious complications of pregnancy such as fetal growth restriction. Genomic imprinting is an epigenetic process that silences one parental allele, resulting in monoallelic expression. Imprinted genes are important in mammalian fetal growth and development. Evidence has emerged showing that genes that are paternally expressed promote fetal growth, whereas maternally expressed genes suppress growth. We have assessed whether the expression levels of key imprinted genes correlate with fetal growth parameters during pregnancy, either early in gestation, using chorionic villus samples (CVS), or in term placenta. We have found that the expression of paternally expressing insulin-like growth factor 2 (IGF2), its receptor IGF2R, and the IGF2/IGF1R ratio in CVS tissues significantly correlate with crown-rump length and birthweight, whereas term placenta expression shows no correlation. For the maternally expressing pleckstrin homology-like domain family A, member 2 (PHLDA2), there is no correlation early in pregnancy in CVS but a highly significant negative relationship in term placenta. Analysis of the control of imprinted expression of PHLDA2 gave rise to a maternally and compounded grand-maternally controlled genetic effect with a birthweight increase of 93/155 g, respectively, when one copy of the PHLDA2 promoter variant is inherited. Expression of the growth factor receptor-bound protein 10 (GRB10) in term placenta is significantly negatively correlated with head circumference. Analysis of the paternally expressing delta-like 1 homologue (DLK1) shows that the paternal transmission of type 1 diabetes protective G allele of rs941576 single nucleotide polymorphism (SNP) results in significantly reduced birth weight (-132 g). In conclusion, we have found that the expression of key imprinted genes show a strong correlation with fetal growth and that for both genetic and genomics data analyses, it is important not to overlook parent-of-origin effects.
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK gudrun.moore@ucl.ac.uk.
authors.forename: Gudrun E
authors.initials: GE
authors.lastname: Moore
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Miho
authors.initials: M
authors.lastname: Ishida
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Demetriou
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Lara
authors.initials: L
authors.lastname: Al-Olabi
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Lydia J
authors.initials: LJ
authors.lastname: Leon
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Thomas
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Sayeda
authors.initials: S
authors.lastname: Abu-Amero
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Frost
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Stafford
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chaoqun
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Duncan
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Baigel
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Marina
authors.initials: M
authors.lastname: Brimioulle
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Iglesias-Platas
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Sophia
authors.initials: S
authors.lastname: Apostolidou
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Reena
authors.initials: R
authors.lastname: Aggarwal
authors.affiliation: Noncommunicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, University of London, London WC1E 7HT, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Whittaker
authors.affiliation: Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London SE5 9RS, UK.
authors.forename: Argyro
authors.initials: A
authors.lastname: Syngelaki
authors.affiliation: Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London SE5 9RS, UK.
authors.forename: Kypros H
authors.initials: KH
authors.lastname: Nicolaides
authors.affiliation: Department of Obstetrics and Gynaecology, Imperial College London, St Mary's Campus, London W2 1NY, UK.
authors.forename: Lesley
authors.initials: L
authors.lastname: Regan
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: David
authors.initials: D
authors.lastname: Monk
authors.affiliation: Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Stanier
mesh_terms: D001724:Birth Weight / Q000502:physiology; D002135:Calcium-Binding Proteins; D002824:Chorionic Villi / Q000378:metabolism; D005260:Female; D047109:Fetal Development / Q000235:genetics* / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D017451:Receptors, Somatomedin / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; C035170:IGF2 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D017451:Receptors, Somatomedin; C109277:TSSC3 protein; D007335:Insulin-Like Growth Factor II
keywords: birth weight; chorionic villus sampling; fetal growth restriction; genomic imprinting; placenta; type 1 diabetes