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  1. Amanda Beaini

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Components of Participating Organizations

National Institute of Diabetes and Digestive and Kidney  Diseases

Application Receipt Date(s): February 29, 2012

Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing pancreatic beta cells. It has a strong genetic basis that is modified by environmental factors. T1D is a “polygenic” disease; it arises from the interaction of variations in multiple genes. Many studies have been conducted to identify genes for T1D. Just a few years ago, only five genes involved in the disease were known. Now approximately 50 genes or gene regions have been identified.

Genetic, functional, structural, and animal model studies all indicate that the highly polymorphic HLA class II molecules, namely the DR and DQ α-β heterodimers, are central to susceptibility to T1D. In addition to the class II genes HLA-DRB1 and HLA-DQB1, independent effects of HLA-A, HLA-B, and HLA-DPB1 were also recently observed as contributing to the overall risk for T1D. It is estimated that HLA contributes 40–50% of the risk. Other, non-HLA, T1D loci have comparatively small effects on disease risk relative to HLA but comparable effect sizes to risk loci identified in other common disorders. These include the INS locus, where variation is thought to impact the transcription and expression of insulin, modulating thymic selection of T cells specific for this autoantigen. Variants at the CTLA4 locus are implicated in T1D risk, potentially by altering the production of differentially spliced products from the locus which affects T cell activation. SNPs in the IL2RA region, that encodes one chain of the heterodimeric IL-2 cytokine receptor, are associated with T1D. Finally, a non-synonymous coding region SNP in the PTPN22 gene has been associated with T1D as well as a number of other autoimmune disorders. This SNP, which predicts an Arg to Trp substitution at position …

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