Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and <i>β</i>‐cell apoptosis

<jats:p>Genome‐wide association studies (<jats:styled-content style="fixed-case">GWAS</jats:styled-content>) have identified more than 50 <jats:italic>loci</jats:italic> associated with genetic risk of type 1 diabetes (<jats:styled-content style="fixed-case">T1D</jats:styled-content>). Several <jats:styled-content style="fixed-case">T1D</jats:styled-content> 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 <jats:styled-content style="fixed-case">T1D</jats:styled-content> candidate genes are expressed in human pancreatic islets, suggesting that they contribute to <jats:styled-content style="fixed-case">T1D</jats:styled-content> 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 <jats:styled-content style="fixed-case">RIG</jats:styled-content>‐like receptors (particularly <jats:italic><jats:styled-content style="fixed-case">MDA5</jats:styled-content></jats:italic>) and regulators of type I <jats:styled-content style="fixed-case">IFNs</jats:styled-content> (i.e. <jats:italic><jats:styled-content style="fixed-case">PTPN2</jats:styled-content></jats:italic> and <jats:italic><jats:styled-content style="fixed-case">USP18</jats:styled-content></jats:italic>), and genes related to β‐cell phenotype and susceptibility to pro‐apoptotic stimuli (i.e. <jats:italic><jats:styled-content style="fixed-case">GLIS3</jats:styled-content></jats:italic>). These observations reinforce the concept that the early pathogenesis of <jats:styled-content style="fixed-case">T1D</jats:styled-content> 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.</jats:p>