Genetics of Type 1 Diabetes

Abstract

BACKGROUND Type 1 diabetes, a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic β cells. The major susceptibility locus maps to the HLA class II genes at 6p21, although more than 40 non-HLA susceptibility gene markers have been confirmed. CONTENT Although HLA class II alleles account for up to 30%–50% of genetic type 1 diabetes risk, multiple non-MHC loci contribute to disease risk with smaller effects. These include the insulin, PTPN22, CTLA4, IL2RA, IFIH1, and other recently discovered loci. Genomewide association studies performed with high-density single-nucleotide–polymorphism genotyping platforms have provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remain to be performed. Children born with the high-risk genotype HLADR3/4-DQ8 comprise almost 50% of children who develop antiislet autoimmunity by the age of 5 years. Genetic risk for type 1 diabetes can be further stratified by selection of children with susceptible genotypes at other diabetes genes, by selection of children with a multiple family history of diabetes, and/or by selection of relatives that are HLA identical to the proband. SUMMARY Children with the HLA-risk genotypes DR3/4-DQ8 or DR4/DR4 who have a family history of type 1 diabetes have more than a 1 in 5 risk for developing islet autoantibodies during childhood, and children with the same HLA-risk genotype but no family history have approximately a 1 in 20 risk. Determining extreme genetic risk is a prerequisite for the implementation of primary prevention trials, which are now underway for relatives of individuals with type 1 diabetes.

Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes

“…It is likely that the interplay among genetic, epigenetic, and environmental factors ultimately play a role (34,35). However, in most cases the mechanism does not seem to be via a general breakdown in thymic deletion or peripheral regulatory mechanisms, but rather is related to MHC allele-specific antigen presentation.…”

From Markers to Molecular Mechanisms: Type 1 Diabetes in the Post-GWAS Era

“…Stimulation of peripheral blood mononuclear cells (PBMCs) from people at increased risk of T1D with an overlapping panel of synthetic peptides from the T1D-associated autoantigen glutamate decarboxylase (GAD) [27] identified a major determinant (amino acids 247-279) that had significant sequence similarity to the P2-C protein of Coxsackie B virus, which had been previously associated with the onset of T1D [28]. Furthermore, PBMC from individuals responding to GAD peptides also responded to a Coxsackie P2-C peptide (amino acids [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47]. Rudy et al (1995) [29] subsequently identified a 13 amino acid peptide of another T1D-associated autoantigen, proinsulin (amino acids [24][25][26][27][28][29][30][31][32][33][34][35][36] [30], which bears marked similarity to a peptide of GAD65 (amino acids 506-518).…”

Impact of anti-glutamic acid decarboxylase-65, anti-insulin and anti-tyrosine phosphatase autoantibodies on disease activity in type 1 diabetes patients

“…This provides a window for therapeutic intervention, and considerable effort has been devoted for identification of autoantigens as biomarkers of T1D. In the absence of reliable T-cell tests, dissection of autoantibody responses in subjects of genetic risk should prove useful in identifying triggers of islet autoimmunity by examining seroconversion and maturation of the autoantibody response that may mark time to onset of T1D [4]. The complexity ofthe disease process is exemplified by multiple clinical phenotypes, including autoimmune diabetes masquerading as type 2 diabetes in youth and adults [5].…”