title: Role of DNA methylation at the placental RTL1 gene locus in type 1 diabetes.
abstract: Genome-wide association studies (GWAS) have identified more than 40 T1D loci associated with type 1 diabetes (T1D). How these polymorphisms interact with environmental factors to trigger T1D is unknown, but recent evidence suggests that epigenetic mechanisms could play a role. To begin to explore the contribution of epigenetics to T1D, we have examined DNA methylation in a pilot study of whole blood cells DNA from 10 young T1D patients and 10 young controls. Through the study of >900 000 CG loci across a diverse set of functionally relevant genomic regions using a custom DNA methylation array, we identified 250 T1D-differentially methylated region (DMR) at p < 0.05 and 1 DMR using next a permutation-based multiple testing correction method. This DMR is located in an imprinted region previously associated with T1D on the chromosome 14 that encompasses RTL1 gene and 2 miRNAs (miR136 and miR432). Using pyrosequencing-based bisulfite PCR, we replicated this association in a different and larger set of T1D patients and controls. DNA methylation at this DMR was inversely correlated with RTL1 gene expression and positively correlated with miR136 expression in human placentas. The DMR identified in this study presents suggestive evidence for altered methylation site in T1D and provide a promising new candidate gene. RTL1 is essential for placental permeability function in the mid-to-late fetal stages. We suggest that hypo-methylation could increase the fetal exposure to environmental factors in T1D susceptibility.
authors.affiliation: INSERM U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Belot
authors.affiliation: INSERM U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France.
authors.forename: Kambiz
authors.initials: K
authors.lastname: Nadéri
authors.affiliation: INSERM U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France.
authors.forename: Clémence
authors.initials: C
authors.lastname: Mille
authors.affiliation: Université Pierre et Marie Curie, Service de Biostatistique - INSERM U707, Paris, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Boëlle
authors.affiliation: Department of Obstetric and Gynecology, Antoine Béclère Hospital, Paris Sud University, Clamart, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Benachi
authors.affiliation: INSERM U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France.|Department of Pediatric Endocrinology, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bougnères
authors.affiliation: INSERM U1169, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Fradin
mesh_terms: D000328:Adult; D001773:Blood Cells / Q000378:metabolism; D002648:Child; D015331:Cohort Studies; D000073399:DNA Demethylation; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D010865:Pilot Projects; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D014015:Tissue Banks
chemical_list: C577037:MIRN136 microRNA, human; C582553:MIRN432 microRNA, human; D035683:MicroRNAs; D011257:Pregnancy Proteins; C579465:RTL1 protein, human
keywords: DNA methylation; RTL1; T1D; children; placenta