Candidate genes expressed in human islets and their role in the pathogenesis of type 1 diabetes.
In type 1 diabetes (T1D), the insulin-producing β cells are destroyed by an immune-mediated process leading to complete insulin deficiency. There is a strong genetic component in T1D. Genes located in the human leukocyte antigen (HLA) region are the most important genetic determinants of disease, but more than 40 additional loci are known to significantly affect T1D risk. Since most of the currently known genetic candidates have annotated immune cell functions, it is generally considered that most of the genetic susceptibility in T1D is caused by variation in genes affecting immune cell function. Recent studies, however, indicate that most T1D candidate genes are expressed in human islets suggesting that the functions of the genes are not restricted to immune cells, but also play roles in the islets and possibly the β cells. Several candidates change expression levels within the islets following exposure to proinflammatory cytokines highlighting that these genes may be involved in the response of β cells to immune attack. In this review, the compiling evidence that many of the candidate genes are expressed in islets and β cells will be presented. Further, we perform the first systematic human islet expression analysis of all genes located in 50 T1D-associated GWAS loci using a published RNA sequencing dataset. We find that 336 out of 857 genes are expressed in human islets and that many of these interact in protein networks. Finally, the potential pathogenetic roles of some candidate genes will be discussed.
Copenhagen Diabetes Research Center, Department of Paediatrics, Herlev University Hospital, Herlev Ringvej, DK-2730, Herlev, Denmark, joachim.stoerling@regionh.dk.
Joachim
J
Storling
Caroline Anna
CA
Brorsson
D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D015203:Reproducibility of Results