Key Points
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Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulin-producing pancreatic β-cells by T lymphocytes. It is one of the most heritable of complex traits.
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A large part of the genetic risk for T1D (almost half) is due to alleles of the human leukocyte antigen (HLA) genes, primarily of the class II HLAs. These alleles are common in the general population but are enriched in T1D and as a result are carried by the vast majority of T1D cases.
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Insulin is a major autoantigen in T1D. After HLA, variants of the gene encoding insulin are responsible for the second strongest genetic effect on T1D risk. The predisposing alleles are associated with reduced insulin expression in the thymus, hypothesized to lead to defective development of central self-tolerance.
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Candidate gene approaches and genome-wide association studies have revealed over forty genetic associations with T1D, some of which involve known genes of the innate and adaptive immune responses. Where the functional effect of the T1D-associated polymorphism is known, it appears to inhibit T cell activation.
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Known genetic associations explain almost three-quarters of the sibling relative risk and genetic prediction is approaching metrics that are meaningful in planning application of preventive interventions.
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Gene–gene and especially gene–environment interactions will need to be studied in the future. This will require the assembly of large data and sample resources.
Abstract
Starting with early crucial discoveries of the role of the major histocompatibility complex, genetic studies have long had a role in understanding the biology of type 1 diabetes (T1D), which is one of the most heritable common diseases. Recent genome-wide association studies (GWASs) have given us a clearer picture of the allelic architecture of genetic susceptibility to T1D. Fine mapping and functional studies are gradually revealing the complex mechanisms whereby immune self-tolerance is lost, involving multiple aspects of adaptive immunity. The triggering of these events by dysregulation of the innate immune system has also been implicated by genetic evidence. Finally, genetic prediction of T1D risk is showing promise of use for preventive strategies.
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Acknowledgements
C.P.'s academic activities are supported by the Sessenwein Award from the Montreal Childrens' Hospital Foundation, the US National Institutes of Health (NIH), the Juvenile Diabetes Research Foundation and the Canadian Diabetes Association. Q.L. is the recipient of a post-doctoral fellowship from the Montreal Children's Hospital Research institute.
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Glossary
- Sibling relative risk
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(λS). The probability of a disease in a sibling of a case divided by the prevalence in the general population.
- Secular
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In this context, seen in the entire population.
- Nonsynonymous SNP
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(nsSNP). Also referred to as a nonsynonymous single nucleotide variant (nsSNV), this is a nucleotide change that results in an amino acid change.
- Linkage disequilibrium
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(LD). The property of two linked polymorphic loci whereby the probability of allele A at locus 1 as a function of allele identity (A or B) at locus 2 on the same chromosome is different from that expected from its frequency (that is, the loci provide information about each other). Because of close proximity, few or no recombinations occur between the loci and equilibration of allele frequencies has not occurred.
- Minor allele frequency
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(MAF). In a biallelic polymorphism, this is the frequency of the less abundant allele.
- Conditional regression
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An analytical approach by which the contribution of a polymorphism to a genetic association is assessed after accounting for linkage disequilibrium with other associated polymorphisms in the region. In fine mapping, it is used to define the one or more polymorphisms whose association can account for all other known associations in the region.
- Expression QTL
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(eQTL). A locus at which genetic allelic variation is associated with variation in gene expression.
- T cell receptors
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(TCRs). Surface molecules through which T cells can recognize a practically unlimited number of antigens, a molecular diversity that is assured by random somatic rearrangement of the exons encoding the TCR in individual T cells.
- Peripheral tissues
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In immunology, tissues outside the thymus and spleen.
- Pre-proinsulin
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The protein product of insulin (INS) mRNA. Cleavage of the signal peptide in the endoplasmic reticulum converts it to proinsulin, and digestion by protein convertase 1 removes the C peptide to produce mature insulin.
- Alanine scanning mutagenesis
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Methodology for probing the important of each amino acid in a protein domain by serially mutating each amino acid to alanine.
- Peripheral blood mononuclear cells
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(PBMCs). A mixture of T and B lymphocytes and monocytes. T cells are the major component.
- Avidity
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The strength of cell–cell interactions. It depends on both the affinity of the molecules involved (that is, the T cell receptor (TCR) and the human leukocyte antigen complex) and their abundance in the immunological synapse. Thus, low-affinity TCRs could interact with high avidity in the presence of abundant antigen as, for example, with insulin-specific TCRs in the lymph nodes draining the pancreas in the presence of β-cell death.
- Receiver operating characteristic curve
-
(ROC curve). A graphical plot based on signal detection theory that plots sensitivity along the y axis and 1 – specificity along the x axis for a binary classifier system, such as a genetic test or indeed any clinical test. ROC curve analysis can help select optimal diagnostic models and is fundamental to cost versus benefit analysis of diagnostic decision making.
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Polychronakos, C., Li, Q. Understanding type 1 diabetes through genetics: advances and prospects. Nat Rev Genet 12, 781–792 (2011). https://doi.org/10.1038/nrg3069
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DOI: https://doi.org/10.1038/nrg3069
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