title: Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and β-cell apoptosis.
abstract: Genome-wide association studies (GWAS) have identified more than 50 loci associated with genetic risk of type 1 diabetes (T1D). Several T1D candidate genes have been suggested or identified within these regions, but the molecular mechanisms by which they contribute to insulitis and β-cell destruction remain to be clarified. More than 60% of the T1D candidate genes are expressed in human pancreatic islets, suggesting that they contribute to T1D by regulating at least in part pathogenic mechanisms at the β-cell level. Recent studies by our group indicate that important genetically regulated pathways in β-cells include innate immunity and antiviral activity, involving RIG-like receptors (particularly MDA5) and regulators of type I IFNs (i.e. PTPN2 and USP18), and genes related to β-cell phenotype and susceptibility to pro-apoptotic stimuli (i.e. GLIS3). These observations reinforce the concept that the early pathogenesis of T1D is characterized by a dialogue between the immune system and pancreatic β-cells. This dialogue is probably influenced by polymorphisms in genes expressed at the β-cell and/or immune system level, leading to inadequate responses to environmental cues such as viral infections. Further studies are needed to clarify how these disease-associated variants affect pancreatic β-cell responses to inflammation and the subsequent triggering of autoimmune responses and progressive β-cell loss.
authors.affiliation: Laboratory of Experimental Medicine, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium. izortze.santin@gmail.com
authors.forename: I
authors.initials: I
authors.lastname: Santin
authors.forename: D L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D015551:Autoimmunity / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
keywords: apoptosis; candidate genes; cytokines; inflammation; pancreatic β-cells; type 1 diabetes