title: Post-transcriptional control of candidate risk genes for type 1 diabetes by rare genetic variants.
abstract: The genetic variation causal for predisposition to type 1 diabetes (T1D) remains unidentified for the majority of known T1D risk loci. MicroRNAs function as post-transcriptional gene regulators by targeting microRNA-binding sites in the 3' untranslated regions (UTR) of mRNA. Genetic variation within the 3'-UTR of T1D-associated genes may contribute to T1D development by altering microRNA-mediated gene regulation. In silico analysis of variable sites predicted altered microRNA binding in established T1D loci. Functional implications were assessed for variable sites in the 3'-UTR of T1D candidate risk genes CTLA4 and IL10, both involved in immune regulation. We confirmed that in these genes 3'-UTR variation either disrupted or introduced a microRNA-binding site, affecting the repressive capacity of miR-302a* and miR-523, respectively. Our study points to the potential of 3'-UTR variation to affect T1D pathogenesis by altering post-transcriptional gene regulation by microRNAs.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: V M
authors.initials: VM
authors.lastname: de Jong
authors.forename: A
authors.initials: A
authors.lastname: Zaldumbide
authors.forename: A R
authors.initials: AR
authors.lastname: van der Slik
authors.forename: S P
authors.initials: SP
authors.lastname: Persengiev
authors.forename: B O
authors.initials: BO
authors.lastname: Roep
authors.forename: B P C
authors.initials: BP
authors.lastname: Koeleman
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D001665:Binding Sites; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide
chemical_list: D020413:3' Untranslated Regions; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C508609:IL10 protein, human; C532169:MIRN302A microRNA, human; D035683:MicroRNAs; D016753:Interleukin-10